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 Heart, Lung, and Blood Institute (NHLBI), (http://www.nhlbi.nih.gov)

Title: NHLBI Exploratory Program in Systems Biology (R33)

Announcement Type
This is a reissue of RFA-HL-06-004 which was previously released November 18, 2005.

NOTICE: Applications submitted in response to this Funding Opportunity Announcement (FOA) for Federal assistance must be submitted electronically through Grants.gov (http://www.grants.gov) using the SF424 Research and Related (R&R) forms and SF424 (R&R) Application Guide.

APPLICATIONS MAY NOT BE SUBMITTED IN PAPER FORMAT.

This FOA must be read in conjunction with the application guidelines included with this announcement in Grants.gov/Apply for Grants (hereafter called Grants.gov/Apply).

A registration process is necessary before submission and applicants are highly encouraged to start the process at least four weeks prior to the grant submission date. See Section IV.

Request For Applications (RFA) Number: RFA-HL-07-005

Catalog of Federal Domestic Assistance Number(s)
93.837, 93.838, 93.839, 93.233

Key Dates
Release/Posted Date: June 5, 2006
Opening Date: July 24, 2006 (Earliest date an application may be submitted to Grants.gov)
Letters of Intent Receipt Date(s): August 24, 2006, and August 24, 2007
NOTE: On time submission requires that applications be successfully submitted to Grants.gov no later than 5:00 p.m. local time (of the applicant institution/organization).
Application Receipt Date(s): September 25, 2006, and September 25, 2007
Peer Review Date(s): January February 2007, January February 2008
Council Review Date(s): June 2007, June 2008
Earliest Anticipated Start Date(s): July 2007, July 2008
Additional Information To Be Available Date (Url Activation Date): http://www.nhlbi.nih.gov/funding/inits/sysbio-faq.htm
Expiration Date: September 26, 2007

Due Dates for E.O. 12372
Not Applicable

Additional Overview Content

Executive Summary

• The National Heart, Lung, and Blood Institute (NHLBI) invites applications for collaborative research projects to initiate high-risk, high impact research by multidisciplinary teams of investigators. These projects will combine computational modeling and simulation approaches with experimental validation of model predictions to advance understanding the normal physiology and perturbations associated with heart, lung, blood, and sleep (HLBS) disorders.
• Applications must comprise of a cluster of two or more applications, with a minimum of one application for a computational/modeling component and one application for a biomedical/experimental component of the cluster. Please see Section IV., heading 6. Other Submission Requirements for Specific Instructions for Preparing a Cluster of R33 Award Applications
• Project Period and Award Levels: The NHLBI intends to award up to $2.7 million in FY2007 and FY 2008 to fund three new cluster grants in each year in response to this FOA. Clusters may request a project period of up to three years and a budget for direct costs for the entire cluster of up to $600,000 in each year.
• The total amount awarded will be $16.2 million over 4 years for six clusters.
• This FOA will use the NIH Exploratory/Development Research Grant Phase II (R33) award mechanism.
• An individual may submit only one application as the Project Director/Principal Investigator (PD/PI) for any receipt date. Once funded as a PD/PI by this FOA, an individual is then ineligible to submit another application as a PD/PI.
• Eligible organizations: Domestic, foreign, for profit and non-profit, public and private institutions such as universities, colleges, hospitals, laboratories, faith-based or community-based organizations, units of state/local government; eligible agencies of the federal government, Indian/Native American Tribal government (Federally recognized); Indian/Native American Tribal government (other than Federally recognized); and Indian/Native American Tribally Designated Organization.
• Eligible Project Directors/Principal Investigators (PD/PIs): Any individual with the skills, knowledge, 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.
• Multidisciplinary teams of investigators are required for this FOA.
• See Section IV.1 for application materials. The SF424 (R&R) Application Guide for this FOA is located at these Web sites:
  • http://grants1.nih.gov/grants/funding/424/SF424_RR_Guide_General_Ver2.doc (MS Word)
  • http://grants1.nih.gov/grants/funding/424/SF424_RR_Guide_General_Ver2.pdf (PDF)
• For general information on SF424 (R&R) Application and Electronic Submission, see these the following Web sites:
• SF424 (R&R) Application and Electronic Submission Information: http://grants.nih.gov/grants/funding/424/index.htm
• General information on Electronic Submission of Grant Applications: http://era.nih.gov/ElectronicReceipt/
• 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 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. Request Application Information
2. Content and Form of Application Submission
3. Submission Dates and Times
A. Submission, Review and Anticipated Start Dates
1. Letter of Intent
B. Submitting an Application Electronically 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
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

Purpose

The purpose of this Funding Opportunity Announcement (FOA) is to apply Systems Biology approaches to innovative, high-risk, high-impact research on heart, lung, blood, and sleep (HLBS) physiology and pathophysiology by multidisciplinary teams of investigators. For the purposes of this FOA, systems biology is defined as an approach to explaining and predicting complex cellular and physiological phenomena of living organisms in terms of underlying physical and chemical processes and accompanying feedback regulations at molecular, cellular, tissue, or whole organ levels. This systems biology approach will combine mathematical modeling and simulation to complement the traditional empirical and experimental approach of biomedical research. Mathematical modeling and simulation may range from the molecular scale through to organ scale models. These models and simulations will be driven by empirical observations and will generate specific, explicitly testable predictions that will enable refinement of the models in response to experimental validation. This iterative development of models and experiments is a critical feature of the systems biology research supported by this FOA.

This FOA will support projects that integrate multi-investigator, multidisciplinary approaches and have a high degree of interplay between computational and experimental approaches. Collaborative, multidisciplinary teams supported by this FOA may include researchers from such fields as biomedical, physical, informatic, and mathematical disciplines. Applications responsive to this FOA shall comprise a cluster of two or more applications, with a minimum of one application for a computational/modeling component and one application for a biomedical/experimental component of the cluster. Clustered applications which do not include both predictive computational models and biomedical experiments to validate models and test predictions will be deemed non-responsive and will not be reviewed.

Background

The maintenance of healthy physiology and function involves many cells, tissues, and organs operating together in distinct patterns and intricate interactions. Complex diseases, such as atherosclerosis, thrombosis, stroke, hypertension, heart failure, asthma, and sleep disordered breathing, result from multiple perturbations in the systems and pathways that are required for optimal function. The NHLBI has made a significant investment towards understanding the components of biological systems underlying heart, lung, blood, and sleep disorders through support of programs that exploit cutting-edge technologies, such as genotyping, genomics, and proteomics. However, knowledge of the components of a system (such as gene polymorphisms, gene and protein expression patterns, metabolites, signaling cascades, post-translational modifications, etc.) provides limited insight into the behavior, interaction, and function of complex systems. Thus, predicting the normal and disease responses of complex physiological processes, such as heart rhythm, vascular flow and remodeling, or respiration, remains a considerable challenge.

In order to significantly advance our understanding of the function of such complex phenomena, it is necessary to integrate different types of data and use quantitative models to predict behavior and outcomes. The systems biology approach uses both experimental data and computational models to understand complex phenomena and systems underlying HLBS function and to predict outcomes to specific perturbations. The rapid growth in biological databases, models of cells, tissues, and organs, and the development of powerful computing hardware and algorithms now make it possible to apply quantitative analyses spanning from the level scales from genes and molecules to the physiological function of whole organs and regulatory systems. Applications for multiscale modeling that directly and explicitly address how to link multiple scales (two or more scales from the molecular to organ levels) within a model are strongly encouraged.

Some examples of research topics for investigation may include, but are not limited to:

• Networks involved in regulating oxygen delivery, including regulation of hemoglobin levels though control of red cell production, changes in vascular tone, and regulation of distribution of blood flow in different vasculatures.
• Perturbations in vascular endothelial function (e.g., oxidative stress and inflammatory mechanisms) that contribute to atherosclerosis, systemic and pulmonary hypertension, thrombosis, and coronary artery and pulmonary diseases.
• Pivotal control points in the organization of pulmonary immunological pathways and tissue repair mechanisms associated with asthma, chronic pulmonary disease, pulmonary fibrosis or pulmonary infections (including tuberculosis) to predict outcomes of perturbations, such as intermittent hypoxia, antigen exposure, and therapeutic agents.
• Electrical and structural simulations of the heart, including expression of ion channel genes, that predict occurrence of arrhythmias and responses to potential treatments.
• Networks of hematopoietic stem cell commitment in determining different definitive lineages (e.g., blood cell production; red cells, neutrophils, and platelets).
• Studies integrating the effects of blood pressure and regulation of ion transport throughout the nephron, including networks of gene regulation and genetic polymorphisms that result in gain-of-function and loss-of-function transport phenotypes.
• Studies on mechanisms by which the autonomic nervous system orchestrates long-term control of blood pressure and modulates the selective activation of specific vascular beds.
• Regulatory elements that predict therapeutic response to pharmacological perturbations in diseases such as sickle cell, hemophilia, Fanconi anemia, arrhythmia, hypertension, or atherosclerosis.
• The role of inflammation in the development of pulmonary, thrombotic, and cardiovascular diseases and responses to pharmacological intervention, targeting NSAID therapy.
• The role of the biological clock as a system-wide control point and develop simulations predicting the functional effects of circadian disturbances, such as genetically-based sleep phase disorders or sleep deprivation, on interlinked subsystems influencing heart, lung, and blood function.
• Studies on dynamic fluid phase coagulation networks and interactions.

Applicants should consider research areas within HLBS in which systems approaches are likely to make significant contributions. Applications must provide a balance of computational/modeling and biomedical/experimental approaches. As this FOA aims to improve understanding of physiology and pathophysiology underlying cardiovascular, lung, blood, and sleep function, the main thrust of applications must be to understand the functioning of these tissues and organs in mammalian model systems. Studies of sleep and circadian regulation must be coupled to the pathophysiology of heart, lung, and blood disorders or risk factors for these disorders. Models that incorporate clinical variables into quantitative and predictive computational models are welcome. Applications using cell culture for experimental validation of model predictions are limited to primary cell cultures.

Some examples of applications which would be considered non-responsive to this FOA are:

• Applications exclusively based on non-mammalian model systems
• Applications whose experimental component is entirely based on immortalized cell lines.
• Applications that lack iterative development of computational models and biomedical experiments, such as those that only include in silico modeling and lack experimental/ biomedical component to validate and further refine the model.
• Applications whose mathematical component is limited to statistical analyses of data rather than quantifying underlying physical and chemical processes and accompanying feedback regulations at molecular, cellular, tissue, or whole organ levels.
• Projects that propose only incremental advancements in current knowledge may be deemed unresponsive to the solicitation, as this solicitation seeks innovative, high-risk, high-impact research in the HLBS area.
• Applications focusing on integrative physiology of HLBS diseases or disorders without including a predictive, computational model of underlying processes.
• Applications that propose high-throughput approaches to generate data sets but do not incorporate data into a predictive computational model of underlying processes.
• Applications with the goal of continuing high-throughput genomic and proteomic facilities, large clinical studies, or the establishment of epidemiological cohorts that collect data for future studies are not within the scope of this program.
• Applications on infectious or inflammatory agents whose main research thrust is not on the organ or tissue response.
• The elucidation of environmental factors producing sleep abnormalities such as shift work, time zone changes, cultural and socioeconomic factors will not be supported under this FOA. Studies limited to sources of excessive daytime sleepiness, alcohol abuse, pain syndromes, cancer, mental disorders, and the relationship of sleep to behavioral endpoints such as workplace performance would also be unresponsive to this FOA.

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

This program will use the exploratory and developmental R33 mechanism, which is not renewable

To foster new collaborations and facilitate partnerships among different disciplines, programs will comprise clustered grant applications. Within each cluster, a lead PD/PI must be identified who will be the point of contact and will represent the cluster of applications to NHLBI staff. PD/PIs of other application(s) in the cluster will be collaborating PD/PIs. A minimum of 25% effort is required for the lead PD/PI, and a minimum 20% effort is required for the PD/PIs of the collaborating grants in the cluster.

The cluster of applications must clearly describe the management of the collaborative research. To ensure this, they must include a management plan and identify a scientific steering committee. The management plan will:

• Outline plans and mechanisms to keep the project focused and progressing.
• Set intermediate milestones on a timeline to allow for the evaluation of progress towards the project's goal.
• Explain how collaborators can be added or removed as the expertise, knowledge, and skills necessary to advance the project change.
• Describe how intellectual property issues will be handled.

Each cluster of applications must identify a scientific steering committee, consisting of those individuals identified in the management plan, who together would have the intellectual and leadership responsibilities for the collaborative research project normally attributed to the PD/PI. At a minimum, the steering committee must have a representative from each collaborating application in the cluster. Funds should be budgeted for administrative oversight by the scientific steering committee and activities noted in the management plan.

The NHLBI expects to convene annual meetings of the awardees of the Systems Biology Exploratory Programs to discuss progress on each project and to exchange information among the different projects. Travel funds should be budgeted for this purpose. NHLBI will evaluate the progress of this program in assembling multidisciplinary collaborative teams, their success at building predictive models and in combining both quantitative and experimental approaches. Based upon this assessment, NHLBI will explore funding opportunities to further systems biology analysis of complex heart, lung, blood, and sleep diseases and disorders.

Plans to share research data, software, and unique research resources must be addressed in the application.

Section II. Award Information

1. Mechanism of Support

This funding opportunity will use the NIH Exploratory/Development Research Grant Phase II (R33) award mechanism. The total requested project period for an application submitted in response to this may not exceed three years. The R33 mechanism is intended to encourage highly innovative and potentially risky exploratory and developmental research for which feasibility has been demonstrated and thus are ready for extended development. An R33 is not renewable.

Only one resubmission (amended) application will be accepted for HL-07-005. If an application has been submitted for HL-06-004, then only one resubmission will be allowed for HL-07-005 for either the September 25, 2006 or the September 25, 2007 receipt dates. If an application is initially submitted for the September 25, 2006 receipt, then a resubmission (amended) application will be accepted for the September 25, 2007 receipt date.

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. Use the SF424 (R&R) Budget Component described in the SF424 (R&R) Application Package and Instructions Guide.

2. Funds Available

The NHLBI plans to commit $16.2 million over 4 years. For FYs 2007 and 2008, NHLBI intends to commit approximately $2.7 million each year to fund a total of six clusters (three each year) of new grants in response to this FOA.

• NHLBI anticipates funding up to 6 clusters of awards: up to three clusters will be awarded in FY2007 and up to three in FY2008.
• Applicants may request up to $600,000 in direct costs per cluster in each year; this total excludes F&A costs of consortium subcontracts.
• The length of the award will not exceed three years.
• The earliest anticipated start dates for each annual competition are July 1, 2007, and July 1, 2008.

The NHLBI intends to commit approximately 2,700,000 dollars in FY 2007 and 2,700,000 dollars in FY 2008 to fund six clusters of new grants in response to this FOA.

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 (F&A) 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
• Indian/Native American Tribal government (Federally recognized)
• Indian/Native American Tribal government (other than Federally recognized)
• Indian/Native American Tribally Designated Organization

1.B. Eligible Individuals

Any individual with the skills, knowledge, and resources necessary to carry out the proposed research as the Project Director/Principal Investigator (PD/PI) 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.

This initiative is not part of the Multiple Principal Investigator policy (http://grants2.nih.gov/grants/guide/notice-files/NOT-OD-06-036.html). Each component application in a cluster submitted in response to this FOA (HL-07-005) will have only one PD/PI.

2. Cost Sharing or Matching

This program does not require cost sharing as defined in the current NIH Grants Policy Statement.

3. Other-Special Eligibility Criteria

For each receipt date, an applicant may submit only one application as a Project Director/Principal Investigator (PD/PI) in response to this FOA. If funded as a PD/PI by this FOA, a person is ineligible from applying again as a principal investigator. An institution or organization may submit more than one application in response to this FOA.

Responsiveness Criteria: This solicitation is not intended to support projects that would result in routine or incremental progress. NHLBI understands and accepts that applications that are responsive to this solicitation will be much riskier than most applications. Applications responsive to this FOA must comprise of a cluster of two or more applications of two or more applications, with a minimum of one application for a computational/modeling component and one application for a biomedical/experimental component of the cluster. As this FOA aims to improve understanding of physiology and pathophysiology underlying cardiovascular, lung, blood, and sleep function, the main thrust of applications must be to understand the functioning of these tissues and organs in mammalian model systems. Applications exclusively using non-mammalian models will be non-responsive. Applications whose experimental component is entirely based on immortalized cell lines will be deemed non-responsive.

Annual Grantee Meeting: Upon initiation of the program, the NHBLI will arrange annual meetings to encourage the exchange of information among the investigators who participate in this program. In the preparation of the budget for the grant application, applicants should include travel funds for one meeting each year to be held in or near Bethesda, MD, for the principal investigators and key collaborators. At these meetings awardees will be expected to share their results and to help evaluate the progress of the Centers. Attendance at these meetings is required.

Section IV. Application and Submission Information

To download a SF424 (R&R) Application Package and SF424 (R&R) Application Guide for completing the SF424 (R&R) forms for this FOA, link to http://www.grants.gov/Apply/ and follow the directions provided on that Web site.

A one-time registration is required for institutions/organizations at both:

• Grants.gov (http://www.grants.gov/GetStarted) and
• eRA Commons (http://era.nih.gov/ElectronicReceipt/preparing.htm)

PD/PIs should work with their institutions/organizations to make sure they are registered in the eRA Commons.

Several additional separate actions are required before an applicant institution/organization can submit an electronic application, as follows:

1) Organizational/Institutional Registration in Grants.gov/Get Started

• Your organization will need to obtain a Data Universal Number System (DUNS) number and register with the Central Contractor Registration (CCR) as part of the Grants.gov registration process.
• If your organization does not have a Taxpayer Identification Number (TIN) or Employer Identification Number (EIN), allow for extra time. A valid TIN or EIN is necessary for CCR registration.
• The CCR also validates the EIN against Internal Revenue Service records, a step that will take an additional one to two business days.
• Direct questions regarding Grants.gov registration to:
  Grants.gov Customer Support
  Contact Center Phone: 800-518-4726
  Business Hours: M-F 7:00 a.m. - 9:00 p.m. Eastern Time
  Email [email protected]

2) Organizational/Institutional Registration in the eRA Commons

• To find out if an organization is already Commons-registered, see the "List of Grantee Organizations Registered in NIH eRA Commons.
• Direct questions regarding the Commons registration to:
  eRA Commons Help Desk
  Phone: 301-402-7469 or 866-504-9552 (Toll Free)
  TTY: 301-451-5939
  Business hours M-F 7:00 a.m. 8:00 p.m. Eastern Time
  Email [email protected]

3) Project Director/Principal Investigator (PD/PI) Registration in the NIH eRA Commons: Refer to the NIH eRA Commons System (COM) Users Guide.

• The individual designated as the PD/PI on the application must also be registered in the NIH eRA Commons. It is not necessary for PDs/PIs to register with Grants.gov.
• The PD/PI must hold a PD/PI account in the Commons and must be affiliated with the applicant organization. This account cannot have any other role attached to it other than the PD/PI.
• This registration/affiliation must be done by the Authorized Organization Representative/Signing Official (AOR/SO) or their designee who is already registered in the Commons.
• Both the PD/PI and AOR/SO need separate accounts in the NIH eRA Commons since both are authorized to view the application image.

Note that if a PD/PI is also an NIH peer-reviewer with an Individual DUNS and CCR registration, that particular DUNS number and CCR registration are for the individual reviewer only. These are different than any DUNS number and CCR registration used by an applicant organization. Individual DUNS and CCR registration should be used only for the purposes of personal reimbursement and should not be used on any grant applications submitted to the Federal Government.

Several of the steps of the registration process could take four weeks or more. Therefore, applicants should immediately check with their business official to determine whether their organization/institution is already registered in both Grants.gov and the Commons. The NIH will accept electronic applications only from organizations that have completed all necessary registrations.

1. Request Application Information

Applicants must download the SF424 (R&R) application forms and SF424 (R&R) Application Guide for this FOA through Grants.gov/Apply.

Note: Only the forms package directly attached to a specific FOA can be used. You will not be able to use any other SF424 (R&R) forms (e.g., sample forms, forms from another FOA), although some of the "Attachment" files may be useable for more than one FOA.

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

Prepare all applications using the SF424 (R&R) application forms and the SF424 (R&R) Application Guide (MS Word or PDF).

The SF424 (R&R) Application Guide is critical to submitting a complete and accurate application to NIH.

There are fields within the SF424 (R&R) application components that, although not marked as mandatory, are required by NIH (e.g., the Credential log-in field of the Research & Related Senior/Key Person Profile component must contain the PD/PI’s assigned eRA Commons User ID). Agency-specific instructions for such fields are clearly identified in the Application Guide. For additional information, see Tips and Tools for Navigating Electronic Submission on the front page of Electronic Submission of Grant Applications.

The SF424 (R&R) application is comprised of data arranged in separate components. Some components are required, others are optional. The forms package associated with this FOA in Grants.gov/APPLY will include all applicable components, required and optional. A completed application in response to this FOA will include the following components:

Required Components:
All of these required components must be included in each application in the cluster.
SF424 (R&R) (Cover component)
Research & Related Project/Performance Site Locations
Research & Related Other Project Information
Research & Related Senior/Key Person
Research & Related Budget
PHS398 Cover Page Supplement
PHS398 Research Plan
PHS398 Checklist

Additional Components:
PHS398 Cover Letter File
R&R Subaward Budget Attachment(s) Form

Note: While both budget components are included in the SF424 (R&R) forms package, this FOA uses ONLY the Research & Related Budget. (Do not use the PHS 398 Modular Budget.)

This FOA is not part of the pilot multiple-PI program (NOT-OD-06-069). Only one Project Director/Principal Investigator (PD/PI) must be designated on the face page of each application. While this individual is responsible for the scientific and technical aspects, as well as the proper conduct of the project, the structure of the systems biology exploratory programs will involve more than one individual in developing the application and in making decisions concerning planning, management, staffing, and resource allocation. In recognition of the essential intellectual and/or technical contributions of the lead scientists responsible for developing and implementing the goals of the project, applications shall comprise of a cluster of two or more applications. The minimum application cluster will comprise two applications, with one computational/modeling application and one biomedical/experimental application. The total direct costs from all applications in the cluster should not exceed $600,000 in any year. The need and purposes for each collaborating application in the cluster must be carefully and completely described and justified. The review of the application will evaluate the entire project as a whole, the strength of the collaborating component projects, and the balance of computational and experimental approaches.

A lead PD/PI for the cluster of applications must be designated and must be a PD/PI of one of the applications in the cluster. The lead PD/PI will be the point of contact between NHLBI and participants in the cluster. The lead PD/PI’s application must contain relevant information for the overall application, including a management plan, composition of the scientific steering committee, and timeline and milestones.

All applications in a cluster must share identical titles and project summary and must refer to the lead PD/PI s application in the cover letter.

Please see Section IV. , heading 6. Other Submission Requirements for specific instructions to be used to prepare a Cluster of R33 award applications.

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.
• Additional information regarding foreign grants is available in the NIH Grants Policy Statement (http://grants.nih.gov/grants/policy/nihgps_2003/NIHGPS_Part12.htm#_Toc54600260).

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

Applications must be submitted on or before the receipt date described below (Section IV.3.A).

3.A. Submission, Review and Anticipated Start Dates
Opening Date: July 24, 2006 (Earliest date an application may be submitted to Grants.gov)
Letters of Intent Receipt Date(s): August 24, 2006, and August 24, 2007
Application Submission Date(s): September 25, 2006, and September 25, 2007
Peer Review Date(s): January February 2007, January February 2008
Council Review Date(s): June 2007, June 2008
Earliest Anticipated Start Date(s): July 2007, July 2008

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:

Chief, Review Branch
Division of Extramural Affairs
National Heart, Lung, and Blood Institute
Two Rockledge Center, Room 7214
6701 Rockledge Drive
Bethesda, MD 20892-7924 (Express 20817)
Telephone: (301) 435-0270
FAX: (301) 480-0730
Email: [email protected]

3.B. Sending an Application to the NIH

To submit an application in response to this FOA, applicants should access this via http://www.grants.gov/Apply and follow steps 1-4. Note: Applications must only be submitted electronically
PAPER APPLICATIONS WILL NOT BE ACCEPTED.

3.C. Application Processing

Applications may be submitted on or after the opening date and must be successfully received by Grants.gov no later than 5:00 p.m. local time (of the applicant institution/organization) on the application submission/receipt date(s). (See Section IV.3.A. for all dates.) If an application is not submitted by the receipt date(s) and time, the application may be delayed in the review process or not reviewed.

Once an application package has been successfully submitted through Grants.gov, any errors have been addressed, and the assembled application has been created in the eRA Commons, the PD/PI and the Authorized Organization Representative/Signing Official (AOR/SO) have two business days to view the application image.

• If everything is acceptable, no further action is necessary. The application will automatically move forward for processing by the Division of Receipt and Referral, Center for Scientific Review, NIH, after two business days.
• Prior to the submission deadline, the AOR/SO can Reject the assembled application and submit a changed/corrected application within the two day viewing window. This option should be used if the AOR/SO determines that warnings should be addressed. Reminder: warnings do not stop further application processing. If an application submission results in warnings (but no errors) it will automatically move forward after two business days if no action is taken. Please remember that some warnings may not be applicable or may need to be addressed after application submission.
• If the two day window falls after the submission deadline, the AOR/SO will have the option to Reject the application if, due to an eRA Commons or Grants.gov system issue, the application does not correctly reflect the submitted application package (e.g., some part of the application was lost or didn t transfer correctly during the submission process). The AOR/SO should first contact the eRA Commons Helpdesk to confirm the system error, document the issue, and determine the best course of action. NIH will not penalize the applicant for an eRA Commons or Grants.gov system issue.
• If the AOR/SO chooses to Reject the image after the submission deadline for a reason other than an eRA Commons or Grants.gov system failure, a changed/corrected application still can be submitted but it will be subject to the NIH late policy guidelines and may not be accepted. The reason for this delay should be explained in the cover letter attachment.
• Both the AOR/SO and PD/PI will receive e-mail notifications when the application is rejected or the application automatically moves forward in the process after two days.

Upon receipt, applications will be evaluated for completeness by the Center for Scientific Review, NIH. Incomplete applications will not be reviewed.

There will be an acknowledgement of receipt of applications from Grants.gov and the Commons. Information related to the assignment of an application to a Scientific Review Group is also in the Commons.

The NIH will not accept any application in response to this FOA that is essentially the same as one currently pending initial merit review unless the applicant withdraws the pending application. The NIH will not accept any application that is essentially the same as one already reviewed. This does not preclude the submission of an application already reviewed with substantial changes, but such application must include an Introduction addressing the previous critique. Note such an application is considered a "resubmission" for the SF424 (R&R).

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 (http://grants.nih.gov/grants/policy/policy.htm).

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

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

6. Other Submission Requirements

The NIH requires the PD/PI to fill in his/her Commons User ID in the PROFILE Project Director/Principal Investigator section, Credential log-in field of the Research & Related Senior/Key Person Profile component. The applicant organization must include its DUNS number in its Organization Profile in the eRA Commons. This DUNS number must match the DUNS number provided at CCR registration with Grants.gov. For additional information, see Tips and Tools for Navigating Electronic Submission on the front page of Electronic Submission of Grant Applications.

Renewal (formerly competing continuation or Type 2 ) applications are not permitted.

All application instructions outlined in the SF424 (R&R) Application Guide (MS Word or PDF) are to be followed, with the following requirements for R33 applications:

• R33 appendix materials should be limited, as is consistent with the exploratory nature of the R33 mechanism. The following materials may be included in the appendix:
• Up to five publications, manuscripts (accepted for publication), abstracts, patents, or other printed materials directly relevant to this project. Do not include manuscripts submitted for publication.
• Publications in press: Include only a publication list with a link to the publicly available on-line journal article or the PubMed Central (PMC) submission identification number. Do not include the entire article.
• Manuscripts accepted for publication but not yet published: The entire article may be submitted electronically as a PDF attachment.
• Manuscripts published but an online journal link is not available: The entire article may be submitted electronically as a PDF attachment.
• Surveys, questionnaires, data collection instruments, clinical protocols, and informed consent documents.
• Graphic images of gels, micrographs, etc. provided that the image (may be reduced in size) is also included within the 15-page limit of Items 2-5 of the Research Plan. No images may be included in the Appendix that are not also represented within the Research Plan.
• Do not use the Appendix to circumvent the page limitations of the Research Plan. An application that does not observe these limitations may be delayed in the review process.

Specific Instructions for Preparing a Cluster of R33 Award Applications

• All applications in the cluster (lead PD/PI and collaborating PD/PIs) must submit all of the required components listed in Section IV #2: Content and Form of Application Submission . In addition to the instructions accompanying the SF 424 (R&R), applicants should use the following guidance:
• These applications must comprise of a cluster of two or more applications each of which has a different PD/PI. One of the Project Director/Principal Investigators should be identified as the lead PD/PI and the other PD/PIs should be identified as collaborating PD/PIs.
• The SF424 (R&R) Cover Component page of the lead PD/PI application and collaborating PD/PI’s applications should only include information regarding their own application.
• The PHS 398 Cover Letter Component must include the application title, the FOA number (HL-07-005), and the names and institutions of the lead PD/PI and the collaborating PD/PIs that comprise the cluster.
• All applications in a cluster must share identical titles and project summaries and must refer to the lead PD/PI’s application in the cover letter.

Project Summary (Abstract): All applications in the cluster must share an identical Project Summary. The Project Summary should be submitted on the SF424 (R&R) form Other Project Information , under attachments 6 and 7. The Project Summary/Abstract (in attachment 6) must identify the specific goal of the project, the innovative or high-risk, high-impact nature of the project, the relationship to current knowledge or capabilities, the need for a multidisciplinary research team, the approach(es) planned to achieve the proposed goal, and the expected impact on the field. This portion of the Project Summary should be informative to other persons working in the same or related fields and insofar as possible understandable to a scientifically or technically literate reader. In attachment 7 (Project Narrative) include the Relevance statement. Using no more than two or three sentences, describe the relevance of this research to public health. Use plain language for this section so that it can be understood by a general, lay audience.

Senior/Key Person Profiles: In Lead PD/PI applications, the collaborating PD/PIs should be named as key persons in addition to any other senior/key persons for that application. The Project Role of the Lead PD/PI in their own application should be listed as PD/PI . In the Lead PD/PIs application, the Project Role of the collaborating PD/PIs (from the other applications in the cluster) should be listed as Other and their Other Project Role Category should be listed as Collaborating PD/PI. The Project Role of Collaborating PD/PIs in their own applications should be listed as PD/PI.

Budget: The Lead PD/PI and each collaborating PD/PI in the cluster must submit a detailed, non-modular budget for their own application. The detailed budget with complete categorical budget information with justification for the initial and future years should be prepared and submitted on the Research and Related Budget Component of the SF 424 application.

The cluster may request a project period of up to 3 years and a budget of up to $600,000 in direct costs in each year for the entire cluster, where this total excludes F&A costs of consortium subcontracts. The budget may not exceed $600,000 in direct costs in any year for the cluster.

Each collaborative PD/PI must devote a minimum of 20% effort during each year of the project, and the lead PD/PI must commit an additional 5% effort toward the overall coordination and administration of the cluster.

Separate from the research budget for their own application, the Lead PD/PI must also submit an overall budget for the entire cluster project including all collaborating applications and subcontracts on the SF424 (R&R) form Other Project Information Component, under section 11 Other Attachments. This overall budget for the cluster should use the suggested budget format available at http://www.nhlbi.nih.gov/funding/inits/sysbio-faq.htm and that completed form must be submitted as a PDF file attachment to the Other Project Information Component, # 11 Other Attachments.

Research Plan Component: SF424 (R&R) Form PHS 398 Research Plan : All of the applications in the cluster must submit relevant administrative pages in the Research Plan which includes other sections such as Human Subjects, Vertebrate Animals, Consortium/Contractual Arrangements, Letters of Support, and Resource Sharing Plans.

Applications submitted by the collaborating PD/PIs in the cluster must include all required SF424 (R&R) components stated Section IV #2. Content and Form of Application Submission , as well as all relevant administrative attachments in the Research Plan as stated above. In each of the attachments 2-5 of the collaborating PD/PI’s application they should reference readers to the cluster’s Lead PD/PI application by stating See the Lead PD/PI s application for details. The lead PD/PI for this cluster is Dr. XXX.

Only the Lead PD/PI s application will include detailed Research Plan Component Attachments 2-5 (30 page limit). These are:

• Attachment 2: Specific Aims, Management Plan, Timeline, and Milestones
• Attachment 3: Background/Significance
• Attachment 4: Preliminary Studies
• Attachment 5: Research Design and Methods.

Page Limitations: Thirty pages are allotted for items 2-5 of the Research Plan for all applications in the research cluster.

The Research Plan of the lead PD/PI must include an overview of the cluster’s scientific program that couples all study components to the project aims. The synergy achieved from interactions between collaborating applications should be clearly presented. The Specific Aims for the overall cluster should clearly indicate the roles of the lead and collaborating PD/PIs in each Specific Aim. The application must also include the Management Plan, the Timeline and Milestones, the Background/Significance, the Preliminary Studies, and the integrated Research Design and Methods for the overall cluster.

• Specific Aims (Attachment 2). The Specific Aims section should identify the goal of the project and list what will be done during the proposed funding period. The role of the lead and collaborating PD/PIs in each Specific Aim should be clearly identified. The need for a multidisciplinary approach for the project, the synergy of the component projects, and the innovation and potential impact of the project should be apparent from these specific aims.
• Management Plan (Attachment 2): The management plan should specify the organizational structure with the roles and responsibilities of the lead and collaborating PD/PIs and other key individuals. This management plan must include descriptions of the organizational structure of the collaborative partnership that clearly defines the collaborative team and relationships among the various components. The project size, structure, and mode of operation should match the needs and scope of the proposed research. Explain how the structure of the team facilitates the research. Provide an administrative and project management plan that outlines plans and mechanisms to keep the project focused and progressing, explains how collaborators and/or consultants can be added or removed as the expertise, knowledge, and skills necessary to advance the project change, and explain how decisions will be made to alter the project depending on the success or failure of individual milestones. The management plan should also include plans for a scientific steering committee consisting of those individuals identified in the management plan that collectively represent the intellectual and technical leadership required to accomplish the approved scientific aims. Each application in the cluster must be represented on the steering committee. The management plan must identify the composition of the scientific steering committee, including the chair of the steering committee. The steering committee chair need not be a PD/PI on one of the component applications in the cluster, but her or his role and percent effort must be documented. In addition to regular steering committee meetings to discuss project status, problems, and directions, the steering committee may propose the reallocation of future year commitments within the cluster of collaborating grants, subject to NHLBI approval. Funds should be budgeted for administrative oversight by the scientific steering committee and activities noted in the management plan. The management plan should include a description of what will be done to achieve the goals of the project, and a plan for managing intellectual property issues while ensuring rapid public dissemination of research data and resources.
• Timeline and Milestones (Attachment 2): A Timeline and Milestones section must be included following the Management Plan. The timeline should describe the expected progression of the research activities over the life of the three-year project. Project milestones should be identified along the timeline. Milestones should be well described, quantifiable, and scientifically justified. The milestones should be regarded as criteria for evaluating the progress and direction of the research project and should not be just a restatement of the specific aims. During the project period, the applicant will be expected to refer to these milestones in his or her annual progress reports. The NHLBI will use the milestones, the annual progress reports, and other measures of productivity and success to judge the progress, impact, and value of the program. Applicants should write the milestones assuming that a scientifically literate non-expert will use them to evaluate the progress that has been achieved. Milestones should not be simply a restatement of the specific aims or a timeline. Applications lacking this information will be not be reviewed.
• Background and Significance (Attachment 3). This section should explain why the research project is important. Define why a multidisciplinary approach is required to solve the proposed problem. Elaborate on the innovation, risk, and impact of the project. Identify how the project, if it is successful, could produce significant improvements understanding of the integrated systems biology of the HLBS fields.
• Preliminary Studies (Attachment 4). The R33 mechanism is intended to encourage highly innovative and potentially risky exploratory and development research for which feasibility has been demonstrated and thus are ready for extended development. Thus, minimal preliminary results that directly substantiate the feasibility of the project or provide proof-of-principle are expected. As this solicitation seeks innovative, high-risk, high-impact research in the HLBS area, projects that propose only incremental advancements in current knowledge may be deemed unresponsive to the solicitation. This section should be used to explain how current evidence or thinking in the specific field of HLBS research is addressed in this cluster application.
• Research Design and Methods (Attachment 5). This section should explain how the specific aims will be accomplished and what approaches will be taken during the research project in order to achieve the goals of the project. The role of each PD/PI in each Specific Aim should be clearly presented. Describe how the specific experiments will be conducted and explain how success or failure at critical milestones might change the proposed plans. Identify how experimental and computational components of the application will each incorporate information and advances from the other.

Research Plan Component Attachment 1: Introduction to Application (Resubmission or Revision - ONLY). Use only if you are submitting an R&R Resubmission or Revision (Cover Page Item 8). All Resubmission applications (previously known as a revision or amendment) must include an Introduction. The Introduction should not exceed three pages for a resubmission application and must be identical in all applications in the cluster. The Introduction is excluded from the 30 page limit of the Research Plan.

Annual Grantee Meeting: Upon initiation of the program, the NHBLI will arrange annual meetings to encourage the exchange of information among the investigators participating in the program. In the preparation of the budget for the grant application, applicants should include travel funds for one meeting each year to be held in or near Bethesda, MD, for the principal investigators and key collaborators. At these meetings awardees will be expected to share their results and to help evaluate the progress of the Centers. Attendance at these meetings is required.

WARNING: Please be sure that you observe the direct costs, project period, and page number limitations specified for this FOA. Application processing may be delayed or the application may be rejected if it does not comply with these requirements.

Note: While each section of the Research Plan needs to be uploaded separately as a PDF attachment, applicants are encouraged to construct the Research Plan as a single document, separating sections into distinct PDF attachments just before uploading the files. This approach will enable applicants to better monitor formatting requirements such as page limits. All attachments must be provided to NIH in PDF format, filenames must be included with no spaces or special characters, and a .pdf extension must be used.

Plan for Sharing Research Data

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

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

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

Sharing Research Resources

NIH policy requires that grant 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.

A plan for disseminating computational models, algorithms, and simulations must be included in the application, with appropriate timelines. A plan for managing intellectual property issues while ensuring rapid public dissemination of research data, models, algorithms, and resources must be included.

Plan for Sharing Software

A software dissemination plan, with appropriate timelines, must be included in the application. There is no prescribed single license for software produced in this project.

The initial review group will comment on the appropriateness of the proposed plan for data and materials dissemination. Program staff and advisors will also consider the adequacy of the dissemination plan as one of the criteria for award. The proposed sharing plan, after negotiation with the applicant when necessary, will be made a condition of the award. Evaluation of annual non-competing progress reports will include assessment of the responsiveness to NIH guidelines of data, materials, methods, and software dissemination practice by the grantee.

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 to program priorities

2. Review and Selection Process

Applications that are complete and responsive to the RFA will be evaluated for scientific and technical merit by an appropriate peer review group convened by NHLBI 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 Heart, Lung, and Blood Advisory Council (NHLBAC).

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.

Applications responding to this solicitation must propose a multidisciplinary team. The project(s) should apply the principles, technologies and analytical methods of systems biology to specific problems in defined and well-characterized biological systems that have high program relevance to the NHLBI mission. The systems selected for study should have a significant foundation of knowledge, resources, and technologies that can be leveraged to take studies of that system to a deeper level of mechanistic understanding.

These applications should propose research that is highly innovative and potentially high impact. This solicitation is not intended to support projects that would result in routine or incremental progress. NHLBI understands and accepts that applications that are responsive to this solicitation will be much riskier than most applications. The NHLBI understands that applications which satisfy the requirement for high innovation, high significance, and potential high impact are likely to have much higher than average risk and may have minimal preliminary data.

A combination of a multidisciplinary team, high innovation, high significance, high potential impact, and appropriate risk are required for high scientific and programmatic merit. Additionally, the approach should not only contain the experimental design but also a description of the structure of the multidisciplinary team, a timeline, a set of milestones, and a management plan. The evaluation of these additional components will be included in the determination of the scientific merit of the project.

Applications responding to this FOA must propose research whose main thrust is to improve our understanding of mammalian physiology or pathophysiology of the cardiovascular system, lung, blood, or sleep. Applications exclusively using non-mammalian models or those whose experimental component is entirely based on immortalized cell lines will be deemed non-responsive.

The review of the application will evaluate the entire project as a whole, the strength of the collaborating component projects, and the balance of computational and experimental approaches.

Significance: Does this study address an important problem? If the aims of the application are achieved, how will scientific knowledge or clinical practice be advanced? What will be the effect of these studies on the concepts, methods, technologies, treatments, services, or preventative interventions that drive this field? Is the main thrust of the research proposed focused on elucidating mechanisms underlying physiology or pathophysiology of cardiovascular, lung, blood or sleep function?

Approach: Are the conceptual or clinical framework, design, methods, and analyses adequately developed, well integrated, well reasoned, and appropriate to the aims of the project? Does the applicant acknowledge potential problem areas and consider alternative tactics? How effectively integrated are the proposed research projects? Is the balance of computational/modeling and biomedical/experimental approaches adequate for the science being proposed? How well does the project integrate information across multiple scales?

Innovation: Is the project original and innovative? For example: Does the project challenge existing paradigms or clinical practice; address an innovative hypothesis or critical barrier to progress in the field? Does the project develop or employ novel concepts, approaches, methodologies, tools, or technologies for this area? Is the proposed research highly innovative and potentially high impact?

Investigators: Are the investigators appropriately trained and well suited to carry out this work? Is the work proposed appropriate to the experience level of the principal investigator and other researchers? Does the investigative team bring complementary and integrated expertise to the project (if applicable)? Does the multidisciplinary research team have the right mix and balance of skills, expertise, knowledge, time, and resources to efficiently address the research problem? Are the proposed collaborating applications necessary and appropriate for the proposed research? Does each collaborative application display synergy to the overall application?

Environment: Does the scientific environment in which the work will be done contribute to the probability of success? Do the proposed studies benefit from unique features of the scientific environment, or subject populations, or employ useful collaborative arrangements? Is there evidence of institutional support?

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:

Milestones: Are the milestones well described, quantifiable, and scientifically justified? Can the milestones be used to evaluate the progress of the project?

Management Plan: Does the management plan ensure that there will be extensive coordination and collaboration? Does the plan explain how the focus and progress of the project will be maintained, how collaborators and/or consultants will be added or removed if the expertise, knowledge, and skills necessary for the project change, and how decisions will be made to alter the project as milestones are or are not achieved?

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 item 6 of the Research Plan component of the SF424 (R&R).

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 item 7 of the Research Plan component of the SF424 (R&R).

Care and Use of Vertebrate Animals in Research: If vertebrate animals are to be used in the project, the five items described under item 11 of the Research Plan component of the SF424 (R&R) will be assessed.

2.B. Additional Review Considerations

These criteria will be evaluated during the review, but will not affect scoring of the application.

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.

Budget: The reasonableness of the proposed budget and the requested period of support in relation to the proposed research may be assessed by the reviewers. Is the percent effort listed for the PD/PI appropriate for the work proposed? Is each budget category realistic and justified in terms of the aims and methods?

Period of Support: The appropriateness of the requested period of support in relation to the proposed research may be assessed by the reviewers.

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.

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

Awards through this program will include the following special terms and conditions:

The NHLBI expects to convene annual meetings of the awardees of the Exploratory Program in Systems Biology. It is expected that these meetings will be held in or near Bethesda, MD. At these meetings awardees will be expected to share their results and to help evaluate the success of the program. Attendance at these meetings is required. Travel funds should be requested for this purpose for the Principal Investigator and for one or two other participants.

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).

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:

Jennie Larkin, Ph.D.
Division of Heart and Vascular Diseases
National Heart, Lung, and Blood Institute
6701 Rockledge Drive
Rockledge II, Room 9142
Bethesda, MD 20892
Telephone: (301) 435-0513
FAX: (301) 480-1335
Email: [email protected]

Pankaj Qasba, Ph.D.
Division of Blood Diseases and Resources
National Heart, Lung, and Blood Institute
6701 Rockledge Drive
Rockledge II, Room 10161
Bethesda, MD 20892
Telephone: (301) 435-0050
FAX: (301) 480-0867
Email: [email protected]

2. Peer Review Contacts:

Chief, Review Branch
Division of Extramural Affairs
National Heart, Lung, and Blood Institute
Two Rockledge Center, Room 7214
6701 Rockledge Drive
Bethesda, MD 20892-7924 (Express 20817)
Telephone: (301) 435-0270
FAX: (301) 480-0730
Email: [email protected]

3. Financial or Grants Management Contacts:

David Reiter
NHLBI Grants Operations Branch
National Heart, Lung, and Blood Institute
Two Rockledge Center, Room 7172
6701 Rockledge Drive
Bethesda, MD 20892-7924 (Express 20817)
Telephone: (301) 435-0177
FAX: (301) 480-3310
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).

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

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

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 SF424 (R&R), 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: (1) 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 (2) 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. Unless otherwise specified in an NIH solicitation, Internet addresses (URLs) should not be used to provide information necessary to 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

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