Expired RFA-ES-06-012: Biological Response Indicators of Environmental Stress Centers (U54)

Department of Health
and Human Services (HHS)

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EXPIRED

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 Environmental Health Sciences (NIEHS) http://www.niehs.nih.gov)

Title: Biological Response Indicators of Environmental Stress Centers (U54)

Announcement Type
New

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

October17, 2006 (NOT-OD-07-007) - See Notice NOT-OD-07-007 for notice to inform potential applicants that NIH IRP will be eligible to participate in the NIH-wide GEI.

Request For Applications (RFA) Number: RFA-ES-06-012

Catalog of Federal Domestic Assistance Number(s)
93.113

Key Dates
Release Date: September 27, 2006
Letters of Intent Receipt Dates: November 22, 2006
Application Receipt Dates: December 22, 2006
Peer Review Dates: March 2007
Council Review Dates: May 2007
Earliest Anticipated Start Dates: July 2007
Additional Information To Be Available Date (URL Activation Date): N/A
Expiration Date: December 23, 2006

Due Dates for E.O. 12372

Not Applicable

Additional Overview Content

Executive Summary

These Centers represent one part of a comprehensive program that develops and refines panels of biomarkers and biosensors of biological response to environmental stressors. By measuring the cellular, molecular and physiologic responses to environmental stressors in key physiologic and pathophysiologic pathways, the relationships between genetic and non-genetic factors that contribute to disease will be better defined. This program will focus on a product-driven approach for the development, confirmation, and application of innovative biomarkers and biosensors, especially those with potential for scale-up for use in large population studies.
The total amount of funding to be committed to this program is $18 million (total costs) over 4 years. Each year $4.5 million will be awarded.
Anticipated number of awards: 4
Type of mechanism: U54 Specialized Centers.
Budget and Project Period: Because the nature and scope of the proposed research will vary from application to application, it is anticipated that the size each award will also vary. The total amount awarded and the number of awards will depend upon the number, quality, and costs of the applications received. The total project period for an application submitted in response to this funding opportunity may not exceed four years. Awards issued under this funding opportunity announcement (FOA) are contingent upon the availability of funds.
Eligible organizations include for-profit organizations, non-profit organizations, public or private institutions, such as universities, colleges, hospitals, and laboratories, units of state government, units of local government, eligible agencies of the federal government, foreign institutions, domestic institutions, faith-based or community-based organizations .
Eligible Principal Investigators include any individual with the skills, knowledge, experience and resources necessary to carry out the proposed research. Individuals from underrepresented racial and ethnic groups as well as individuals with disabilities are always encouraged to apply for NIH support.
Applicants may submit more than one application, provided they are scientifically distinct.
See Section IV.1 for 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

Nature of the Research Opportunity

The NIH invites applications to support research to develop and refine panels of biomarkers and biosensors of biological response to environmental stressors, for the NIH-wide Genes and Environment Initiative (GEI).

The GEI is a four-year, NIH-wide program proposed in the President’s 2007 budget and currently awaiting Congressional approval. If approved, the program will support efforts to identify major genetic susceptibility factors for diseases of public health significance and to develop technologies for reliable and reproducible measurement of potentially causative environmental exposures. The GEI is being developed and implemented by an NIH-wide Coordinating Committee, and administered via two complementary programs, the Exposure Biology Program led by the National Institute of Environmental Health Sciences (NIEHS) and the Genetics Program led by the National Human Genome Research Institute (NHGRI).

The Exposure Biology Program of the GEI is intended to be a multi-component program involving several solicitations. A major component will support the development of technology to make precise, quantitative measurements of personal exposure to environmental chemical/biological agents, diet, physical activity, and psychosocial stress. The other exposure biology component includes development of biological response indicators for a variety of environmental stressors. These activities will generate new exposure assessment tools that can be applied in future population-based and whole genome association studies supported by the GEI to better inform about the role of gene-environment interactions in human disease.

The GEI will also consider pathways to disparities in health outcomes, including but not limited to environmental exposures, genetic variations and/or other underlying biological, race/ethnic, social, and familial factors. Health disparities research provides an important opportunity to integrate biological with social/behavioral knowledge in better identification and understanding of the determinants of disease, reducing disease risks, and providing better treatment. How genetic variation contributes to health disparities remains largely unclear since most genetic studies do not have adequate measures of behavioral, physical, social, and environmental factors. The GEI will provide a valuable scientific contribution to health disparities research by its collection and analyses of genotype, phenotype, and exposure data, while simultaneously measuring other factors within disease subgroups (e.g., race, ethnicity, behaviors, geography, genetic backgrounds, exposures and social environments) that may lead to differential health outcomes.

There are 5 RFAs being announced concurrently that define the scope of the Exposure Biology Program. The RFA numbers and titles are as follows: ES-06-011, Environmental Sensors for Personal Exposure Assessment (U01); CA-07-032, Improved Measures of Diet and Physical Activity for the Genes and Environment Initiative (GEI) (U01); DA-07-005, Field-deployable Tools for Quantifying Exposures to Psychosocial Stress and to Addictive Substances for Studies of Health and Disease (U01); ES-06-012, Biological Response Indicators to Environmental Stressors Centers (U54); and ES-06-013, Biological Response Indicators to Environmental Stressors (U01).

The purpose of this initiative is to implement a comprehensive program that develops and refines panels of biomarkers and biosensors of biological response to environmental stressors. By measuring the cellular, molecular and physiologic responses to environmental stressors in key physiologic pathways also involved in disease pathogenesis, it is hoped that the relationships between genetic and non-genetic factors that contribute to disease will be better defined. This program will adopt a product-driven approach to the development, confirmation, and application of innovative biosensors and panels of biomarkers, especially those with potential for scale-up for use in large population studies as part of the Genes and Environment Initiative.

For the purposes of this FOA, the primary goal is the development of technologies of biological measures of exposure in key biological pathways that are reliable, valid, and are economically feasible for use in studies of diverse populations. Diverse populations include subgroups based on gender, culture, and socio-economic status and age, including infants, children and adults.

This FOA encourages the creation of multidisciplinary teams of scientists to develop or refine existing biomarkers and biosensors, such that patterns of biological response to environmental stressors can be adequately characterized by panels of such markers. New technology, assays or markers developed through this FOA should be available for confirmation in and application to large-scale studies soon after the end of the four-year funding period.

Background

Traditional approaches used to characterize the exposure of individuals to non-genetic factors have relied on methods that quantify the intake, contact, or internal dose of agents using questionnaires or analytic assays to quantify body burden or extrapolations from external sources. These estimates were made either by focusing on a single exposure or on a period of time that could span months or years of exposure. These methods have many known limitations; misclassification error, individual variability, temporal uncertainty, and temporal relevance to the natural history of disease. These limitations in exposure assessment methodologies have produced conflicting data and hampered our ability to prevent, predict, and treat disease.

As we seek to understand the causes of complex human diseases, characterizing exposure to a variety of stressors accurately and precisely is critically important. Tools are available to carefully measure changes in genes at the base pair level across the entire genome. In contrast, traditional tools to assess exposure may not give reproducible results or may give results that have questionable validity. Studies that continue to use traditional ways to measure diet, environmental chemicals and other toxicants, biological agents, physical activity and psychosocial stress, will have difficulty assessing interactions between genetic and environmental factors due to inherent differences in the way these two sets of factors are estimated in human populations. On May 15-16, 2006, NIEHS and NHGRI convened a workshop in order to discuss methods and approaches to improve exposure characterization in human populations. Opportunities to further development and application of environmental sensors, biosensors and panels of biomarkers of exposure and biological response to such stressors were discussed with a group of experts in the fields of engineering, environmental health sciences, epidemiology, clinical medicine, nutrition, exercise science, and molecular and cellular biology. The executive summary of this meeting is available on the Exposure Biology website (http://www.gei.nih.gov/exposurebiology/index.asp). Everyday stressors from one’s environment modulate physiological pathways, leading to transient and permanent biological changes. Some stressors, such as lead exposure, have deleterious effects on key pathways, which can affect cognitive development in utero and early life. In contrast, some stressors, such as dietary antioxidants, have positive or protective effects on health, which may protect against DNA damage associated with carcinogenesis. Exposure to stressors can lead to alterations in nuclear, cellular or organ system function and/or structure. These changes can be characterized at molecular, cellular, or physiologic levels and measured grossly in target tissues. This initiative will stimulate research to determine if these changes can be reliably measured in easily accessible specimens including body fluids, cells isolated from blood, and exfoliated cells in urine.

Biosensors and panels of biomarkers are needed that can quantify the presence of an exposure and the response to exposure in key physiologic pathways. Markers and sensors that can track response over a relevant time course are highly desirable. For the purposes of this FOA, a biomarker is an indicator of a biologic response to an environment exposure or stressor that is objectively measured. In order to adequately define a response, multiple markers may be necessary to characterize the full response of the pathway to the stressor. A panel of markers, which includes those at the physiologic, cellular and molecular level, may be more valuable than a single marker. For the purposes of this FOA, biosensors are defined as devices or technologies that measure markers of biological responses to environmental stressors in vivo or in banked biological specimens. Single or multiple measurements may be captured in real time, as serial measurements, or in archived tissues. New sensing devices and systems that can provide quantitative data of a given response with high accuracy and reliability are needed. For example, biosensors that utilize lab-on-a-chip methods should be developed to in order to enhance the ability to characterize exposure responses in the field.

For this program, pathways known to be perturbed by environmental stressors and disease are of greatest interest. These include inflammation, oxidative stress, DNA damage, mitochondrial perturbations, endocrine disruption, xenobiotic biotransformation, immune activation, and epigenetic regulation. Important classes of exposures include, but are not limited to: environmental tobacco smoke, alcohol and ethanol, diet, air pollution and its components, mycotoxins, pesticides, herbicides and insecticides, and addictive substances.

Technology that could be applied to the development of the required biosensors and biomarkers includes genomics, proteomics, metabolomics, comparative biology, systems biology, and computational or in- silico, analyses. Physiologic responses could also be measured using biosensors and incorporated into the panels of response indicators. A goal of this product-development program is to invest in assays that can be scaled up for high-throughput application to large populations quickly and efficiently.

Scientific Knowledge to be Achieved

The goal of the trans-NIH Genes and Environment Initiative is to determine the etiology of common diseases by focusing on the interaction of genetic and environmental factors that increase the risk of these diseases. The Exposure Biology component of the GEI will develop, confirm and apply new methods to assess personal exposure to stressors in the environment and the response to these stressors in key biological pathways that are also involved the pathogenesis of common diseases. During the period of performance, products, (i.e., assays, technologies, markers, sensors), will be developed that will be suitable for validation and application in large-scale human populations studies.

Objectives of the Research Program

In order to develop, confirm, and apply biomarkers and biosensors of key biological pathways affected by environmental stressors, a multidisciplinary team science approach is needed. Each application should be focused around a central theme. A minimum of three research projects is necessary for a Center application. Four phases of research define an experimental paradigm that permits researchers to leverage existing biomarker and biosensor studies when possible and that encourages new research innovations. Research groups can be at any phase in this continuum and work in a forward or reverse direction in order to meet their goals.

Discovery exploratory research to identify reproducible patterns of response to environmental stressors in key biological specimens.
Predictive Analysis capacity of the biomarkers to distinguish between homeostasis and response to challenge
Assay Refinement conduct confirmatory studies on test sets of specimens to improve predictive power of the marker
Sensor development development of a device or system that can measure single or multiple biomarkers that reflect the biological response to an environmental stressor with proven accuracy, reliability and technical validity in the field or which may be applied to banked specimens

Research may include the use of animal models to characterize response in key pathways to agents of choice in target and peripheral tissues, the extensive characterization of a suite of biomarkers in clinical specimens, and the development and application of technology to measure responses in biological systems in vivo in animals in order to translate findings to banked biological samples from human studies. Centers must include research involving human specimens in at least one research project and must include research related to biosensor development.

Types of Research and Experimental Approaches to be Used

Research conducted as part of these multi-project programs could include the use of technologies such as genomics, proteomics, metabolomics, and more precise quantification of DNA damage products, coupled with clinical biochemistry, histology, or physiologic markers (such as pulmonary function or cardiac activity). Such technology should be considered in the assessment of patterns of response due to environmental stressors and be incorporated into biomarker development. Biosensors that utilize lab-on-a-chip technology and can be applied to banked biosamples are of interest. Assays and devices that can be scaled up for use in large human populations and could be readily applied to specimens stored in biobanks would be advantageous for the application of these biomarkers to the Genome Wide Association Studies in GEI.

Research can include any of the following: the study of clinical samples from persons who are exposed to environmental stressors and controls, persons who display interesting and relevant clinical manifestations of pre-clinical or clinically apparent disease, or the study of animal model systems or other cell culture systems. For human studies supporting data on historical or current exposure status should be available for comparison and confirmation. For groups working in animal models, the Center must include a translational component to human specimens to be eligible. This FOA is not intended to support large-scale application of markers and sensors involving the recruitment of large numbers of humans study subjects, although it is desirable that assays and systems be tested on a smaller scale. Field testing on banked biological specimens is encouraged when feasible.

An example of one approach to the development of a biomarker that would accurately define a person’s response to the complex mixture of chemicals found in cigarette smoke is described. It may be possible to characterize the molecular changes resulting from tobacco smoke exposure in multiple ways using different technologies (i.e., gene expression changes, proteomic signatures, DNA adducts, methylation changes, microsatellite instability, or changes in oxidant state.) For example, by using lung tissue and blood samples in a gene expression array, a signature of genetic response to the chemicals in cigarette smoke can be defined and compared to results in non-smokers. If a defined panel of genes is identified with exposure and these genes are not expressed in non-smokers, then this marker defines components of the genetic response to cigarette smoke exposure. This marker should be compared to traditional measures of cigarette smoke: smoker/non-smoker status, frequency of use, recentness of exposure, (gathered by questionnaire) and cotinine level to determine if the marker categorizes smokers and non-smokers adequately. Learning about the interrelation of these patterns, and developing multiple biomarkers to define response will be helpful in identifying a useful suite of markers to characterize these responses.

Another example relates to the assessment of gene-specific and global epigenetic changes influenced by dietary exposures. A recent study showed that supplementation with folic acid, vitamin B12, choline, and betaine altered phenotype in agouti (A(vy)) mice through increased DNA methylation at the A(vy) locus. Beginning with animal studies, the effects of dietary supplementation with folic acid and other B vitamins could be assessed with respect to gene-specific epigenetic changes (e.g., alterations in imprinted genes, including IGF2 and CDKN1C), global methylation changes, or histone modification changes. Results from these animal studies could be used to design relevant probes for global DNA methylation arrays that could be used to study epigenetic changes in human dietary intervention studies.

A third example relates to development of micro-total analysis systems (lab-on-a-chip) technology that can detect altered protein profiles or changes in specific cell populations related to an environmental stressor using antibodies, peptides or aptamers with high affinity to the proteins or cell-surface markers of interest. Miniaturization of these devices using advances in spectroscopy, luminescent nanocrystals (quantum dots), or development of piezoelectric affinity biosensors can allow for new ways to analyze biomarkers of interest in tissue, serum, plasma, and urine samples collected in clinical or epidemiology studies. Development of biosensor technology must be applicable to biomarkers within a central research theme or program related to the biological response to environmental stressors.

Research Topics: Examples of research that would be relevant for the development of the U54 applications under this FOA include, but are not limited to:

Development or adaptation of biomarkers of response to environmental stressors in order to clearly define a pattern of response at a single level (i.e., a molecular signature) or at multiple levels (i.e., molecular, cellular and/or physiological responses).
Development of sensing methodologies that can quantitate the response of the key pathway over time and in response to environmental stressors.
Comparison of patterns of response to environmental stressors across species including humans.
Comparison of panels of biomarkers in multiple tissues progressing from invasive to noninvasive specimens.
Study of the performance of biomarkers under different exposure conditions, including dose, frequency, and timing of exposure in order to improve the predictive power of the markers to measure response following exposure.
Development of biomarkers of response to a number of exposure scenarios, such as acute vs. chronic exposure, present vs. past exposure.
Development of high-throughput capacity for analyzing a panel of biomarkers in biospecimens collected from large populations.

General Description of a Biological Response to Environmental Stressors Center and Center Components

These Centers must have a strong central theme that focuses on the biological response of one or more key pathways after exposure to single or multiple environmental exposures or stressors. The development of products that improve our ability to characterize exposure in large-scale human studies is the overall goal of these Centers. The applicant organization must include a minimum of 50% of the research effort. Partnerships may consist of investigators at a single institution or at multiple sites and may include collaborative arrangements as appropriate with organizations, domestic or foreign, public or private (such as universities, colleges, hospitals, laboratories, for profit and non-profit, units of State and local governments and eligible agencies of the Federal government), as necessary to conduct portions of the research. Teams that are geographically distributed must be well justified and steps to minimize the effects of geography should be clearly stated.

The U54 Center grant mechanism fosters collaborative and integrative research across disciplines such as engineering, clinical medicine, nutrition, environmental health sciences, exercise science, psychology and behavioral medicine, and molecular biology. This mechanism provides funds to support personnel, equipment, supplies, services for research projects, facility cores, and an administrative core.

1. The Director of the U54 Center is the designated leader and provides leadership for the administrative, scientific, and programmatic direction. It is expected that the Director will commit a minimum of 10% effort to the administration of the Center. The Director must have the scientific knowledge and expertise to oversee the scientific aims of the Center and work towards the development of successful products emanating from this effort.

2. The research projects provide the intellectual and scientific direction for the program. These projects should be product-oriented and include clear milestones and timelines for completion. A minimum of three research projects are required and one of those projects must include research on clinical specimens. Project leaders are expected to devote at least 20% of their effort to these projects.

3. A required Administrative Core oversees the organizational, budgeting and reporting aspects of the U54 Center. The Administrative Core should provide the infrastructure to promote cross-discipline interactions among all projects and cores and should support product development to facilitate translation of knowledge, resources and tools to the overall goals of the Genes and Environment Initiative. An external advisory board is not required. No funds can be used to support an external advisory board.

4. Facility Cores are principally designed as a service or resource component to the research projects within the Center. Cores serve to enhance or make more cost-effective the services, techniques or instrumentation used by the center. A proposed facility core must support at least two research projects if resources are not available through other institutional infrastructure such as P30 Core Centers or Clinical and Translational Service Award Centers. The number of facility cores can not exceed the total number of research projects and facility cores are not a requirement of this FOA. Applicants must include a discussion of the cost saving and other efficiencies provided by the inclusion of such core facilities. Facility cores are not required for this FOA.

Application Information Meeting

NIH staff will conduct an Application Information Meeting and videoconference in Research Triangle Park, NC, on October 20, 2006. This meeting will allow potential applicants to discuss and clarify any issues related to this FOA with NIH staff. Detailed information about the meeting (e.g., time, location, videoconference information, etc.) will be available on the Exposure Biology website (http://www.gei.nih.gov/exposurebiology/index.asp). Whether you plan to attend or videoconference into the meeting, please register online at this website. Potential applicants are encouraged to submit their questions via email to Dr. Daniel Shaughnessy ([email protected]) in advance of the meeting.

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 U54 Specialized Centers Cooperative Agreement award mechanism.

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

This funding opportunity uses the 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 NIH U54 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 proposed project, with NIH staff being substantially involved as a partner with the Principal Investigator, as described under the Section VI. 2. Administrative Requirements, "Cooperative Agreement Terms and Conditions of Award".

2. Funds Available

The total amount of funding committed to this program is $18 million (total costs) over a 4-year period. NIH intends to commit approximately $4.5 million in FY2007 to fund 4 new grants in response to this FOA. An applicant may request a project period of up to 4 years and a budget for direct costs up to $825,000 dollars per year.

The anticipated start date is July 2007 and the program period will be from July 1, 2007 to June 30, 2011.

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. 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(s) if your organization has any of the following characteristics:

For-profit organizations
Non-profit organizations
Public or private institutions, such as universities, colleges, hospitals, and laboratories
Units of State government
Units of local government
Eligible agencies of the Federal government
Foreign Institutions
Domestic Institutions
Faith-based or community-based organizations

1.B. Eligible Individuals

Any individual with the skills, knowledge, and resources necessary to carry out the proposed research is invited to work with their institution to develop an application for support. Individuals from underrepresented racial and ethnic groups as well as individuals with disabilities are always encouraged to apply for NIH support.

2. Cost Sharing or Matching

No cost sharing is not required.

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

3. Other-Special Eligibility Criteria

In order to be considered for peer review and funding, the U54 Centers must have a minimum of three highly meritorious research projects, must include an Administrative Core, and can have one or more highly meritorious facility cores that meet the general description laid out in Section I, General Characteristics of a U54 Exposure Biology Center. The applicant must name a Center Director who commits a minimum of 10% to Center leadership and administration. At least one research project must include research involving human specimens.

Milestones

All applications must include a specific section labeled Milestones for each year. Milestones should be annual, well-described, quantitative, and scientifically justified and not simply a restatement of the specific aims. Rather, the milestones should offer a timeline and a pathway for the development of the proposed technology. These milestones will be used to judge the success of the proposed research on an individual-project basis. It is expected that the milestones will be adjusted annually at the award anniversary dates to incorporate the group's scientific accomplishments and progress and to reflect any recommendations of the Steering and Advisory Committees.

Meetings

The Exposure Biology Program investigators will be expected to attend Steering Committee meetings two times per year and participate in monthly conference calls to discuss their research progress. Funds to support travel of the key investigators to attend these meetings should be included in the application budget.

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 GrantsInfo, Telephone (301) 710-0267, Email: [email protected].

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

2. Content and Form of Application Submission

Applications 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.

Foreign Organizations

Several special provisions apply to applications submitted by foreign organizations:

Charge back of customs and import fees is not allowed.
Format: every effort should be made to comply with the format specifications, which are based upon a standard US paper size of 8.5" x 11."
Funds for up to 8% administrative costs (excluding equipment) can now be requested (http://grants.nih.gov/grants/guide/notice-files/NOT-OD-01-028.html)
Organizations must comply with federal/NIH policies on human subjects, animals, and biohazards.
Organizations must comply with Federal/NIH biosafety and biosecurity regulations. See Section VI.2., Administrative and National Policy Requirements.
Applications from foreign (non-U.S.) institutions submitted using the PHS 398: Follow the NON-MODULAR FORMAT instructions and submit Form Page 4 and Form Page 5. Do not complete or submit the Modular Budget Format Page.

Proposed research should provide special opportunities for furthering research programs through the use of unusual talent, resources, populations, or environmental conditions in other countries that are not readily available in the United States or that augment existing U.S. resources.

3. Submission Dates and Times

See Section IV.3.A for details.

3.A. Receipt, Review and Anticipated Start Dates
Letters of Intent Receipt Dates: November 22, 2006
Application Receipt Dates: December 22, 2006
Peer Review Dates: March 2007
Council Review Dates: May 2007
Earliest Anticipated Start Dates: July 2007

3.A.1. Letter of Intent

Prospective applicants are 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 in Section IV.3.A.

The letter of intent should be sent to:

Linda K. Bass, PhD
Division of Extramural Research and Training
National Institute of Environmental Health Sciences
79 T.W. Alexander Drive
Building 4401, 3d Floor, Room 3172
Research Triangle Park, NC 27709
Telephone: (919) 541-1307
Fax: (919) 541-2503
Email: [email protected]

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:

Linda K. Bass, PhD
Division of Extramural Research and Training
National Institute of Environmental Health Sciences
79 T.W. Alexander Drive
Building 4401, 3d Floor, Room 3172
Research Triangle Park, NC 27709
Telephone: (919) 541-1307
Fax: (919) 541-2503
Email: [email protected]

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 NIH. Incomplete and non-responsive applications will not be reviewed. If the application is not responsive to the FOA, NIH staff may contact the applicant to determine whether to return the application to the applicant or submit it for review in competition with unsolicited applications at the next appropriate NIH review cycle.

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. However, when a previously unfunded application, originally submitted as an investigator-initiated application, is to be submitted in response to a funding opportunity, it is to be prepared as a NEW application. That is, the application for the funding opportunity must not include an Introduction describing the changes and improvements made, and the text must not be marked to indicate the changes from the previous unfunded version of the 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 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 award.

The incurrence of pre-award costs in anticipation of a 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

Guidance for Applicants Submitting a U54 Center Grant

Applicants should use the following guidance, in addition to the instructions accompanying the PHS 398 form. The U54 Center grant proposal consists of three general sections of information:

Section I. This section includes PHS 398 Form Pages 1-3, PHS 398 Form Page 4 - Detailed Composite Budget for the First 12-month Period Description and Form Page 5 Composite Budget for All Years, All Projects as well as the corresponding budgets for each individual project and core supported by the U54 Center application. In addition, a table that indicates the percentage use of each facility core relative to the individual projects should be included to assist the reviewers in determining the relationship between Facility Cores and Research Projects. Biographical Sketches should be provided for all KEY investigators using the PHS 398 Biographical Sketch Format Page. List the Center Director first followed by all other key personnel in alphabetical order. Use duplicate copies of the Biographical Sketch Format page for each investigator. Include only one copy of each biosketch in the application. Lastly, Section I should include Institutional Environment and Resources using the PHS 398 Resources Format Page. Include a brief description of the environment where the overall program and other activities will be conducted. If more than one campus or location will be involved, briefly describe each setting. If unique resources are available, briefly describe these and their relevance to the proposed program.

Section II. This section is unique to the U54 application. The information covered in this section for the most part, is not covered in the PHS 398. The page limit for this section is 15 pages. This Section includes:

Program Introduction and Statement of Objectives

Describe the major theme of the Center, its goals and objectives, background information and the overall importance of the research to the Genes and Environment Initiative on Exposure Biology. A successful U54 Center grant application will include a well-integrated research plan that clearly shows development, confirmation and application of innovative biomarkers and biosensors of response to environmental exposures and stressors in key pathways and a plan for product development relevant to those areas of research. The program should be viewed as a group of interrelated research projects, each of which is not only individually scientifically meritorious but is also complementary to the other projects, and related to the overall theme developed for the Center.

Describe the rationale for the total proposed program. Explain the strategy for achieving the goals defined for the overall program and how each research project and core relates to that strategy. Describe milestones for the Center and a timeline for achieving them in each sub-project. Describe in general terms the plans to ensure that the findings of the research efforts can be applied to human studies of gene and environment interaction like those being carried out in the Genes and Environment Initiative.

Explain how different components of the organization, including key personnel, will interact, why they are essential to accomplishing the overall goal of the research, and how combined resources create capabilities that are more than the sum of the parts. Very clear evidence that the key personnel will collaborate effectively must be presented in the application.

Organizational and Administrative Structure

Describe in detail and by diagram, if appropriate, the organizational structure of the program including an administrative and management plan that achieve an integrated, coordinated product-oriented multidisciplinary research program. A diagram may be useful in demonstrating the interactions between the different program units.

Describe the role of the Director, who is the Principal Investigator for U54 Center, and the investigators responsible for the subprojects; the leaders of the individual projects are referred to as project leaders.

Section III - V. These sections contain the research plans of the individual research projects, facility cores, and administrative core.

General Instructions for all Projects and Cores

All Projects and Cores

For the title page of individual projects/cores use the PHS 398 Continuation Page and clearly denote the project/core number, the title of the project/core, and the project/core leader. The title must not exceed 56 characters/spaces. DO NOT provide a face page (i.e., PHS 398 Form Page 1) for individual projects.

The "Description" of the project/core should be prepared on a duplicate copy of PHS 398 Form Page 2. All performance sites and key personnel on the project/core should be identified.

The name of the Principal Investigator of the U54 grant application is placed in the upper right corner of each page, not the name of the project/core leader. Also note: individual projects and cores must not exceed the 25-page limitation for items a - d of the Research Plan (follow PHS 398 instructions).

Subsequent pages (following the Description, Performance, and Key Personnel, Form Page 2) should use Continuation Pages and follow PHS 398 Instructions. If collaborative or consortium arrangements are included in the application, follow PHS 398 Instructions. Discussion should be included as to how the collaborative arrangements will be of value in achieving the specific objectives of the project.

The following information should NOT be included in the individual projects or cores. They should be included only in Section I of the application. "Face Page"(Form Page 1); "Research Grants Table of Contents" (Form Page 3); "Detailed Budget for Initial Cost Period" (Form Page 4); "Budget for Entire Proposed Period of Support" (Form Page 5); "Biographical Sketch Format Page"

Include Letters of Commitment and collaborative arrangements/consultants (Research Plan item h ) that are identified in the application.

Include "Resources Format Page" within the individual Research Projects and Core sections. Include at the end of the Research Plan (a-i).

Applicants should carefully read and adhere to the PHS 398 instructions concerning children, gender and minority inclusion in human study populations.

Appendix material is not a part of the application and should not be used to circumvent the page limitations of the Research Plan . See PHS 398 Instructions for list of appropriate Appendix Material. Please submit five collated copies of appendix material to Dr. Linda Bass, SRA, as listed in "B. Submission Instructions" of these guidelines. Appendix materials should be collated by Research Project and Core, and presented in the same order that they appear in the application. Do not staple or bind Appendix materials. The Appendix material should follow all copies of the application.

Section III Individual Research Projects.

Follow the instructions in the PHS 398 for the Research Plan (a-i) for describing each research project. Each project should clearly state its overall objective and explain its relevance to the central theme of the Center. In addition, an explanation should be included describing how the project relates to and both complements and enhances the other research projects and cores of the program. Specify the overall biomedical significance of the work proposed.

The research plan (a-d; 25 page limit per project) includes:

Specific Aims List the specific aims of the research project and indicate the priority of each aim in the overall research plan.

Background and Significance Review the most significant previous work and describe the current status of research in this field and document with complete references.

Preliminary Studies Refer to PHS 398 Instructions for Preliminary Studies Research Design and Methods - Give details of the research plan, including a description of the experiment or other work proposed; present the methods and techniques to be used; note the limitations, if any, of the procedures proposed. Describe the experiments in the sequence in which they would be conducted. (It is important to convey to the reader that the proposed effort would require the time requested for the project period.)

The instructions in the PHS 398 form should be used to complete sections e-i for the individual research projects.

Section IV Facility Cores

Follow the instructions in the PHS 398 Research Plan (a-i) as is appropriate for describing a Facility Core. A facility core is defined as a resource for the U54 Center that provides centralized services to two or more research projects. Information that should be included is as follows:

Describe the function of the core as a resource to the program. This section must clearly present the facilities, techniques, and professional skills that the core will provide. As justification for the core, briefly indicate the specific Research Projects that will use the resources of the core. A Facility Core is principally designed as a service or resource component; it would be highly unusual to include research in a core (a possible exception would be methodology development). Please contact the Institute staff if you require guidance on this issue.

Describe the role of the core as a resource to the program as a whole. Discuss ways in which these centralized services will produce an economy of effort and/or savings in overall costs compared to their inclusion as part of each project in the program. To aid in the review of your application it is recommended that you prepare in tabular form information concerning the research projects that each facility core unit would serve and the proportion of the cost of the facility core unit associated with each research project involved.

Note: An Applicant is not required to include facility cores in their Center. If facility cores are not proposed as part of the Center, the applicant must provide strong justification including a discussion of available resources (such as P30 core centers, GCRCs, CTSAs, etc.) which will be utilized to support the proposed research effort. The page limit for this section is 15 pages.

Section V Administrative Core

Follow the instructions in the PHS 398 Research Plan (a-i) as is appropriate for describing the Administrative Core.

A successful U54 application will include a well-integrated project plan. Within the Administrative Core, the specific administrative and organizational structure that is needed to support the research and the synergies enabled by the Center needs to be clearly articulated. U54 projects will be multidisciplinary and will draw from a variety of resources. Thus, a well thought out and carefully described organizational structure will be required.

A narrative description should be provided that includes the planning and coordination of research activities; the integration of cross-disciplinary research; the oversight of fiscal and resource management; and the maintenance of ongoing communication. Indicate who will be responsible for each of these activities.

The process for identifying product development/technology transfer projects should be fully described. Additional funds to support these activities may be available in years 3-5 and should not be included in the initial proposal. Projects are intended to result in products, tools, and or resources (for example biomarker panels or biosensors, or technology that support the identification of specific response signatures) that are directly applicable to improving exposure characterization in human populations. The page limit for this section is 15 pages.

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.

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 may 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.

Sharing Research Resources

NIH policy requires that grant awardee 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.

The NIH will support the research and technology needed to accelerate the development and commercialization of exposure assessment devices and technologies that support them in order to characterize the response to environmental stressors.

Applicants are expected to include a plan addressing how they will exercise their intellectual property rights, while making such research resources available within and across the Gene Environment Initiative (GEI) programs, and to the broader scientific community for research purposes consistent with the goals of the GEI. A reasonable time frame for release of materials should be specified in the data sharing plan and will be considered by program staff. Furthermore, transfers of research resources must be made consistent with the NIH Research Tools Policy (http://www.ott.nih.gov/policy/rt_guide_final.html) and other NIH sharing policies. In the development of any sharing and intellectual property plans, applicants should confer with their own institution's office(s) responsible for handling technology transfer related matters and/or their sponsored research office. If applicants or their representatives require additional guidance in preparing these plans, they are encouraged to make further inquiries to the appropriate contacts listed below for such matters.

Program staff, in determining whether the application shall be awarded, will consider the adequacy of the proposed plans. The plans as approved after negotiation with the applicant when necessary will be part of the terms and conditions of the award. Evaluation of progress reports (PHS 2590) will include assessment of the awardee's adherence to the proposed plans, and will be a criterion for continued funding of the award.

Applicants also are reminded that the grantee institution is required to disclose each subject invention within 2 months after the inventor discloses it in writing to grantee institutional personnel responsible for patent matters. The lead institute reserves the right to monitor awardee activity in this area to ascertain if patents or patent applications are adversely affecting the goals of this FOA.

Public Domain of Data

All awards made under this FOA are subject to the Final NIH Statement on Sharing Research Data (http://grants.nih.gov/grants/guide/notice-files/NOT-OD-03-032.html) and the Principles and Guidelines for Recipients of NIH Research Grants and Contracts on Obtaining and Disseminating Biomedical Research Resources (http://www.ott.nih.gov/policy/rt_guide_final.html). This document also defines terms, parties, responsibilities, prescribes the order of disposition of rights, prescribes a chronology of reporting requirements, and delineates the basis for and extent of government actions to retain rights. Patent rights clauses may be found at 37 CFR Part 401.14 and are accessible from the Interagency Edison web page, http://www.iedison.gov. It is expected that research resources generated through the award will be shared by awardees according to these guidelines. The plans for the development of resources for use by the biomedical community will have the appropriate timelines and milestones. Program staff will evaluate the compliance with the sharing plan and scientific progress in the non-competing progress report (Form 2590); such compliance will be a criterion for continued funding of the award.

The GEI Exposure Biology Program expects that all data relating to the identification of biomarkers of response resulting from this program will be released in appropriate publicly accessible data repositories.

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

Applications that are complete and responsive to the FOA will be evaluated for scientific and technical merit by an appropriate peer review group convened by NIEHS in accordance with the review criteria stated below.

As part of the initial merit review, all applications will:

Undergo a selection process in which only those applications deemed to have the highest scientific merit, generally the top half of applications under review, will be discussed and assigned a priority score.
Receive a written critique.
Receive a second level of review by the National Advisory Environmental Health Sciences Council.

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 research 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 for each application. 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.

Evaluation of the Overall Program

The overall application is evaluated by considering the integrative research projects, supporting cores, and the administrative structure, and how these multi- disciplinary components function together to achieve the goals of the program. For the application to receive an overall priority score, it must consist of at least three approved integrative research projects, each of which has multiple specific aims and are found to have significant and substantial merit. Scientific relevance of the project should guide the overall merit of the project.

Specific scientific consideration factors to be evaluated in the consideration of the program are as follows:

Significance: Does this study address an important exposure measurement problem that, if addressed, will further the assessment of individual exposure to environmental stressors that have significant public health burden? If the aims of the application are achieved, how will scientific knowledge be advanced? What will be the effect of these studies on the concepts, methods, technologies, treatments, services, or preventative interventions that drive this field?

What is the scientific merit of the program as a whole, as well as that of the individual parts?
What is the significance of the overall program goals including; importance of the research program to further current knowledge of biomarkers of response to environmental stressors that have significant public health burden, and development of biosensors based on this new biomarker knowledge?

Approach: Are the conceptual framework, design, methods, and analyses adequately developed, well-integrated, and appropriate to the aims of the project? Does the approach employ a product-development framework? Has the applicant adequately described the measurement problem being addressed by the proposed technology and articulated appropriate and sufficient milestones and timelines?

Is there adequate cohesiveness and multidisciplinary scope such that coordination and interrelationships of all individual research projects and cores provide a common theme of the program overall?
What is the effectiveness of the program to translate information from non-human model systems to human specimens and to develop new methods and devices for measuring the biological response to an environmental stressor?
Are the milestones and timeframe realistic to achieve the research goals?

Innovation: Does the project employ new, existing, or emerging concepts, approaches, methods, or technologies in a novel way? Is the proposed technology likely to either be an improvement over existing methods or provide unique information?

Investigator: Is the investigator 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?

How appropriate are leadership and scientific ability of the Principal Investigator, his or her commitment and ability to develop a well-defined central research focus, and time and effort, to work within the parameters of the program initiatives?
Are the past accomplishments of the research team (Principal Investigator, Project and Core Leaders) consistent with the proposed areas of research?

Environment: Does the scientific environment in which the work will be done contribute to the probability of success? Do the proposed experiments take advantage of unique features of the scientific environment or employ useful collaborative arrangements? Is there evidence of institutional support?

Review Criteria- Integrative Research Projects

Review Criteria-Individual Technical Facility/Service Cores

Does each core provide essential facilities or services for two or more projects judged to have substantial merit (e.g., the number of projects that will benefit from centralized administrative and research services, the economy of effort that will be realized through use of shared services, etc.)?
Are the following elements of the facility cores including; quality or services provided (including procedures, techniques, and quality control), criteria for prioritization of usage, and qualifications/experience and commitment of the personnel involved in the core appropriate for the research projects?
How appropriate is the budget in conducting the project?

Review Criteria - Administrative Core

Are the environment and resources in which the research will be conducted, including availability of space, equipment, or other resources as required, and the potential for interaction with scientists from other departments appropriate?
Is there evidence of Institutional commitment to the program, including fiscal responsibility and management capability of the institution to assist the Principal Investigator and his or her staff in following DHHS, PHS, and NIH policy?
Is the Administrative planning and leadership in this core capable of providing adequate: internal quality control of ongoing research; research needs of the Center; allocation of funds; enhancement of internal communication and cooperation among Center investigators; and replacement of the Principal Investigator if required on an interim or permanent basis?

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:

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 awardee 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 (U54) Specialized Centers Cooperative Agreement, 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 reside 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.

This award is made in response to RFA-ES-06-012, Biological Response Indicators of Environmental Stress Centers (U54), which is one of five RFAs that define the scope of the Exposure Biology Program of the NIH-wide Genes and Environment Initiative (GEI); the Exposure Biology Program is led by the National Institute of Environmental Health Sciences (NIEHS).

2.A.1. Principal Investigator Rights and Responsibilities

The Principal Investigator will have the primary responsibility for defining the scope, specific aims and the details for the projects that will comprise the Center within the guidelines of this FOA and for performing the scientific activities. The Principal Investigator or Center Director will agree to accept close coordination, cooperation and management of the project as described under NIH Responsibilities. Specifically, the Center Director will:

Determine experimental approaches, design protocols, set program and project milestones and conduct experiments.
Participate in all group activities, including meetings of awardees.
Serve as a voting member of the GEI-Exposure Biological Response (EBR) Steering Committee, which is the governing board for the GEI-EBR Program, to meet the Program’s goals and timeline.
Not disclose confidential information obtained from other members of the project.
Adhere to NIH policies regarding intellectual property and other policies that might be established as part of this activity.
Submit periodic progress reports in a standard form, as agreed upon by the GEI-EBR Steering Committee.
Attend Steering Committee meetings and accept and implement the common guidelines and procedures approved by the GEI-EBR Steering Committee and NIH.
Consider opportunities for collaborations within the overall GEI-Exposure Biology Program when it will benefit the overall goals and enhance product development and implementation.

The Principal Investigator will retain custody of, and have primary rights to information developed under the cooperative agreement, subject to Government rights of access consistent with the current HHS, PHS, and NIH policies. Publication and copyright agreements and the requirements for financial status reports, retention of records, and terminal progress reports will be as stated in the NIH Grants Policy Statement.

2.A.2. NIH Responsibilities

An NIH Project Scientist will have substantial programmatic involvement that is above and beyond the normal stewardship role in awards, as described below.

An NIH Project Scientist will be assigned to each of the awarded U54 Centers. This staff member is a scientist from the staff of any of the participating NIH institutes who is selected because of relevant scientific content-area expertise and experience with regard to the scientific goals and objectives of a given U54 award. These staff members will have substantial scientific and programmatic involvement during the conduct of this activity through technical assistance, advice and coordination. However, the role of the NIH staff will be to facilitate and not to direct the activities. It is anticipated that decisions in all activities will be reached by consensus of the GEI-EBR Steering Committee and that NIH will be given the opportunity to offer input into this process. There will be no more than 5 NIH Project Scientists participating as members of the Steering Committee; however, there will be only one NIH vote, reached by consensus. The Project Scientists will have the following substantial involvement:

Participate with other GEI-EBR Steering Committee members in the group process of setting research priorities, setting and monitoring program milestones, and determining unique opportunities to enhance product development and implementation. The Project Scientists will assist and facilitate the group process not direct it.
Serve as a liaison, helping to coordinate activities among and for the awardees, including acting as a liaison to the NHGRI, and as an information resource about exposure biology research activities. The project scientist will also coordinate the effort of the GEI-EBR project with other groups conducting similar research.
Attend all GEI-EBR Steering Committee meetings and assist in developing operating guidelines, quality control procedures, and consistent policies for dealing with recurrent situations that require coordinated action. The Project Scientists should be informed of all major interactions of members of the GEI-EBR Steering Committee.
The NIH Project Scientists will be responsible to work with a lead coordinator to organize information to be brought before the NIH GEI-Exposure Biology Subcommittee and the NIH GEI Coordinating Committee as needed.
Report periodically on the progress of the U54 Center to the Director, NIEHS and to the National Environmental Health Sciences Advisory Council.
Serve on subcommittees of the GEI-EBR Steering Committee as appropriate.
Assist awardees in the development, if needed, of policies for dealing with situations that require coordinated action.
Provide advice in the management and technical performance of the investigation.
Assist in promoting the availability of the resultant products of the program to the scientific community at large
Participate in data analysis, interpretations and, where warranted, co-authorship of the publication of results of research conducted in this Center.

Additionally, a Center Director will be responsible for the normal scientific and programmatic stewardship of the award and will be named in the Notice of Grant Award. The Center Director will closely monitor progress of assigned grants and recommend the withholding or reduction of support from any project that fails to achieve its goals or comply with the Terms and Conditions of award. The Center Director may also serve as one of the Project Scientists.

2.A.3. Collaborative Responsibilities

All involved investigators will meet two times a year in order to share information. Key co-investigators and pre- and postdoctoral trainees, in addition to the Principal Investigators, are eligible to attend these meetings. Close interaction among the participating investigators will be required, as well as significant involvement from the NIH to develop and monitor program milestones and timelines for research and product development, small-scale field testing, and functional validation in order to meet the overall goals of the Genes and Environment Initiative.

The GEI-EBR Steering Committee will serve as the governing board for the Cooperative Agreements made in response to this FOA and the companion RFA-ES-06-013 for U01 awards. Membership will consist of the Principal Investigator and another investigator from each U54 award, the Principal Investigator from each U01 award, and the NIH Project Scientists. The chair of the Steering Committee will be selected by vote. Center Directors or other extramural members of the Steering Committee are eligible to become the chair of the Steering Committee. Each of the NIH Project Scientists assigned to a cluster of awards (U54 and U01s in the content area) will also be a member of the Steering Committee. It is anticipated that there will be no more than 5 NIH staff on the Steering Committee; if more are assigned to the awards, then membership will be rotated. There will be only one NIH vote, reached by consensus.

The GEI-EBR Steering Committee will meet face to face two times a year and monthly on conference calls. The roles and responsibilities of the Steering Committee include:

As governing board, developing common policies, guidelines and procedures for the GEI-Exposure Biological Response (EBR) Program
Defining and monitoring milestones for the overall Exposure Biology Response program (U54 and U01s) and setting annual goals for the program.
Identifying unique opportunities and providing recommendations to the NIEHS Director when collaborations, expediting a timeline, or additional supplement support, would substantially push forward products that are in the pipeline in the research laboratories.
Setting procedures and guidelines for program operations such as publication of research findings, data sharing, or distribution of unique resources emanating from the Centers.
Creating subcommittees as needed that include other Project Scientists not members of the Steering Committee.
Provide liaison with the NIH GEI Exposure Biology Subcommittee as needed to provide summaries of progress and other pertinent information.

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. It will have three members: 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.

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:

Daniel Shaughnessy, PhD
Division of Extramural Research And Training
National Institute of Environmental Health Sciences
P. O. Box 12233
Research Triangle Park, NC 27709
Telephone: (919) 541-2506
Fax: (919) 316-4606
Email: [email protected]

2. Peer Review Contacts:

Linda K. Bass, PhD
Division of Extramural Research and Training
National Institute of Environmental Health Sciences
79 T. W. Alexander Drive
Building 4401, 3d Floor, Room 3172
Research Triangle Park, NC 27709
Telephone: (919) 541-1307
Fax: (919) 541-2503
Email: [email protected]

3. Financial or Grants Management Contacts:

Lerlita Garcia
Division of Extramural Research and Training
National Institute of Environmental Health Sciences
PO Box 12233
Research Triangle Park, NC 27709
Telephone: (919) 316-4638
Fax: (919) 541-2843
Email: [email protected]

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 in response to this FOA regardless of cost, 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 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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NIH Funding Opportunities and Notices