Part I Overview Information

Department of Health and Human Services

Participating Organizations
National Institutes of Health (NIH) (http://www.nih.gov)

Components of Participating Organizations
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) ( http://www.niddk.nih.gov/)
National Institute on Aging (NIA) (http://www.nia.nih.gov/)
National Heart, Lung and Blood Institute (NHLBI) (http://www.nhlbi.nih.gov/)
National Institute of Environmental Health Sciences (NIEHS) (http://www.niehs.nih.gov)
National Institute of Child Health and Human Development (NICHD) (http://www.nichd.nih.gov)

Title: RFA-Announcement of a Limited Competition for the Continuation of the Nuclear Receptor Signaling Atlas (U19)

Announcement Type
This is a reissue of RFA-DK-01-026, which was previously published June 7, 2001.

Update: The following update relating to this announcement has been issued:

• October 21, 2011 - This RFA has been reissued as RFA-DK-11-017.

Request For Applications (RFA) Number: RFA-DK-06-503

Catalog of Federal Domestic Assistance Number(s)
93.847, 93.866, 93.837, 93.116, 93.865

Key Dates
Release Date: October 18, 2006
Letters of Intent Receipt Date(s): November 15, 2006
Application Submission Date(s): December 15, 2006
Peer Review Date(s): March 2007
Council Review Date(s): May 30-31, 2007
Earliest Anticipated Start Date(s): August 1, 2007
Additional Information To Be Available Date (Url Activation Date): Not applicable
Expiration Date: December 16, 2006

Due Dates for E.O. 12372:
Not applicable

• The National Institute of Diabetes and Digestive and Kidney Diseases, the National Institute on Aging, the National Heart, Lung and Blood Institute, the National Institute of Environmental Health Sciences, and the National Institute of Child Health and Human Development invite a competing continuation application to participate in a trans-NIH consortium to complete the development and implementation of an Atlas of Nuclear Hormone Receptors.
• The main objective will be to accrue, develop, analyze, and communicate information on the role(s) of Nuclear Hormone Receptors (NHR) in health and disease and to design studies with immediate translational impact on human disease, to catalyze the translation of basic knowledge into approaches that will help to understand and treat disease.
• The NIDDK and co-sponsoring NIH partners will commit $2.85M Total Costs to fund one award for up to five years.
• The NIH U19 cooperative agreement award mechanism will be used.
• The only eligible organization is the institution that received a Notice of Grant Award to develop the Functional Atlas of Orphan Nuclear Receptors (U19DK62434)
• The eligible principal investigator (PI) is the current PI of the grant U19 DK62434
• The applicant may submit only one application in response to this limited competition RFA as a PI.
• Application must be prepared using the PHS398 research grant application forms.
• See Section IV.1 for more details on application materials.
• Telecommunications for the hearing impaired is available at: TTY 301-451-5936

Table of Contents

Part I Overview Information

Part II Full Text of Announcement

Section I. Funding Opportunity Description
1. Research Objectives

Section II. Award Information
1. Mechanism(s) of Support
2. Funds Available

Section III. Eligibility Information
1. Eligible Applicants
A. Eligible Institutions
B. Eligible Individuals
2.Cost Sharing or Matching
3. Other - Special Eligibility Criteria

Section IV. Application and Submission Information
1. Address to Request Application Information
2. Content and Form of Application Submission
3. Submission Dates and Times
A. Receipt and Review and Anticipated Start Dates
1. Letter of Intent
B. Sending an Application to the NIH
C. Application Processing
4. Intergovernmental Review
5. Funding Restrictions
6. Other Submission Requirements

Section V. Application Review Information
1. Criteria
2. Review and Selection Process
A. Additional Review Criteria
B. Additional Review Considerations
C. Sharing Research Data
D. Sharing Research Resources
3. Anticipated Announcement and Award Dates

Section VI. Award Administration Information
1. Award Notices
2. Administrative and National Policy Requirements
A. Cooperative Agreement Terms and Conditions of Award
1. Principal Investigator Rights and Responsibilities
2. NIH Responsibilities
3. Collaborative Responsibilities
4. Arbitration Process
3. Reporting

Section VII. Agency Contact(s)
1. Scientific/Research Contact(s)
2. Peer Review Contact(s)
3. Financial/ Grants Management Contact(s)

Section VIII. Other Information - Required Federal Citations

Part II - Full Text of Announcement

Section I. Funding Opportunity Description

1. Research Objectives

The National Institute of Diabetes and Digestive and Kidney Diseases, the National Institute on Aging, the National Heart, Lung and Blood Institute, the National Institute of Environmental Health Sciences, and the National Institute of Child Health and Human Development invite a competing continuation application to participate in a trans-NIH consortium to complete the development and implementation of an Atlas of Nuclear Hormone Receptors (Nuclear Receptor Signaling Atlas; NURSA). The NURSA project is designed to systematically explore Genomics and Proteomics aspects of Nuclear Hormone Receptor (NHR) and Co-regulator function in animals and humans. The information is then transferred to an Informatics arm of NURSA for world wide distribution. NURSA is a prototype of concerted (or team) science that develops synergy and cost savings through integration of labs and the sharing of technology and reagents. NURSA is focused on understanding the regulation of NHR action as it affects lipid, carbohydrate, and drug metabolism and how this, in turn, affects the development and/or progression of obesity, type 2 diabetes (T2D), cardiovascular disease (CVD), hormone-dependent cancer, response to the environment, reproduction, and processes of aging. Thus, the main objective will be to accrue, develop, analyze and communicate information about the role(s) of Nuclear Hormone Receptors (NHR) in health and disease with the goal of catalyzing the translation of basic knowledge into approaches that will help to understand and treat disease. The means for accomplishing this objective will be formation of a consortium using a cooperative agreement funding mechanism. The project resulting from this funding opportunity will form a consortium to be known as the Nuclear Receptor Signaling Atlas ( NURSA ). As part of NURSA the grantees will be expected to participate in collaborative (Team Science) efforts directed at: (1) developing critical resources, datasets and reagents; (2) developing novel technologies and new concepts in NHR and coregulator biology; (3) designing studies with immediate translational impact on human disease, and (4) outreach activities to ensure communication of such ideas, resources and technologies to the broader research community. It is intended that such an infrastructure will not only establish repositories of data, animal and cell models, other resources, and information, but also promote and facilitate interdisciplinary collaborations and progress in understanding the role(s) of NHRs in health and disease.

Background: NHRs comprise a large family of hormone-dependent and -independent transcription factors involved in reproduction, growth, differentiation, and homeostasis. Members of the NHR superfamily consist of receptors for steroid hormones (estrogen, androgen, glucocorticoid, mineralocorticoid, and progesterone; ER, AR, GR, MR, and PR, respectively), nuclear hormones (vitamin D, retinoids, thyroid hormone; VDR, RAR/RXR, TR, respectively), and orphan, or adopted orphan, nuclear receptors (PPAR, LXR, FXR, COUP-TFI/II, SF-1, etc.). The latter have functions in tissues and cells but with no, or only poorly, defined ligand(s). While some orphan receptors have recently been shown to respond to defined ligands (e.g. PPARgamma) the identity of true natural ligands in many instances remains to be elucidated. The Atlas concept began through an RFA (Functional Atlas of Orphan Nuclear Receptors; http://grants.nih.gov/grants/guide/rfa-files/RFA-DK-01-026.html) designed to catalyze formation of a multi-disciplinary team of investigators to advance knowledge in the area of nuclear hormone receptor signaling. The initial focus was curation of existing knowledge, and acquisition of new knowledge through development of interactions centered on the Orphan Nuclear Receptors, one important subset of the larger NHR superfamily. Considerable progress has been made reflected in NURSA publications and release to the broader research community of complex and important data sets (http://www.nursa.org). Through the web portal NURSA has provided a bridge to discovery for new insights in human disease.

Nuclear receptors and associated coactivators and corepressors regulate numerous physiological and pathophysiological processes related to the development and progression of obesity, type 2 diabetes, heart, lung and blood diseases, response to the environment, development and reproduction, and processes of aging. NHRs play a central role in the regulation of lipid and carbohydrate metabolism, in inflammation, and in the ability of the body to rid itself of harmful metabolites and xenobiotics. NHRs also contribute to the factors that have been grouped together and called the metabolic syndrome (obesity, dyslipidemia, impaired glucose tolerance, and hypertension) and insulin resistance. Perturbations in metabolic regulation and inflammation appear to be hallmarks of an aging population and contribute to considerable morbidity in all parts of the world. Such perturbations can also impact on normal regulation of growth and reproduction and contribute to the development of cancer. Environmental factors (diet, endocrine disruptors, and xenobiotics) are also thought to impact on NHR signaling with implications for human health. While the connection between metabolic syndrome and susceptibility to T2D, Cardiovascular Diseases (CVD), and associated vascular complications, and cancer, is not fully understood, the various components of the metabolic syndrome represent important focal points for understanding disease (Smyth and Heron, Nat. Med. 12:75, 2006). This is particularly so for NHRs given their position as ligand-dependent and independent transcription factors, responding to endogenous hormones, dietary metabolites, endocrine disruptors, and endo-/xeno-biotics. NHRs act to modulate the activity of gene regulatory networks (GRN), and play an important role in the regulation of metabolism and response to the environment (Shulman and Mangelsdorf, NEJM 353:604, 2005). The emerging understanding that cofactors, including coactivators/corepressors, histone modifying enzymes, components of the proteosome, kinases, and mediator complexes, served to create a combinatorial overlay to the regulation of gene expression by NHRs (McKenna and O Malley, Cell 108:465, 2002). NHRs and coregulators represent targets for interventions that can modulate downstream metabolic responses and play important roles in disease development, progression, and therapeutic intervention. Key tissues, including liver, skeletal muscle, adipose, macrophage, cardiovascular tissues, and breast/prostate, as well as other reproductive tissues, as opportunities present, may serve as the ideal physiological targets for study to more finely develop an understanding of NHR biology and role in disease.

Many accomplishments of particular and wide-spread importance emerged during the initial project period for the NURSA project, with the expression profiling of the 49 mouse NHR mRNAs across both time (circadian) and space (anatomical) using high-throughput, quantitative real-time PCR (QPCR) among the highest priority findings. These results helped to create a transcriptional blueprint of the murine NR superfamily. This platform was built specifically for NURSA and published on line via the NURSA website. The same QPCR platform was used to generate dynamic maps of NHR expression during normal physiological processes such as macrophage activation, adipogenesis, muscle differentiation, liver function, and embryogenesis and was extended to human pathology in pilot studies and will be a major goal for the current NURSA competition. Unsupervised cluster analysis of NR expression in normal tissue has produced massive but validated relational data sets for each receptor. This is the first time such equivalent information has been gathered. The informatics analyses of the expression patterns for all receptors has produced an unrooted dendrogram that has been formulated into an hypothesis that NHRs constitute a principal component set of genes responsible for many key developmental and metabolic processes. The putative functional relationships of NHR subfamilies to each other have been referred to as the "Ring of Physiology (Bookout et al. and Yang et al., Cell 126:789-800 and 801-810, respectively, 2006)." By including study of co-expression analysis of the co-regulators and additional downstream gene families (e.g. ABC transporters and cytochrome p450s) it may be possible to create a super-Ring of Physiology as the basis for a systems biology approach to understanding integrated NHR action. In addition, NURSA has shown that each cell can be described by a unique NHR signature. This signature can be applied to (e.g.) cancer cells, and developed into novel diagnostic tools and may be predictive of new therapeutic targets. Thus the NHR signature may represent a principal component set of genes that can be used to define and subsequently predict the expression of the majority of genes in the entire transcriptosome for any cell or tissue. To further test the hypothesis that NHRs are indeed a principal component set that may be used as diagnostic, prognostic and therapeutic predictors for human disease, use of QPCR-based expression profiling in conjunction with appropriate GeneChip arrays, as developed during the initial phase of NURSA, can be used to identify and measure NHR and other target gene expression in animal models of disease and in human disease samples.

The functional partners of the NHRs are the coregulators. For example, Peroxisome Proliferator-Activated Receptor gamma (PPARg?) in association with its binding partner retinoid X receptor (RXRa), functions as a master regulator of adipogenesis in the context of association with relevant coregulator complexes, and is the target of insulin sensitizing drugs. Coactivators (CoAs) mediate NHR energy homeostasis (PGC-1; SRC-1; SRC-2; SRC-3; CBP; TRAP220) by regulating the actions of NHR on mitochondrial biogenesis and oxidative phosphorylation in skeletal muscle and brown adipose tissue. SRC-2^-/- mice are protected against obesity and display enhanced adaptive thermogenesis, whereas SRC-1^-/- mice are prone to obesity due to reduced energy expenditure. Differently from SRC-1 and SRC-2, SRC-3^-/- mice present a significant reduction in fat mass accumulation under basal conditions; the phenotype is linked to impaired white adipocyte differentiation because SRC-3 cannot coactivate C/EBP to control the gene expression of PPARg2. Finally, SRC-3 participates in regulation of mitochondria number and activity, and is an authentic oncogene. Taken together, these observations suggest that coregulators serve as the master gene coordinators for the efficient expression of target gene sets controlling adipogenesis and energy homeostasis, cancer initiation and progression, aging, and reproductive tissue function. Current proteomic data produced by NURSA reveal that there are over 200 coactivators, all functioning in dynamic high molecular weight complexes (co-coactivators and co-corepressors) in cells to regulate functional gene sets; NURSA has been able to isolate and determine the primary coactivator and associated co-coactivators for ~80 functional multimeric complexes (comprising >1200 associated co-coactivators). Thus, a second principal hypothesis developed from NURSA is that the co-coactivator (and co-corepressor) proteins within these complexes serve as master gene products which orchestrate the accurate gene expression required for many processes, including those pertaining to adipogenesis and energy balance. Proof of principle will come from advanced data acquisition and disease relevant metabolic translational studies to complete this multi-institutional project and provide a proteomic atlas for understanding the systems biology of metabolic signal-regulated gene expression in human physiology and disease. The net result of targeted data acquisition projects create the potential to produce accumulated datasets that will greatly stimulate hypothesis driven metabolic research in the entire field of NHRs.

Overriding Objectives: This limited competition RFA is intended to provide continuing support for the team science concept, focused on the role of NHRs in integrative (e.g. systems) physiology and disease. Though the areas of interest relevant to NHRs are broad, the applicants should focus on achievable goals defined through a series of milestones with measurable endpoints. Many examples of questions that remain to be answered can be distilled down to validation of the central hypotheses that NHRs constitute a principal component set of genes with coregulators as master regulatory products that function in concert to regulate gene expression. Thus dysfunctional signaling through the NHR network contributes to disordered metabolism with effects on obesity, T2D, CVD, reproductive diseases, cancer, responses to the environment and aging and reflect a need to understand the integrative physiology of NHR signaling in tissues and cells and the impact(s) this may have on development, progression, treatment and/or prevention of disease. Utilization of informatics to integrate the knowledge gained underlies the NURSA concept, with a web-based interface to serve as the window through which community-based communication of the results can be effected allowing access to the data and newly emerging concepts.

Research scope: Advances both in and outside of NURSA over the past 5 years suggest that there are several key areas and approaches that could serve as the focal point for moving toward completion of the Atlas concept. These areas are framed by the overriding focus on Cell Signaling Systems Biology, and Metabolism and Human Disease and address the continued need for novel resource development with the understanding that once validated such reagents/resources will be freely available community-wide.

Within the overall theme of continued resource and concept development, many possible approaches to this RFA may be envisioned. The suggested research scope that follows covers six general areas and examples representing suggested areas of focus that could serve as the basis for a continuation of the NURSA concept.

RNAi Atlas: Use in Screens for NHRs and Metabolic Function

• Development and validation of a lenti-viral NHR RNAi expression library for use in determining and altering the mRNA expression levels of all members of the nuclear hormone receptor superfamily in specific cells and tissues
• Utilization of RNAi constructs for (e.g.) mouse and human NHRs to facilitate efficient delivery in cultured cells, adult and embryonic stem cells, fertilized embryos, as well as living tissues
• Extension of this approach to subsets of coregulators in studies to analyze role(s) in NHR function in specific cells and tissues
• Construction of Biotin-tagged NRs and CoRs for Genomic and Proteomic Analysis
• Development of biotin-tagged vectors that could allow tagging of the amino terminus of all members of the nuclear receptor family in cells with biotin to provide a uniform set of affinity reagents that can be utilized to define genome wide locations and associated proteins in diverse cell types
• Use of biotin-tagged proteins in ChIP-Chip and proteomics applications. Examples of potential use could include mouse and human macrophage model systems to perform GWLA under control, LPS-stimulated and IFNg-stimulated conditions
• Design of additional uses for such vectors in cell types relevant to metabolic syndrome and cardiovascular disease, including adipocytes, skeletal muscle, liver, etc.
• Integration of the results of these studies using bioinformatics tools to provide points of interaction between genomics and proteomics components of NURSA
• Engineered Coregulators as Ligand Reagents for Studies of NHRs
• Development of engineered CoRs for use in screening for utility as ligand reagents that can regulate NHRs pharmacologically
• Use of adenoviral mediated delivery of such engineered protein-ligands to manipulate NHR activity in rodent livers and correlate with a complete metabolic profile of serum and (e.g.) liver tissue from animals to better understand the dynamic roles that these receptors play in the regulation of metabolism
• Development of a matrix map where along one axis are the NHRs, (e.g., HNF4, PPAR, TR, ROR, PPAR, RAR, LXR, FXR, LRH1, GR, AR ER, etc.) and along the other axis will be CoRs, (e.g., PGC-1, PGC1, SRC1, SRC-2 SRC-3,TRAP220, etc.) to evaluate the resulting metabolic profile and to assist in assigning specific metabolic functions in liver (and other tissues) to individual NHR:coactivator interactions
• Development of mouse ES Cells that over express NHRs and Coregulators for Studies of Metabolic, Reproductive and Cardiovascular Diseases
• Use of such cells to produce mice over expressing NHRs and selected coregulators in a tissue-specific manner
  • Once developed, such animal models could be used for expression in any tissue where the CRE is expressed. The goal would be a single mouse line that can be used to over express coregulator/receptors in any tissue of interest with temporal expression, as an added overlay
  • Design of novel paradigms that could modulate expression of the inserted gene to no more than a few fold over the endogenous level and/or use of dominant negatives of regulatory molecules expressed in specific tissues

Identification of Gene Regulatory Networks Dependent on NHR:Coregulator action in metabolism

• Development of standardized and validated approaches to collect and analyze target gene information from mouse and human cells and tissues, possibly including downstream gene families of particular relevance such as the cytochrome p450s and ABC transporters
• Application of appropriate and state-of-the-art ontology algorithms to the generated raw and processed data for analysis and web-based distribution (e.g. unsupervised cluster analysis, etc).
• Development of mice humanized for the nuclear xenobiotic receptors CAR and PXR to assess roles in regulation of GRNs implicated in detoxification
• Development of approaches for subsets of analyses that focus on adipocyte differentiation and macrophage activation in model cells critical in obesity and heart disease to test the overriding hypotheses that NHRs comprise a principal component sets of genes with coregulators as master gene coordinators of NHR action
  • Where appropriate, this could include analysis of normal and fatty liver cells to correlate with in vivo normal and fatty livers subjected to metabolic analysis (lipid, glycogen and glucose metabolism).
• Studies that could lead to the design, development, build out and validatation of a metabolic syndrome array data platform

Coregulator Systems Biology: Post-Translational Modifications of CoR Complexes

• Studies to investigate the role(s) of Post Transcriptional Modification (PTM) of coregulators as they impact NHR signaling pathways
• Mapping such PTM sites in coactivator complex members, that could include, but not be limited to methylation, acetylation, phosphorylation, and ubiquitination) in the coactivator complexes that are most relevant to metabolic/energy regulation and growth/cancer
• Determining whether modification of the cell levels of coregulators and activities toward specific NHR target genes derive from PTM
• Studies focused on coregulator PTM sites in (e.g.) differentiating lipid loaded adipocyte cell lines in the presence and absence of insulin sensitizing drugs

Mouse Models: NRs and Coregulators in Obesity, Cardiovascular Disease, Diabetes, and its complications, Reproduction and Aging

• Profiling NR and coregulator expression in specific cell types (e.g., adipose, muscle, macrophage) in normal and pathological states (e.g., during fasting/refeeding, diet-induced obesity/atherosclerosis)
  • Other important models of metabolic disease could include the diabetic ob/ob mouse and/or atherosclerosis and receptor/cofactor mutants (SMRT, PGC1, PPAR, PXR).
• Profiling of NR and coregulator expression during the course of the adult mouse lifetime: C57/Bl6 male and female mice at 3, 6, 12, 18, and 24 months of age. This could be combined with tissue and blood serum harvested at each time point and blood chemistries (e.g., serum cholesterol, triglycerides, glucose, estrogen, testosterone, corticosterone, etc.) ,and comparison with patterns of loss or gain of receptor expression/activity and function over lifetime
  • Utilize the bioinformatics core to develop analyses to help reveal NHR functional clusters and predictive information about the murine aging process relative to NHR/CoR expression.
• Profiling of NHR family member expression in tissues such as liver, adipose, muscle, heart and macrophages in animal models that phenocopy metabolic syndrome

NR and CoR Levels in Disease: Human diseases with Immediate Translational Impact

• Designing studies that will allow concerted study of NHRs and coregulators to decipher their roles in physiology and pathology and treatment of disease particularly as related to regulation of intermediary metabolism and the metabolic syndrome. This could include conditions such as PCOS and vascular disease complications of diabetes
  • Such studies might allow for correlation with patient tissue profiles at various stages of disease progression and treatment
• Designing proof of principle studies in human patient tissue samples during and following injection of a variety of orally active compounds known to trigger drug-drug interactions and endocrine disruption to evaluate the human intestinal xenobiotic response
  • Determining the potential role of CAR, PXR and other NHRs in response to numerous drugs that induce clinically significant idiosyncratic hepatotoxicity
• NHR and coregulator expression profiling of biopsies from human patients with lung, skin, and breast cancer; leukemia; obesity; and AIDS-related lipodystrophy
• Development of collaborative relationships designed to exploit ongoing clinical studies, such as the NASH Clinical Research Network (CRN) to establish the expression profile of hepatic nuclear receptors in fatty liver disease
• Additional collaborations could be considered with key laboratories outside of NURSA to obtain samples for studies with skin, breast and lung cancers and myeloid leukemia.
• Investigation of screening strategies that could include direct functional assays for receptor activation, as well as profiling effects of drugs on expression of receptors and key target genes, such as cytochrome P450s, in both humanized transgenic mouse models and appropriate human primary hepatocytes and tissue samples

Bioinformatics

• Providing NURSA investigators with the appropriate statistical and analytical tools for the planning and execution of experiments
• Efforts to design, execute, and maintain a NURSA website as a portal for community-wide access to NURSA activities
  • Formatting and publishing of datasets, reagents and protocols in a user-mineable form, that could be integrated with the rest of the NURSA Knowledge Base
  • Providing models for how to monitor usage and reach of the NURSA web portal
• Efforts to design and maintain a NURSA Extranet to facilitate communication between members of the NURSA laboratories, NURSA administrative workgroups, and relevant NIH scientific program officers
• Design, testing and deployment of software for presenting datasets from NURSA laboratories, and implementing strategies for the curation and presentation of data relevant to nuclear receptor signaling.
• Development and maintenance of integrated molecule pages for NHRs, coregulators and ligands
• Design and implementation of the means for building a picture of the complex developmental, physiological and metabolic networks in nuclear receptor and coregulator biology
• Development and maintenance of an integrated web publishing and bioinformatics solution for data compilation, storage, curation and presentation including a PubMed certified and indexed e-journal
• Expansion of outreach for the comprehensive, freely-accessible NURSA web portal as a community resource
  • Exploration of the development of reciprocal alliances with relevant scientific societies and/or journals
• Development of plans for a Laboratory Information Management System (LIMS) for the documentation and integration of NURSA methods and procedures
• Exploration of the means for consolidating the legacy and future of NURSA data in the nuclear receptor field
• Further development and expansion of a suite of software for NURSA applications to include (i) ligand screening, (ii) siRNA for high-content screenings, (iii) ChIP-on-Chip assays and (iv) post-translational modification analyses; and (v) collaborations with other extra-NURSA genomics, proteomics and/or genetics centers
• Providing informatics support for periodic NURSA steering committee meetings, workshops, and the annual investigators retreat

Role of the Steering Committee: Development of a consortium through use of a cooperative agreement has proven to be an extremely flexible mechanism allowing for application of creative and time/cost-saving integrative collaborations to answer a major problem in biomedical science. A level of synergy has been fostered through development of both an administrative structure and a consensus among the participants on procedures, objectives, and prioritization. A Steering Committee has facilitated rapid responses to changes in technology and the progress made in individual projects and resource cores, as well as for contribution by the NIH in defining objectives. The use of milestones allows interim evaluation of progress toward achieving initial goals and the subsequent ability to change the scope and/or direction, as needed, and allows for external advisors to critically evaluate the trajectory and progress of the program. The role of the NIH, in conjunction with a NURSA Steering Committee, has been to catalyze more rapid progress than might be possible if this were individual investigators working alone or in small collaborations. The concurrent development of bioinformatics and web-based communication capabilities and formal implementation of a research plan also fosters data dissemination via the web-based interface. Integration through a bioinformatics core resource with other, ongoing, informatics efforts in genomics, proteomics, and functional profiling has served as a major vehicle for outreach to the broader domestic and international research communities. New hypothesis generation has allowed the data to be used by others both in and out of the consortium to move beyond what is already known. Thus, the application of a team science approach, in the context of a cooperative agreement governed by a Steering Committee, is an essential element to this initiative allowing individual projects to work synergistically toward a concept that encompasses curation of existing knowledge, development of new information and tools, and information management and subsequent outreach to the broader research communities and greater progress than possible through individual R01s.

See Section VIII, Other Information - Required Federal Citations, for policies related to this announcement.

Section II. Award Information

1. Mechanism(s) of Support

This funding opportunity will use the U19 cooperative agreement mechanism.

As an applicant, you will be solely responsible for planning, directing, and executing the proposed project.

The funding opportunity uses just-in-time budget concepts. It also uses the non-modular budget format described in the PHS 398 application instructions (see http://grants.nih.gov/grants/funding/phs398/phs398.html). A detailed categorical budget for the "Initial Budget Period" and the "Entire Proposed Period of Support" is to be submitted with the application.

The U19 is a cooperative agreement award mechanism. In the cooperative agreement mechanism, the Principal Investigator retains the primary responsibility and dominant role for planning, directing, and executing the project, with NIH staff being substantially involved as a partner with the Principal Investigator, as described under the section "Cooperative Agreement Terms and Conditions of Award". See

Section VI. Award Administration Information. The anticipated award date is August 1, 2007. At this time, it is not known if this RFA will be reissued.

2. Funds Available

• NIDDK expects to award $1.5M Total costs through this announcement
• NIA expects to award $500,000 Total costs through this announcement
• NHLBI expects to award $500,000 Total costs through this announcement
• NIEHS expects to award $250,000 Total costs through this announcement
• NICHD expects to award $100,000 Total costs through this announcement
• It is anticipated that one competing award will be made with an estimated budget of $2.85M Total costs
• The initial period of support provided $3.72M Total Costs/year for each of 5 years
• The competing period of support will be from August 1, 2007-July 31, 2012

The participating IC(s), NIDDK, NIA, NHLBI, NIEHS, and NICHD, intend to commit approximately $2.85M dollars in FY 07 to fund 1 competing continuation grant in response to this RFA. An applicant may request a project period of up to five years and a budget for direct costs that will vary based on consortium costs.

Because the nature and scope of the proposed research will vary from application to application, it is anticipated that the size and duration of each award will also vary. In addition, variations in subcontract costs may result in variations in the allocation of Direct and Total Costs. Although the financial plans of the IC(s) provide support for this program, awards pursuant to this funding opportunity are contingent upon the availability of funds and the receipt of a sufficient number of meritorious applications.

Facilities and administrative costs requested by consortium participants are not included in the direct cost limitation, see NOT-OD-05-004.

Section III. Eligibility Information

1. Eligible Applicants

1.A. Eligible Institutions

You may submit an application if your organization received a Notice of Grant Award (U19 DK62434) for the Functional Atlas of Orphan Nuclear Receptors.

NOTE: Foreign institutions are not eligible to apply. Investigators from foreign institutions may participate as a component of an application submitted by a PI from an institution within the United States of America

1.B. Eligible Individuals

The current Principal Investigator (PI) or a newly designated PI with the skills, knowledge, and resources necessary to carry out the proposed research is invited to work with their institution to develop a competing continuation application for support. Development of a Nuclear Receptor Signaling Atlas requires considerable effort to organize. A U19 application should be headed by a Principal Investigator (PI), who is an expert in the field with experience in cooperative agreements.

Researchers who are intramural staff of the NIH Institutes or Centers may be identified as potential collaborators or consultants. However, for purposes of this RFA, no NIH intramural scientist may agree to collaborate or consult with, commit time and effort to, or be a co-investigator of, any U19 application except for the following situation. When the NURSA consortium is assembled from the component projects, there may be NIH intramural investigators whose expertise is identified in the funded U19 applications as necessary or desirable to achieve their individual goals, or those of the NURSA. Those NIH intramural investigators must then obtain the approval of their Institute's Scientific Director to collaborate with the consortium, or one of its U19 components, in a specified role, including time and effort. NIH intramural investigators, who are designated in this manner to collaborate in the Network, will not serve on the NURSA Steering Committee. The participation of any NIH intramural scientist, including those on the Steering Committee who represent the NIH intramural project components of the NURSA, is independent of, and unrelated to, the role of the NIDDK Project Scientist as described under "Terms and Conditions of Award."

2. Cost Sharing or Matching

The most current Grants Policy Statement can be found at: http://grants.nih.gov/grants/policy/nihgps_2003/nihgps_Part2.htm#matching_or_cost_sharing
In order to further leverage the funding and co-funding of the participating NIH institutes in this program applicants are encouraged to consider seeking Public Private Partnerships (PPP) from private foundations and/or biotechnology or pharma ( http://nihroadmap.nih.gov/publicprivate/). It should be understood that such support will be provided with no proprietary constraints. PPPs may be arranged as part of the initial application or as subsequent supplements to the funded program.

3. Other-Special Eligibility Criteria

An applicant may submit only one application in response to this funding opportunity.

Section IV. Application and Submission Information

1. Address to Request Application Information

The PHS 398 application instructions are available at http://grants.nih.gov/grants/funding/phs398/phs398.html in an interactive format. Applicants must use the currently approved version of the PHS 398. For further assistance contact Grants Info, Telephone (301) 710-0267, Email: GrantsInfo@nih.gov.

Telecommunications for the hearing impaired: TTY 301-451-5936.

2. Content and Form of Application Submission

The application must be prepared using the most current PHS 398 research grant application instructions and forms. Applications must have a D&B Data Universal Numbering System (DUNS) number as the universal identifier when applying for Federal grants or cooperative agreements. The D&B number can be obtained by calling (866) 705-5711 or through the web site at http://www.dnb.com/us/. The D&B number should be entered on line 11 of the face page of the PHS 398 form.

The title and number of this funding opportunity must be typed on line 2 of the face page of the application form and the YES box must be checked.

3. Submission Dates and Times

Applications must be received on or before the receipt date described below (Section IV.3.A). Submission times N/A.

3.A. Receipt, Review and Anticipated Start Dates
Letters of Intent Receipt Date(s): November 15, 2006
Application Submission Date(s): December 15, 2006
Peer Review Date(s): March 2007
Council Review Date(s): May 30-31, 2007
Earliest Anticipated Start Date(s): August 1, 2007

3.A.1. Letter of Intent

The prospective applicant is asked to submit a letter of intent that includes the following information:

• Descriptive title of proposed research
• Name, address, and telephone number of the Principal Investigator
• Names of other key personnel
• Participating institutions
• Number and title of this funding opportunity

Although a letter of intent is not required, is not binding, and does not enter into the review of a subsequent application, the information that it contains allows IC staff to estimate the potential review workload and plan the review.

The letter of intent is to be sent by the date listed at the beginning of this document.

The letter of intent should be sent to:

Francisco O. Calvo, Ph.D.
Chief, Review Branch
National Institute of Diabetes and Digestive and Kidney Diseases
6707 Democracy Boulevard, Room 752
Bethesda, MD 20892-5452
Telephone: (301) 594-8897
FAX: (301) 480-350
Email: fc15y@nih.gov

3.B. Sending an Application to the NIH

Applications must be prepared using the research grant applications found in the PHS 398 instructions for preparing a research grant application. Submit a signed, typewritten original of the application, including the checklist, and three signed photocopies in one package to:

Center for Scientific Review
National Institutes of Health
6701 Rockledge Drive, Room 1040, MSC 7710
Bethesda, MD 20892-7710 (U.S. Postal Service Express or regular mail)
Bethesda, MD 20817 (for express/courier service; non-USPS service)

Personal deliveries of applications are no longer permitted (see http://grants.nih.gov/grants/guide/notice-files/NOT-OD-03-040.html).

At the time of submission, two additional copies of the application and all copies of the appendix material must be sent to:

Francisco O. Calvo, Ph.D.
Chief, Review Branch
National Institute of Diabetes and Digestive and Kidney Diseases
6707 Democracy Boulevard, Room 752
Bethesda, MD 20892-5452
Telephone: (301) 594-8897
FAX: (301) 480-3505
Email: fc15y@nih.gov

Using the RFA Label: The RFA label, available in the PHS 398 application instructions, must be affixed to the bottom of the face page of the application. Type the RFA number on the label. Failure to use this label could result in delayed processing of the application such that it may not reach the review committee in time for review. In addition, the RFA title and number must be typed on line 2 of the face page of the application form and the YES box must be marked. The RFA label is also available at: http://grants.nih.gov/grants/funding/phs398/labels.pdf.

3.C. Application Processing

Applications must be received on or before the application receipt date(s) described above (Section IV.3.A.). If an application is received after that date, it will be returned to the applicant without review. Upon receipt, applications will be evaluated for completeness by the CSR and responsiveness by the NIDDK. Incomplete and non-responsive applications will not be reviewed.

The NIH will not accept any application in response to this funding opportunity that is essentially the same as one currently pending initial review, unless the applicant withdraws the pending application.

Information on the status of an application should be checked by the Principal Investigator in the eRA Commons at: https://commons.era.nih.gov/commons/.

4. Intergovernmental Review

This initiative is not subject to intergovernmental review.

5. Funding Restrictions

All NIH awards are subject to the terms and conditions, cost principles, and other considerations described in the NIH Grants Policy Statement. The Grants Policy Statement can be found at http://grants.nih.gov/grants/policy/policy.htm.

Pre-Award Costs are allowable. A grantee may, at its own risk and without NIH prior approval, incur obligations and expenditures to cover costs up to 90 days before the beginning date of the initial budget period of a new or competing continuation award if such costs: are necessary to conduct the project, and would be allowable under the grant, if awarded, without NIH prior approval. If specific expenditures would otherwise require prior approval, the grantee must obtain NIH approval before incurring the cost. NIH prior approval is required for any costs to be incurred more than 90 days before the beginning date of the initial budget period of a new or competing continuation award.

The incurrence of pre-award costs in anticipation of a competing or non-competing award imposes no obligation on NIH either to make the award or to increase the amount of the approved budget if an award is made for less than the amount anticipated and is inadequate to cover the pre-award costs incurred. NIH expects the grantee to be fully aware that pre-award costs result in borrowing against future support and that such borrowing must not impair the grantee's ability to accomplish the project objectives in the approved time frame or in any way adversely affect the conduct of the project. See NIH Grants Policy Statement http://grants.nih.gov/grants/policy/nihgps_2003/NIHGPS_Part6.htm.

6. Other Submission Requirements

For U19 applicants to this RFA, only the "Research Plan" section of the PHS 398 grant application is changed. The remainder of the PHS 398 application form remains the same.

The applicant should identify clearly in the abstract and more fully in the research plan the specific questions in NHR that are to be explored and the new approaches and collaborations that will result from the establishment and continued development of the NURSA Program. The synergies to be achieved through the establishment of multi-disciplinary teams and novel collaborations should be fully described. It is anticipated that the application projects will be multi-disciplinary and will draw on a variety of resources. Thus, a well thought out and carefully described organization is required. The PI is responsible for ensuring that scientific goals are met, and for developing and managing a decision-making and administrative structure and process that will allow resources to be allocated (and reallocated, if necessary) to meet those goals. This will be particularly important for multi-institutional programs. A management plan outlining the organization and administration of the proposed program should be included. The Principal Investigator of a Research Program must commit a minimum effort of 25%. Prior membership in NURSA should not be construed as leading to automatic inclusion in a Phase II. The PI should make reasonable attempts to assemble a team with broad representation but based on the needs for appropriate expertise.

A detailed Table of Contents should be prepared for the overall project that includes the items listed below. Page limitations are given in the specific descriptions for each section.

SAMPLE TABLE OF CONTENTS

SECTION I

Face Page

Table of Contents (Overall program)

Detailed Budget for First 12-Month Period

Budget Estimate for Each Year of Project

Summary of All Other Sources of Support

Biographical Sketches (PI and all participating investigators, key personnel and collaborators)

SECTION II

Overall Program

• Goals
• Research Plan
  • Program Summary
  • Administrative Management Plan
  • Project Management Plan
  • Preliminary Studies (for competing continuation applications a progress report should be included n this section)
• Plan for Data Sharing and Intellectual Property
• Institutional Environment and Resources
• Organization and Administrative Structure

SECTION III

Shared Resources

Shared Resource A

• Title Page (Title, Resource Director)
• Description of Resource
• Budget for the First 12-Month Period
• Budget Estimate for Each Year of Requested Support
• Role and Justification for the Shared Resource
  • Plan of operation
  • Integration with the program
• Gender and Minority Inclusion
  • Children Inclusion
• Human Subjects
• Vertebrate Animals
• Consortium/Contractual Arrangements
• Consultants/Collaborators

Shared Resource B, etc

• Title Page (Title, Resource Director)
• Description of Resource
• Etc.

SECTION IV

Research Components

Bridging Project 1

• Title Page (Title, Project Leader)
• Description of Research Plan/List of Key Personnel
• Detailed Budget for First 12-Month Period
• Budget Estimate for Each Year of Requested Support
• Resources and Environment
• Research Plan
• Plan for integration with overall program
• Gender and Minority Inclusion
• Children Inclusion
  • Human Subjects
• Vertebrate Animals
• Consortium/Contractual Arrangements
• Consultants/Collaborators

Bridging Project 2, etc.

• Title Page (Title, Project Leader)
• Etc.

Optional Pilot Projects (up to 2)

Title Page (Project 1, 2, etc)

• Detailed Budget for First 12-Month Period
• Budget Estimate for Each Year of Requested Support
• Resources and Environment
• Research Plan
• Plan for integration with overall program
• Gender and Minority Inclusion
• Children Inclusion
  • Human Subjects
• Vertebrate Animals
• Consortium/Contractual Arrangements
• Consultants/Collaborators

Literature Cited with complete titles and authors for the entire program.

Checklist

Salaries for support personnel required for coordination and maintenance of the program, such as secretaries or administrative assistants, may also be included, as necessary, in the Administrative Resource.

Specific Items that may be included:

1. Salaries for the principal investigator, members of the steering committee, participating investigators, technical, and support personnel commensurate with their level of effort in the large-scale collaborative program.

2. Optional Pilot projects to investigators relevant to the NURSA can be without current independent research support in the area. While the original Atlas (DK-01-026) explicitly described inclusion of P&F projects as supplements, this current solicitation provides for optional inclusion. If included, Pilots must not exceed $75,000 each in annual direct costs and must be limited to no more than two such projects. Budgets may include travel of personnel (e.g. pre-doctoral students, postdoctoral trainees, and investigators) to different laboratories to gain specialized expertise. These grants may be for no more than 2 years each, and may be replaced by such new projects as the Steering Committee deems appropriate to achieve the goals of the overall program (see Project Management Plan). The Pilot and Feasibility projects should be listed with a common budget, each project not to exceed the individual cap of $75,000.

3. Travel to and conduct of regular meetings of the steering committee and regular meetings of the participating investigators.

4. Shared Resource facilities (examples: instrumentation, genomics, proteomics, model organism, high-throughput assay, or computational/bioinformatics).

5. Electronic media resources to allow participation of off-site laboratories and/or the means necessary to establish collaborative capabilities and for information dissemination. Travel to and conduct of regular meetings of an external advisory working group.

Composite budget. Use Form Page 4, "DETAILED BUDGET FOR INITIAL BUDGET PERIOD," of Form PHS-398 to present the total budget for all requested support for the first year. For each category such as "Personnel," Equipment," etc., give the amount requested for each Resource unit and each component project, with subtotals. For consortium arrangements involving other institutions or organizations, include total (direct and facilities and administration) costs associated with such third-party participation in the "Consortium/Contractual Costs" category. Note that consortium costs will count against the $2.85 Million Total Costs cap. Costs for purchased services should be itemized under "Other Expenses."

Use Form Page 5, "BUDGET FOR ENTIRE PROPOSED PROJECT PERIOD," of Form PHS-398 to prepare a budget, by category that provides totals for each year of requested support. No yearly escalation in the total project budget will be permitted. The costs for the Optional Pilot and Feasibility studies should be reported as one total figure for the (up to) two such projects.

Individual budgets for shared resource and research components: For the first year budgets of each of the shared resource and research projects, use Form Page 4 of the PHS-398. Use Form Page 5 of the PHS-398 to report the budgets of each of the projects and shared resources for total project period (years 02-05).

Budget justifications and explanations: Describe the specific functions of all key personnel, including consultants, collaborators, and technical staff. Provide justifications for requested equipment. For years 02-05 of the application, justify any significant increases or decreases in any category over the first year budget. Applicants must budget for travel and per diem that will allow the Principal Investigator, and designated participating or senior investigator to participate in at least two steering committee meetings each year. Applicants should plan to attend a workshop or symposium every year of the project period, as needed.

BIOGRAPHICAL SKETCHES AND LETTERS OF COMMITMENT: Biographical sketches and letters of commitment must be included from all participating investigators indicating their willingness to follow guidelines and procedures established for the large-scale collaborative project. The format described in the PHS398 application for modular applications should be followed for this information.

RESOURCES AND ENVIRONMENT: Complete the "Resources" page of PHS-398 for the overall large-scale collaborative project, including both the host institution and any participating institutions. Briefly describe the features of the institutional environment(s) that are relevant to the effective implementation of the proposed program. As appropriate, describe available resources, such as clinical and laboratory facilities, participating and affiliated units, patient populations, geographical distribution of space and personnel, and consultative resources.

RESEARCH PLAN

In the PHS398 application kit a 25 page limit for the Research Plan is described. In lieu of that limitation, for the NURSA, a fifty (50) page limit is in effect for the following four sections (PROGRAM SUMMARY, ADMINISTRATIVE MANAGEMENT PLAN, PROJECT MANAGEMENT PLAN, and PROGRESS REPORT/PRELIMINARY STUDIES). Investigators should endeavor to be concise. For other sections please follow the instructions for each individual part of the application, as below.

PROGRAM SUMMARY: A summary describing the goals and operation of the program. Explain how the scope of this initiative will be addressed and how using a team science approach through a consortium is critical to its solution. Discuss the range of scientific expertise to be brought to bear on the research problem. Explain the interactions that will occur between investigators at the host site and at the participating sites. Explain how each element in the team will contribute to successful attainment of its goals. Explain the programmatic value of the Shared Resources, and the Research Components (bridging and optional pilot projects). Explain how the information resulting from the collaborative efforts of the entire program, to include the laboratories of the participating investigators, will be integrated via the Bioinformatics Core Resource and with the comprehensive program, as a whole. Discuss how information generated by the collaborative program will be disseminated to the general scientific community. Applicants should define the major research questions and opportunities related to NHR biology and role in disease that their group effort proposes to undertake, and the importance of those questions to translation. Applicants should describe how they will function as a team conducting inter-dependent projects. In particular, applicants should address how projects/cores will be integrated and how resources generated will be utilized by the consortium, as a whole, and the broader research community, in general. The description should also outline the rationale for approaches to be used or planned for development. Applicants are encouraged to use this section of the application to highlight how the diverse expertise of the team members contributes to the innovation of which the team is capable, the flexibility they possess to redirect research when scientific progress warrants it, and their ability to anticipate new directions, based on their individual experience and ability to contribute to a collective effort. The roles and expertise of all key personnel, collaborators, and consultants who are associated with the application should be documented; letters from collaborators and consultants should be included in Section I. of the research plan format as specified in the instructions for the PHS form 398 application. Finally, the applicants should discuss how they will be responsive to the broader scientific community.

ADMINISTRATIVE MANAGEMENT PLAN: Describe the structure, organization, and operation of the program. Describe the organizational framework and provide an organizational chart detailing the flow of information within the collaborative program. Discuss arrangements between the collaborating institutions that are important to effective operation of the U19. Detail the usage of the Shared Resources by the participating investigators. Include any outreach efforts to provide access to the Shared Resource to investigators outside the collaborative program. Discuss how the views of the scientific community impacted by the collaborative program will be considered. Policies regarding sharing of resources, publications, and authorship should be addressed and adhere to the initial policies defined by the NURSA Steering Committee (http://www.nursa.org/template.cfm?threadId=60) within the scope of current NIH policies (Section VIII. Other Information - Required Federal Citations).

PROJECT MANAGEMENT PLAN: Provide a timeline for the program, as a whole, and for each component, defining yearly milestones to be used to assess progress. Explain how progress in the bridging and optional pilot projects and efficiency of the Shared Resources will be tracked. Include an evaluation plan to determine how the collaborative program is progressing. Discuss the plan for evolving landmarks. Explain how the External Advisory Working Group will be used to evaluate and update the project management plan. Explain how decisions will be made to add/delete participating investigators and to respond to changes in short term goals that research findings will make necessary. Provide a plan for assessment of the resources cores, bridging and optional pilot studies with emphasis on how it will be decided what duration they should have and whether and how they should be replaced.

PROGRESS REPORT/PRELIMINARY STUDIES: A progress report should be provided that details how the consortium was able to address the objectives contained in the original RFA, as modified by the Steering Committee, the External Advisory Working Group, and/or the NIH. Evidence should be provided for how the web portal, resources generated, and information (e.g. datasets) produced have been utilized by members of the consortium and the broader scientific community. Provide any preliminary studies/data that may be relevant to the overall program and the plan for completion of the Atlas . Data should be in a readily interpretable form, with legends and appropriate identification of figures/tables in the text.

INSTITUTIONAL ENVIRONMENT AND RESOURCES (two page limit): The environment and resources at the host institution that will be available to this program should be described. The environment and resources available at collaborating institutions should be provided in the descriptions of those specific projects.

SHARED RESOURCES

SHARED RESOURCE A. BIOINFORMATICS RESOURCE (required; fifteen page limit):

This Resource will be required for appropriate statistical support for design of experiments, data accumulation and analysis, and coordination and dissemination. Dissemination of information on techniques, scientific findings, and methodologies is a vital component of the large-scale collaborative program. Effective use of computer technology, print media, and telecommunications are relevant. Describe the staffing (including a Resource Core Director, as well as any professional or technical personnel and their duties), facilities, and resources that will be devoted to this goal. Indicate plans to make results of research or other unique features of the collaborative project available for as wide an audience as possible. Describe how data generated by the Shared Resource and Research Components will be processed into the information to be disseminated. Discuss how data will be reviewed prior to inclusion in the bioinformatics database. Discuss plans for dissemination of published and unpublished data. Since the initial phase of NURSA development has included creation of a PubMed Central certified e-journal, describe how this will be maintained and contribute to outreach efforts. Describe plans for any alliances with outside organizations and/or other public or private databases. Discuss plans for maintenance of NURSA legacy datasets and activities.

SHARED RESOURCE B. ADMINISTRATIVE RESOURCE (required; five page limit): This Resource must be directed by the principal investigator. Include the objectives of the Resource, a description of its staffing and services to be provided to other resources and to the participating investigators. Communicating the objectives of the collaborative program and fostering opportunities for collaboration are encouraged. Expenses associated with the operation of the steering committee, meetings of all or subgroups of the participating investigators, and meetings and operation of the External Advisory Working Group would fall under the Administrative Resource.

SHARED RESOURCE C (and others): There is a 10 page limit per additional Core Resource. Provide specific titles for any proposed scientific Shared Resources (e.g., microarray/qPCR; instrumentation; genomics; proteomics; model organism; high-throughput screening; or computational modeling), along with a designated Resource Director who possesses expertise in the area of each Resource. Describe the professional and technical staff to be involved in the Resource(s), and their duties. Include plans to utilize the Resource(s), including services that will be provided, and to whom, and their bearing on productivity and quality of the collaborative research effort.

RESEARCH/DEVELOPMENT COMPONENTS

BRIDGING PROJECTS (ten page limit for each bridging project): A bridging project should be designed to support work in the laboratory of a participating investigator relevant to the objectives of the overall program. For all proposed projects, the underlying rationale and potential impact of the studies should be specifically addressed. The need for the bridging project to tie (or enhance) the independent work of the participating investigator to the goals of the collaborative program must be described. Such work may be hypothesis-generating or hypothesis-driven, as appropriate. Essential information for the research plan should include specific aims, background and significance, preliminary studies/progress report, and research design and methods, and may be presented as a combined summary of these sections emphasizing the following:

Describe the new research or development proposed in the bridging project and explain how this work more fully integrates the participating investigator’s independently supported work into the overall theme and objectives of this collaborative team science program. A bridging project should extend the participating investigator’s independent work in a direction(s) relevant to goals of the NURSA program. A bridging project to do more of what the investigator is already doing should be considered only if there are extraordinary circumstances that make it essential for the effective functioning of the large-scale project. If the participating investigator’s work is already closely tied to the large-scale project, a bridging project should not be needed.

Projects must be described in sufficient detail to permit evaluation through the competitive peer-review process. For each bridging project undertaken as part of the collaborative program, also to be included are sections (where appropriate) that address: Gender and Minority Inclusion for Research Involving Human Subjects, Inclusion of Children as Participants in Research Involving Human Subjects, Human Subjects, Vertebrate Animals, Consortium/Contractual Arrangements, Consultants. Literature Cited should be included in the citations for the entire program, at the end of the application. These sections are in addition to the 10 page limit for the project description.

OPTIONAL PILOT PROJECTS (five page limit for each pilot project for the research plan: specific aims, background and significance, preliminary studies, and research design and methods; maximum of two pilot projects per large scale collaborative program): Pilot projects may support the work of investigators not already supported in the area of the collaborative program but who have unique skills or expertise that add to the collaborative effort. For all proposed projects, the underlying rationale and potential impact of the studies should be specifically addressed. How the pilot project will add new elements essential to achieving the goals of the collaborative program must be described. Projects must be described in sufficient detail to permit evaluation through the competitive peer-review process. For each pilot project undertaken as part of the collaborative project, include the following sections: Abstract (one paragraph), Specific Aims, background and Significance, Preliminary Studies, Research Design and Methods, as well as Gender and Minority Inclusion for Research Involving Human Subjects, Inclusion of Children as Participants in Research Involving Human Subjects, Human Subjects, Vertebrate Animals, Consortium/Contractual Arrangements, and Consultants. Literature Cited should be included in the citations for the entire program, at the end of the application.

INSTITUTIONAL COMMITMENTS: Letters signed by authorized business officials of each of the participating investigators' institutions committing support to the large-scale collaborative project must be included. Applicants for proposals that include consortium arrangements should refer to the NIH Grants Policy Statement appendix on consortium arrangements at: http://grants.nih.gov/grants/policy/nihgps/part_iii_5.htm#Consortium.

OTHER SUPPORT OF PARTICIPATING INVESTIGATORS: For the principal investigator, steering committee members, participating investigators, and heads of Resource resources, provide a listing of all other support for each participant in the usual NIH format for non-modular applications (see http://grants.nih.gov/grants/funding/phs398/phs398.html); support for other investigators such as postdoctoral students should not be listed. For the relevant grant support that allows participating investigators to be part of the large-scale collaborative project, provide the specific aims of the project and describe in sufficient detail for evaluation the relationship of the funded grant to the goals of the proposed collaborative Research Program (U19).

Collaborations and Specific Requirements.

• Applicants should describe the experience of their team in collaborative programs and activities.
• Specific issues related to cooperative agreements must also be addressed in Section 3 of the application as follows:
• Applicants, must agree to the "Cooperative Agreement Terms and Conditions of Award" in Section VI.B "Award Administration Information;" and
• In addition, applicants must include their specific plans to comply with the requirements defined in "Cooperative Agreement Terms and Conditions of Award" section. Applicants should affirm their willingness to collaborate and share data freely with the other NURSA components, to participate in planning and attending workshops and symposia, to serve on the Steering Committee and be bound by its decisions, and to be able and willing to share data and research resources with each other and the NIDDK and co-sponsoring institutes.
• Applicants should define their capabilities for participating in resource development.
• Applicants to this RFA must also provide a Plan for Sharing Research Resources (see below).
• Applicants must also contain a letter from the applicant institution describing how that institution intends to meet the NIH policies for sharing of data or why data sharing is not possible (see below).
• Awardees under the auspices of this RFA should obtain appropriate licenses for technologies that are necessary for the conduct of the proposed research so that the goals that are proposed in the Research Plan can be accomplished. A statement from the applicant institution regarding their intent to obtain any necessary licenses must be incorporated into this section.
• The NIDDK and co-sponsoring Institutes reserve the right to require the transfer of appropriate models and/or reagents, and pertinent data that are generated as the result of participation in research supported under these awards to an eligible third party. Third parties supported under these awards must be informed of this right. A statement from the applicant institution to that effect must be incorporated into Section 3.

ADDITIONAL REQUIREMENTS:

Applicants must budget for travel and per diem expenses for the semi-annual Steering Committee meetings, one of which will be in conjunction with an annual Investigator’s Retreat. In all years, applicants must budget for two investigators, the principal investigator and another key investigator, to attend at least two Steering Committee meetings. Willingness must be expressed for attendance at additional teleconferences, or participation in ancillary workshops or symposia, as needed.

An External Advisory Working Group will be constituted, drawn from experts outside the project. These advisors will meet annually to review and provide guidance on NURSA activities. While a description of the External Advisory Working Group’s activities should be included in the application, the need for additional and/or different expertise may require the recruitment of new members. Therefore, potential members should not be named, contacted, or selected until an award has been made. This situation will allow a wider pool of potential reviewers of the application. Costs for activities of the External Advisors should be included in the budget of the administrative core.

Applicants are advised to send all appendix material in compact discs (CDs). Hard copies of appendices will not be accepted by the NIDDK. After the submission of application, the Scientific Review Administrator will determine at what point additional supplementary material of any kind will be allowed.

Plan for Sharing Research Data

The precise content of the data-sharing plan will vary, depending on the data being collected and how the investigator is planning to share the data. Applicants who are planning to share data may wish to describe briefly the expected schedule for data sharing, the format of the final dataset, the documentation to be provided, whether or not any analytic tools also will be provided, whether or not a data-sharing agreement will be required and, if so, a brief description of such an agreement (including the criteria for deciding who can receive the data and whether or not any conditions will be placed on their use), and the mode of data sharing (e.g., under their own auspices by mailing a disk or posting data on their institutional or personal website, through a data archive or enclave). Investigators choosing to share under their own auspices may wish to enter into a data-sharing agreement. References to data sharing may also be appropriate in other sections of the application.

All applicants must include a plan for sharing research data in their application. The data sharing policy is available at http://grants.nih.gov/grants/policy/data_sharing. All investigators responding to this funding opportunity should include a description of how final research data will be shared, or explain why data sharing is not possible.

The reasonableness of the data sharing plan or the rationale for not sharing research data will be assessed by the reviewers. However, reviewers will not factor the proposed data sharing plan into the determination of scientific merit or the priority score.

Sharing Research Resources

NIH policy requires that grant award recipients make unique research resources readily available for research purposes to qualified individuals within the scientific community after publication (NIH Grants Policy Statement http://grants.nih.gov/grants/policy/nihgps_2003/index.htm and http://grants.nih.gov/grants/policy/nihgps_2003/NIHGPS_Part7.htm#_Toc54600131). Investigators responding to this funding opportunity should include a plan for sharing research resources addressing how unique research resources will be shared or explain why sharing is not possible.

The adequacy of the resources sharing plan and any related data sharing plans will be considered by Program staff of the funding organization when making recommendations about funding applications. The effectiveness of the resource sharing will be evaluated as part of the administrative review of each non-competing Grant Progress Report (PHS 2590, http://grants.nih.gov/grants/funding/2590/2590.htm). See Section VI.3. Reporting.

Section V. Application Review Information

1. Criteria

Only the review criteria described below will be considered in the review process.

The following will be considered in making funding decisions:

• Scientific merit of the proposed project as determined by peer review
• Availability of funds
• Relevance of program priorities

2. Review and Selection Process

An application that is complete and responsive to the RFA will be evaluated for scientific and technical merit by an appropriate peer review group convened by NIDDK in accordance with the review criteria stated below.

As part of the initial merit review, the application will:

• Undergo an initial peer review and assigned a priority score.
• Receive a written critique.
• Receive a second level of review by the appropriate national advisory councils.

The goals of NIH supported research are to advance our understanding of biological systems, to improve the control of disease, and to enhance health. In their written critiques, reviewers will be asked to comment on each of the following criteria in order to judge the likelihood that the proposed project will have a substantial impact on the pursuit of these goals. Each of these criteria will be addressed and considered in assigning the overall score, weighting them as appropriate. Note that an application does not need to be strong in all categories to be judged likely to have major scientific impact and thus deserve a high priority score. For example, an investigator may propose to carry out important work that by its nature is not innovative but is essential to move a field forward (hypothesis-generating as opposed to hypothesis-driven).

Significance: Does this program address an important problem? If the aims of the application are achieved, how will scientific knowledge or translation to potential clinical problems be advanced? What will be the effect of these studies on the concepts, methods, technologies, treatments, services, or preventative interventions that drive this field?

Approach: Is the conceptual framework, design, methods, and analyses adequately developed, well integrated, well reasoned, and appropriate to the aims of the project? Does the applicant acknowledge potential problem areas and consider alternative tactics? Is there a level of integration that contributes to the overall synergy of the program?

Innovation: Is the project and/or component approaches original and innovative? For example: Does the project challenge existing paradigms; address an innovative hypothesis or critical barrier to progress in the field? Does the project develop or employ novel concepts, approaches, methodologies, tools, or technologies for this area?

Investigators: Are the investigators appropriately trained and well suited to carry out this work? Is the work proposed appropriate to the experience level of the principal investigator and other researchers? Does the investigative team bring complementary and integrated expertise to the project (if applicable)? Is there evidence of Team Science collaborative or cooperative interactions between and among participating investigators?

Environment: Does the scientific environment in which the work will be done contribute to the probability of success? Do the proposed studies benefit from unique features of the scientific environment, or subject populations, or employ useful collaborative arrangements? Is there evidence of institutional support? Is there evidence of development of a viable informatics platform that contributes to achieving the overall objectives?

2.A. Additional Review Criteria:

In addition to the above criteria, the following items will continue to be considered in the determination of scientific merit and the priority score:

For a competing continuation application, is there evidence that a team science approach has served to advance knowledge and understanding in this field?

Protection of Human Subjects from Research Risk: The involvement of human subjects and protections from research risk relating to their participation in the proposed research will be assessed (see the Research Plan, Section E on Human Subjects in the PHS Form 398).

Inclusion of Women, Minorities and Children in Research: The adequacy of plans to include subjects from both genders, all racial and ethnic groups (and subgroups), and children as appropriate for the scientific goals of the research will be assessed. Plans for the recruitment and retention of subjects will also be evaluated (see the Research Plan, Section E on Human Subjects in the PHS Form 398).

Care and Use of Vertebrate Animals in Research: If vertebrate animals are to be used in the project, the five items described under Section F of the PHS Form 398 research grant application instructions will be assessed.

Biohazards: If materials or procedures are proposed that are potentially hazardous to research personnel and/or the environment, determine if the proposed protection is adequate.

2.B. Additional Review Considerations

Budget: The reasonableness of the proposed budget and the requested period of support in relation to the proposed research. The priority score should not be affected by the evaluation of the budget.

2.C. Sharing Research Data

Data Sharing Plan: The reasonableness of the data sharing plan or the rationale for not sharing research data will be assessed by the reviewers. However, reviewers will not factor the proposed data sharing plan into the determination of scientific merit or the priority score. The presence of a data sharing plan will be part of the terms and conditions of the award. The funding organization will be responsible for monitoring the data sharing policy.

2.D. Sharing Research Resources

NIH policy requires that grant award recipients make unique research resources readily available for research purposes to qualified individuals within the scientific community after publication (See the NIH Grants Policy Statement http://grants.nih.gov/grants/policy/nihgps/part_ii_5.htm#availofrr and

http://www.ott.nih.gov/policy/rt_guide_final.html). Investigators responding to this funding opportunity should include a sharing research resources plan addressing how unique research resources will be shared or explain why sharing is not possible.

Program staff will be responsible for the administrative review of the plan for sharing research resources.

The adequacy of the resources sharing plan will be considered by Program staff of the funding organization when making recommendations about funding applications. Program staff may negotiate modifications of the data and resource sharing plans with the awardee before recommending funding of an application. The final version of the data and resource sharing plans negotiated by both will become a condition of the award of the grant. The effectiveness of the resource sharing will be evaluated as part of the administrative review of each non-competing Grant Progress Report (PHS 2590). See Section VI.3. Reporting.

3. Anticipated Announcement and Award Dates

Not applicable

Section VI. Award Administration Information

1. Award Notices

After the peer review of the application is completed, the PD/PI will be able to access his or her Summary Statement (written critique) via the eRA Commons.

If the application is under consideration for funding, NIH will request "just-in-time" information from the applicant. For details, applicants may refer to the NIH Grants Policy Statement Part II: Terms and Conditions of NIH Grant Awards, Subpart A: General (http://grants.nih.gov/grants/policy/nihgps_2003/NIHGPS_part4.htm).

A formal notification in the form of a Notice of Award (NoA) will be provided to the applicant organization. The NoA signed by the grants management officer is the authorizing document. Once all administrative and programmatic issues have been resolved, the NoA will be generated via email notification from the awarding component to the grantee business official (designated in item 12 on the Application Face Page). If a grantee is not email enabled, a hard copy of the NoA will be mailed to the business official.

Selection of an application for award is not an authorization to begin performance. Any costs incurred before receipt of the NoA are at the recipient's risk. These costs may be reimbursed only to the extent considered allowable pre-award costs. See Also Section IV.5. Funding Restrictions.

2. Administrative and National Policy Requirements

All NIH grant and cooperative agreement awards include the NIH Grants Policy Statement as part of the NoA. For these terms of award, see the NIH Grants Policy Statement Part II: Terms and Conditions of NIH Grant Awards, Subpart A: General (http://grants.nih.gov/grants/policy/nihgps_2003/NIHGPS_Part4.htm) and Part II Terms and Conditions of NIH Grant Awards, Subpart B: Terms and Conditions for Specific Types of Grants, Grantees, and Activities (http://grants.nih.gov/grants/policy/nihgps_2003/NIHGPS_part9.htm).

The following Terms and Conditions will be incorporated into the award statement and will be provided to the Principal Investigator as well as to the appropriate institutional official, at the time of award.

2.A. Cooperative Agreement Terms and Conditions of Award

The following special terms of award are in addition to, and not in lieu of, otherwise applicable OMB administrative guidelines, HHS grant administration regulations at 45 CFR Parts 74 and 92 (Part 92 is applicable when State and local Governments are eligible to apply), and other HHS, PHS, and NIH grant administration policies.

The administrative and funding instrument used for this program will be the cooperative agreement (U 19), an "assistance" mechanism (rather than an "acquisition" mechanism), in which substantial NIH programmatic involvement with the awardees is anticipated during the performance of the activities. Under the cooperative agreement, the NIH purpose is to support and stimulate the recipients' activities by involvement in and otherwise working jointly with the award recipients in a partnership role; it is not to assume direction, prime responsibility, or a dominant role in the activities. Consistent with this concept, the dominant role and prime responsibility resides with the awardees for the project as a whole, although specific tasks and activities may be shared among the awardees and the NIH as defined below.

The components of this award will form a consortium to be known as the Nuclear Receptor Signaling Atlas ( NURSA ).

Defining objectives and approaches, and planning, conducting, analyzing, and publishing results, interpretations, and conclusions of studies conducted under the terms and conditions of the cooperative agreement award;

Conducting the research supported by the project in accordance with the terms and conditions of the award;

Participating as a permanent, voting member of the Steering Committee;

Contributing to and implementing the goals, priorities, procedures, and policies agreed upon by the Steering Committee;

Coordinating and collaborating with the other components of the NURSA and with the NIDDK, and other NIH institute staff;

Contributing to NURSA Core resources and serving on NURSA subcommittees, as needed;

Sharing both data and unique research resources that are generated by the projects in accordance with the NURSA and NIH policies;

Awardees will retain custody of and have primary rights to the data and software developed under these awards, subject to Government rights of access consistent with current HHS, PHS, and NIH policies.

2.A.2. NIH Responsibilities

As lead institute and in order to avoid conflicts of interest and maintain appropriate stewardship of the award, the NIDDK will name two separate program officials for this project. A Program Official will be responsible for the review of progress reports and budgetary oversight while a Project Scientist will represent the interests of the NIH on the Steering Committee and work with the investigators in the context of the cooperative agreement mechanism.

The NIDDK Project Scientist will have substantial scientific-programmatic involvement during conduct of this activity, through technical assistance, advice and coordination. Additional Project Scientists from co-sponsoring institutes may become involved in such activities, as well. The dominant role and primary responsibility for the activity resides with the awardees for the project as a whole, although specific tasks and activities in carrying out the studies will be shared among the awardees and the NIDDK Project Scientist and other NIH cosponsoring institutes.

An NIDDK Project Scientist will have substantial involvement in the project above and beyond normal stewardship and monitoring of the award, as described below:

Being a voting member of the Steering Committee and, as determined by that committee, its subcommittees; representing the interests of the other cosponsoring institutes of the NIH to the Steering Committee

Being the contact point for all facets of the scientific interaction with awardee(s). As required for the coordination of activities and to expedite progress, NIDDK may designate additional NIH staff to provide advice to the awardee on specific scientific issues.

Serving as a resource with respect to other ongoing NIH activities that may be relevant to the research of the NURSA in order to facilitate compatibility and avoid unnecessary duplication of effort.

Serving as liaison to the other co-sponsoring NIH institutes that provide funding for the NURSA consortium.

In the role of program official, the NIDDK Program Official will be responsible for the normal program and budgetary stewardship of the award and will be named in the Notice of Grant Award. This includes:

Retaining overall programmatic responsibility for the award, and will clearly specify to the awardee the name(s) and role(s) of any additional individuals with substantial involvement in the project and the lines of reporting authority

Interacting with the Principal Investigator(s) on a regular basis to monitor research progress. Monitoring may include: regular communications with the principal investigator and staff, periodic conference calls for discussions with awardee research teams, quality control, fiscal review, and other relevant matters; as well as attendance at Steering Committee meetings, External Advisory Working Group Meetings, and related meetings. The NIH cosponsoring institutes retain as an option periodic external review of progress.

Making recommendations for continued funding based on: a) overall research progress, b) cooperation in carrying out the research (e.g. attendance at Steering Committee meetings, implementation of group decisions, compliance with the terms of award, and c) maintenance of a high quality of research, which will allow pooling of data and comparisons across multiple cooperative agreement awards for common data elements

The Steering Committee will be composed of the overall Principal Investigator of the award and a Co-Principal Investigator or other senior investigator from each U19 subproject (resource core and bridging project and the NIDDK Project Scientist. Principal Investigators from each U19 project and the NIDDK Project Scientist will each have one Steering Committee vote. The chairperson will be someone other that the NIDDK Project Scientist, and will be selected by NIDDK. The NIDDK Project Scientist will represent the interests of the co-funding NIH Institutes on the Steering Committee with one vote.

The Steering Committee will have primary responsibility for establishing priorities, developing common protocols, and review of progress. The Steering Committee will refine the NURSA scientific objectives consistent with progress in the NURSA components and other laboratories. Major scientific decisions regarding NURSA core data and resources, as well as setting scientific priorities for special programs such as the (optional) Pilot and Feasibility supplements, or ancillary studies, will be determined by the Steering Committee. Awardee members of the Steering Committee will be required to accept and implement policies approved by the Steering Committee. The Steering Committee will document progress in written reports to the Program official and will provide supplementary reports upon request.

There will be four Steering Committee meetings annually, one in the fall, one in conjunction with the annual Investigator’s retreat, one in the spring and one in conjunction with the Annual meeting of the Endocrine Society.

The Steering Committee may, when necessary, invite additional, non-voting scientific advisors to the meetings at which research priorities and opportunities are discussed. The NIDDK and cosponsoring institutes reserve the right to augment the scientific expertise of the NURSA when necessary.

One Steering Committee meeting per year will take place in conjunction with an Investigator's Retreat. All participating investigators will be required to attend the retreat at which time the External Advisors will provide feedback on progress to the NIH Scientific team. At this annual retreat the Steering Committee will formulate plans for any additional meetings or symposia to be held.

The NURSA members will serve on subcommittees, scientifically review applications for special programs such as supplements or subcontracts, as it is deemed appropriate; the NIDDK Project Scientist will serve on subcommittees as appropriate. Staff from NIDDK and other cosponsoring institutes with special expertise may serve on subcommittees at the request of the Steering Committee. Subcommittee chairs will be selected by the Steering Committee and will report progress at Steering Committee Meetings and lead discussions at the Annual Investigator’s Retreat.

External Advisory Working Group

An independent External Advisory Working Group will be established by the NIDDK in consultation with the scientific staff of the cosponsoring institutes. The External Advisory Working Group will periodically review interim progress of the NURSA including the Resource Cores, research projects, and any other special activities of the NURSA and report to NIDDK and the cosponsoring institutes. The External Advisory Working Group will meet annually, but will review progress, as needed, at other times, as well.

2.A.4. Arbitration Process

Any disagreements that may arise in scientific or programmatic matters (within the scope of the award) between award recipients and the NIH may be brought to arbitration. An Arbitration Panel composed of three members will be convened: a designee of the Steering Committee chosen without NIH staff voting, one NIH designee, and a third designee with expertise in the relevant area who is chosen by the other two; in the case of individual disagreement, the first member may be chosen by the individual awardee. This special arbitration procedure in no way affects the awardee's right to appeal an adverse action that is otherwise appealable in accordance with PHS regulations 42 CFR Part 50, Subpart D and HHS regulations 45 CFR Part 16.

3. Reporting

Awardees will be required to submit the PHS Non-Competing Grant Progress Report, Form 2590 annually (http://grants.nih.gov/grants/funding/2590/2590.htm) and financial statements as required in the NIH Grants Policy Statement. In addition, a yearly report will be made to the External Advisory Working Group with a mid-project report by this group forwarded to the National Diabetes and Digestive and Kidney Diseases Advisory Council to assist in evaluating continuation of funding.

Section VII. Agency Contacts

We encourage your inquiries concerning this funding opportunity and welcome the opportunity to answer questions from potential applicants. Inquiries may fall into three areas: scientific/research, peer review, and financial or grants management issues:

1. Scientific/Research Contacts:

Kristin Abraham, Ph.D.
Division of Diabetes, Endocrinology and Metabolic Diseases
National Institute of Diabetes and Digestive and Kidney Diseases
6707 Democracy Boulevard, Room 795
Bethesda, MD 20892-5460
Telephone: (301) 451-8048
FAX: (301) 480-3503
Email: ka136s@nih.gov

Jill Carrington, Ph.D.
Biology of Aging Program
National Institute on Aging
7201 Wisconsin Ave.,Suite 2C231
Bethesda, MD 20892
Telephone: (301) 496-6402
FAX: (301) 402-0010
Email: jc189n@nih.gov

Cristina Rabadan-Diehl, Ph.D.
Division of Heart and Vascular Diseases
National Heart, Lung, and Blood Institute
Rockledge II, Room 10186
6701 Rockledge Drive
Bethesda, MD 20892-7956
Telephone: 301-435-0550
Fax: 301-480-2858
Email: cr60i@nih.gov

Jerrold Heindel, Ph.D.
Division of Extramural Research and Training
National Institute of Environmental Health Sciences
79 T.W. Alexander Drive
4401 Bldg., 3^rd Floor
RTP, NC 27709
Telephone: (919) 541-0781
FAX: (919) 541-5064
Email: jh190f@nih.gov

Koji Yoshinaga, Ph.D.
Center for Population Research
National Institute of Child Health and Human Development
6100 Executive Boulevard, Room 8B01B
Rockville, Maryland 20852
Telephone: 301/435-6992
Fax: 301/480-2389
Email: ky6o@nih.gov

3. Financial or Grants Management Contacts:

Diana O Donovan
Division of Extramural Activities
National Institute of Diabetes and Digestive and Kidney Diseases
6707 Democracy Boulevard, Room 726
Bethesda, MD 20892-5452
Telephone: (301) 594-8868
FAX: (301) 594-9532
Email: do66k@nih.gov

Linda Whipp
Grants and Contracts Management Office
National Institute on Aging
Suite 2N212
7201 Wisconsin Ave.
Bethesda, MD 20892
Telephone: (301) 402-7731
FAX: (301) 402-3672
Email: lw17m@nih.gov

Susan Ricci
Division of Extramural Research and Training
National Institute of Environmental Health Sciences
79 T.W. Alexander Drive
4401 Bldg., 3^rd Floor
RTP, NC 27709
Telephone: (919) 316-4666
FAX: (919) 541-2860
Email: sr302n@nih.gov

Cecilia Bruce
Grants Management Branch
National Institute of Child Health and Human Development
6100 Executive Boulevard, Room 8A17L
Rockville, Maryland 20852
Telephone: 301/496-1304
Fax: 301/480-4782
Email: cb156n@nih.gov

Section VIII. Other Information

Required Federal Citations

Use of Animals in Research:
Recipients of PHS support for activities involving live, vertebrate animals must comply with PHS Policy on Humane Care and Use of Laboratory Animals (http://grants.nih.gov/grants/olaw/references/PHSPolicyLabAnimals.pdf) as mandated by the Health Research Extension Act of 1985 (http://grants.nih.gov/grants/olaw/references/hrea1985.htm), and the USDA Animal Welfare Regulations (http://www.nal.usda.gov/awic/legislat/usdaleg1.htm) as applicable.

Human Subjects Protection:
Federal regulations (45CFR46) require that applications and proposals involving human subjects must be evaluated with reference to the risks to the subjects, the adequacy of protection against these risks, the potential benefits of the research to the subjects and others, and the importance of the knowledge gained or to be gained (http://www.hhs.gov/ohrp/humansubjects/guidance/45cfr46.htm).

Data and Safety Monitoring Plan:
Data and safety monitoring is required for all types of clinical trials, including physiologic toxicity and dose-finding studies (phase I); efficacy studies (Phase II); efficacy, effectiveness and comparative trials (Phase III). Monitoring should be commensurate with risk. The establishment of data and safety monitoring boards (DSMBs) is required for multi-site clinical trials involving interventions that entail potential risks to the participants (NIH Policy for Data and Safety Monitoring, NIH Guide for Grants and Contracts, http://grants.nih.gov/grants/guide/notice-files/not98-084.html).

Sharing Research Data:
Investigators submitting an NIH application seeking $500,000 or more in direct costs in any single year are expected to include a plan for data sharing or state why this is not possible (http://grants.nih.gov/grants/policy/data_sharing).

Investigators should seek guidance from their institutions, on issues related to institutional policies and local IRB rules, as well as local, State and Federal laws and regulations, including the Privacy Rule. Reviewers will consider the data sharing plan but will not factor the plan into the determination of the scientific merit or the priority score.

Access to Research Data through the Freedom of Information Act:
The Office of Management and Budget (OMB) Circular A-110 has been revised to provide access to research data through the Freedom of Information Act (FOIA) under some circumstances. Data that are (1) first produced in a project that is supported in whole or in part with Federal funds and (2) cited publicly and officially by a Federal agency in support of an action that has the force and effect of law (i.e., a regulation) may be accessed through FOIA. It is important for applicants to understand the basic scope of this amendment. NIH has provided guidance at http://grants.nih.gov/grants/policy/a110/a110_guidance_dec1999.htm. Applicants may wish to place data collected under this funding opportunity in a public archive, which can provide protections for the data and manage the distribution for an indefinite period of time. If so, the application should include a description of the archiving plan in the study design and include information about this in the budget justification section of the application. In addition, applicants should think about how to structure informed consent statements and other human subjects procedures given the potential for wider use of data collected under this award.

Sharing of Model Organisms:
NIH is committed to support efforts that encourage sharing of important research resources including the sharing of model organisms for biomedical research (see http://grants.nih.gov/grants/policy/model_organism/index.htm). At the same time the NIH recognizes the rights of grantees and contractors to elect and retain title to subject inventions developed with Federal funding pursuant to the Bayh Dole Act (see the NIH Grants Policy Statement http://grants.nih.gov/grants/policy/nihgps_2003/index.htm). All investigators submitting an NIH application or contract proposal, beginning with the October 1, 2004 receipt date, are expected to include in the application/proposal a description of a specific plan for sharing and distributing unique model organism research resources generated using NIH funding or state why such sharing is restricted or not possible. This will permit other researchers to benefit from the resources developed with public funding. The inclusion of a model organism sharing plan is not subject to a cost threshold in any year and is expected to be included in all applications where the development of model organisms is anticipated.

Inclusion of Women And Minorities in Clinical Research:
It is the policy of the NIH that women and members of minority groups and their sub-populations must be included in all NIH-supported clinical research projects unless a clear and compelling justification is provided indicating that inclusion is inappropriate with respect to the health of the subjects or the purpose of the research. This policy results from the NIH Revitalization Act of 1993 (Section 492B of Public Law 103-43). All investigators proposing clinical research should read the "NIH Guidelines for Inclusion of Women and Minorities as Subjects in Clinical Research (http://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-001.html); a complete copy of the updated Guidelines is available at http://grants.nih.gov/grants/funding/women_min/guidelines_amended_10_2001.htm. The amended policy incorporates: the use of an NIH definition of clinical research; updated racial and ethnic categories in compliance with the new OMB standards; clarification of language governing NIH-defined Phase III clinical trials consistent with the new PHS Form 398; and updated roles and responsibilities of NIH staff and the extramural community. The policy continues to require for all NIH-defined Phase III clinical trials that: a) all applications or proposals and/or protocols must provide a description of plans to conduct analyses, as appropriate, to address differences by sex/gender and/or racial/ethnic groups, including subgroups if applicable; and b) investigators must report annual accrual and progress in conducting analyses, as appropriate, by sex/gender and/or racial/ethnic group differences.

Inclusion of Children as Participants in Clinical Research:
The NIH maintains a policy that children (i.e., individuals under the age of 21) must be included in all clinical research, conducted or supported by the NIH, unless there are scientific and ethical reasons not to include them.

All investigators proposing research involving human subjects should read the "NIH Policy and Guidelines" on the inclusion of children as participants in research involving human subjects (http://grants.nih.gov/grants/funding/children/children.htm).

Required Education on the Protection of Human Subject Participants:
NIH policy requires education on the protection of human subject participants for all investigators submitting NIH applications for research involving human subjects and individuals designated as key personnel. The policy is available at http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-039.html.

Human Embryonic Stem Cells (hESC):
Criteria for federal funding of research on hESCs can be found at http://stemcells.nih.gov/index.asp and at http://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-005.html. Only research using hESC lines that are registered in the NIH Human Embryonic Stem Cell Registry will be eligible for Federal funding (http://escr.nih.gov). It is the responsibility of the applicant to provide in the project description and elsewhere in the application as appropriate, the official NIH identifier(s) for the hESC line(s)to be used in the proposed research. Applications that do not provide this information will be returned without review.

NIH Public Access Policy:
NIH-funded investigators are requested to submit to the NIH manuscript submission (NIHMS) system (http://www.nihms.nih.gov) at PubMed Central (PMC) an electronic version of the author's final manuscript upon acceptance for publication, resulting from research supported in whole or in part with direct costs from NIH. The author's final manuscript is defined as the final version accepted for journal publication, and includes all modifications from the publishing peer review process.

NIH is requesting that authors submit manuscripts resulting from 1) currently funded NIH research projects or 2) previously supported NIH research projects if they are accepted for publication on or after May 2, 2005. The NIH Public Access Policy applies to all research grant and career development award mechanisms, cooperative agreements, contracts, Institutional and Individual Ruth L. Kirschstein National Research Service Awards, as well as NIH intramural research studies. The Policy applies to peer-reviewed, original research publications that have been supported in whole or in part with direct costs from NIH, but it does not apply to book chapters, editorials, reviews, or conference proceedings. Publications resulting from non-NIH-supported research projects should not be submitted.

For more information about the Policy or the submission process please visit the NIH Public Access Policy Web site at http://publicaccess.nih.gov/ and view the Policy or other Resources and Tools including the Authors' Manual (http://publicaccess.nih.gov/publicaccess_Manual.htm).

Standards for Privacy of Individually Identifiable Health Information:
The Department of Health and Human Services (DHHS) issued final modification to the "Standards for Privacy of Individually Identifiable Health Information", the "Privacy Rule", on August 14, 2002 . The Privacy Rule is a federal regulation under the Health Insurance Portability and Accountability Act (HIPAA) of 1996 that governs the protection of individually identifiable health information, and is administered and enforced by the DHHS Office for Civil Rights (OCR).

Decisions about applicability and implementation of the Privacy Rule reside with the researcher and his/her institution. The OCR website (http://www.hhs.gov/ocr/) provides information on the Privacy Rule, including a complete Regulation Text and a set of decision tools on "Am I a covered entity?" Information on the impact of the HIPAA Privacy Rule on NIH processes involving the review, funding, and progress monitoring of grants, cooperative agreements, and research contracts can be found at http://grants.nih.gov/grants/guide/notice-files/NOT-OD-03-025.html.

URLs in NIH Grant Applications or Appendices:
All applications and proposals for NIH funding must be self-contained within specified page limitations. For publications listed in the appendix and/or Progress report, internet addresses (URLs) must be used for publicly accessible on-line journal articles. Unless otherwise specified in this solicitation, Internet addresses (URLs) should not be used to provide any other information necessary for the review because reviewers are under no obligation to view the Internet sites. Furthermore, we caution reviewers that their anonymity may be compromised when they directly access an Internet site.

Healthy People 2010:
The Public Health Service (PHS) is committed to achieving the health promotion and disease prevention objectives of "Healthy People 2010," a PHS-led national activity for setting priority areas. This PA is related to one or more of the priority areas. Potential applicants may obtain a copy of "Healthy People 2010" at http://www.health.gov/healthypeople.

Authority and Regulations:
This program is described in the Catalog of Federal Domestic Assistance at http://www.cfda.gov/ and is not subject to the intergovernmental review requirements of Executive Order 12372 or Health Systems Agency review. Awards are made under the authorization of Sections 301 and 405 of the Public Health Service Act as amended (42 USC 241 and 284) and under Federal Regulations 42 CFR 52 and 45 CFR Parts 74 and 92. All awards are subject to the terms and conditions, cost principles, and other considerations described in the NIH Grants Policy Statement. The CFDA number for NIDDK is 93.848, for NIA 93.866, NHLBI 93.837, NIEHS 93.113, and NICHD 93.865. The NIH Grants Policy Statement can be found at http://grants.nih.gov/grants/policy/policy.htm.

The PHS strongly encourages all grant recipients to provide a smoke-free workplace and discourage the use of all tobacco products. In addition, Public Law 103-227, the Pro-Children Act of 1994, prohibits smoking in certain facilities (or in some cases, any portion of a facility) in which regular or routine education, library, day care, health care, or early childhood development services are provided to children. This is consistent with the PHS mission to protect and advance the physical and mental health of the American people.

Loan Repayment Programs:
NIH encourages applications for educational loan repayment from qualified health professionals who have made a commitment to pursue a research career involving clinical, pediatric, contraception, infertility, and health disparities related areas. The LRP is an important component of NIH's efforts to recruit and retain the next generation of researchers by providing the means for developing a research career unfettered by the burden of student loan debt. Note that an NIH grant is not required for eligibility and concurrent career award and LRP applications are encouraged. The periods of career award and LRP award may overlap providing the LRP recipient with the required commitment of time and effort, as LRP awardees must commit at least 50% of their time (at least 20 hours per week based on a 40 hour week) for two years to the research. For further information, please see: http://www.lrp.nih.gov.

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