Preventing Mitochondrial Oxidative Stress in Diabetes and Obesity

RFA Number: RFA-DK-05-001

Part I Overview Information

Department of Health and Human Services

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

Components of Participating Organizations
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), (http://www.niddk.nih.gov)
National Cancer Institute (NCI), (http://www.nci.nih.gov)
Office of Dietary Supplements (ODS), (http://ods.od.nih.gov)

Announcement Type
New

Catalog of Federal Domestic Assistance Number(s)
93.847, 93.393, 93.396

Key Dates

Release Date: November 23, 2004
Letters of Intent Receipt Date(s): January 27, 2005
Application Receipt Date(s): February 24, 2005
Peer Review Date(s): June – July, 2005
Council Review Date(s) : September 14-15, 2005
Earliest Anticipated Start Date: September 30, 2005
Additional Information To Be Available Date (Url Activation Date): Not Applicable
Expiration Date: February 25, 2005

Due Dates for E.O. 12372
Not Applicable

Executive Summary

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
    2. Research Topics

  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
    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
      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
    3. Merit Review Criteria
      A. Additional Review Criteria
      B. Additional Review Considerations
      C. Sharing Research Data
      D. Sharing Research Resources

  Section VI. Award Administration Information
    1. Award Notices
    2. Administrative 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. Award Criteria
    4. Reporting

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

  Section VIII. Other Information - Required Federal Citations

Part II - Full Text of Announcement
Section I. Funding Opportunity Description

1. Research Objectives

The incidence of diabetes mellitus and obesity are rapidly rising to epidemic levels in the United States and worldwide. Diabetes leads to a number of complications including end-stage renal failure, blindness, lower extremity amputations, gastrointestinal dysmotility, myocardial infarctions and strokes. Obesity and diabetes can also lead to non-alcoholic fatty liver disease, currently the most common liver diseases in the United States. Nonalcoholic steatohepatitis (NASH), a more severe form of non-alcoholic fatty liver disease, can progress to liver failure. Diabetes also increases the risk of several cancers, including colorectal, endometrial, pancreatic, and liver cancers. Likewise, obesity increases the risk of cancer, but characterization of the early triggers of the diabetes-obesity-cancer relationship needs further study.

The metabolic hallmark of diabetes is hyperglycemia that is clearly associated with the microvascular complications of nephropathy, retinopathy and neuropathy, and is also a contributory factor to the macrovascular complications of atherosclerotic vascular disease. Decades of research on the cellular effects of hyperglycemia have elucidated many different molecular abnormalities, such as the formation of advanced glycation end-products, increased flux in the hexosamine and polyol pathways and activation of protein kinase C. Recently, a unifying mechanism has been proposed that places the overproduction of reactive oxygen species (ROS) in the mitochondria as the primary result of elevated cellular glucose, with the other metabolic defects resulting from this central abnormality.

The mitochondrial respiratory chain is the major site of ROS production in the cell. Electrons produced by metabolism of glucose and fatty acids flow through the mitochondrial electron-transport chain leading to ATP production. Hyperglycemia overwhelms the system by increased production of electron donors from the tricarboxylic acid (TCA) cycle, increased membrane potential of the mitochondrial inner membrane and finally, a prolonged half-life of free radical intermediates of Coenzyme Q, which reduces oxygen to superoxide. This oxygen radical can itself cause damage, but is also converted to other ROS, peroxynitrite and the hydroxyl radical that can cause extensive oxidative damage to all classes of biomolecules. The mitochondrion uses a range of antioxidants, including manganese superoxide dismutase (MnSOD) and glutathione reductase, to protect itself from oxidative damage.

Reduction of oxidative stress for prevention of cardiovascular disease has been the focus of several clinical trials. These intervention studies with the naturally occurring antioxidants, Vitamin E and beta-carotene, have failed to demonstrate any significant benefit. An explanation may be that classic antioxidants, such as Vitamin E, act only as scavengers on a subset of already formed oxidants, particularly lipid peroxidation products. They also work in a stoichiometric, rather than a catalytic manner. New compounds that efficiently scavenge intracellular ROS show signs of reversing mitochondrial damage in cells and lessening the effects of ROS in animals. Currently available drugs such as thiazolinediones, statins and angiotensin converting enzyme inhibitors have antioxidant activity within cells. Studies have demonstrated that alpha-lipoic acid, a naturally occurring antioxidant, can bind metal ions and prevent the generation of free radicals. In addition, several trace elements, including copper, zinc, and manganese can influence superoxide dismutase activity. Agents, such as drugs, dietary supplements and bioactive food components that can decrease the production or reduce the activities of excessively generated ROS may potentially abrogate the deleterious effects of hyperglycemia.

2. Research Topics

The objective of this RFA is to translate recent advances in understanding the mitochondrial ROS production associated with hyperglycemia to therapeutic interventions that would target mitochondrial ROS to prevent or ameliorate diabetic complications. Discovering and characterizing molecular targets, agents and assays to prevent and measure the accumulation of mitochondrial ROS secondary to hyperglycemia would be appropriate research topics for this RFA. The proposed research should primarily focus at the cellular and subcellular level, but could expand to studies in tissues, organs, animal models and small, pilot clinical studies. The choice of cell types and model systems should be appropriate for the pathophysiology of diabetic complications and NASH. The long-term goal is to translate research from this RFA on cells and mitochondria, to the tissue injury that results in diabetic nephropathy, peripheral and autonomic neuropathy, including gastroparesis, retinopathy, macrovascular disease and other complications of obesity such as NASH and cancer. NASH is an area of high priority in the trans-NIH Action Plan for Liver Disease Research (http://liverplan.niddk.nih.gov). Several research goals of this solicitation are responsive to recommendations in the Action Plan.

The proposed research should focus on the accumulation of ROS and not downstream events that may be secondary to oxidative damage. ROS contribute to the pathology of many different diseases, but this RFA concentrates on mitochondrial oxidative damage associated with diabetes, obesity and their related cancers. Studies on antioxidants that have already been tested in large clinical trials would generally not be responsive to this RFA, unless a strong justification for their use was presented in the research plan.

Appropriate topics for investigation under this RFA would include, but are not limited to:

Section II. Award Information

1. Mechanism(s) of Support

This funding opportunity will use the R01 and R21 award mechanism(s). As an applicant, you will be solely responsible for planning, directing, and executing the proposed project.

R01 (Research) grants

The R01 award represents an investigator-initiated research grant designed to support a discrete, specified research project performed by a principal investigator.

R21 (Exploratory/Developmental) grants

The R21 mechanism is intended to encourage new exploratory/developmental research projects by providing support for the early stages of their development. Awards are made to demonstrate feasibility of a subsequent project and to obtain preliminary data testing innovative ideas. Therefore, these grants are not renewable. Continuation of projects developed under this program will be through the regular research project grant mechanism (for example, R01). These grants are not intended to support or supplement ongoing funded research of an established investigator, or to serve as an alternative mechanism of support for projects not receiving funding as competitive continuation applications.

This funding opportunity uses just-in-time concepts. It also uses the modular as well as the non-modular budget formats (see http://grants.nih.gov/grants/funding/modular/modular.htm). Specifically, if you are submitting an application with direct costs in each year of $250,000 or less, use the modular budget format described in the PHS 398 application instructions. Otherwise follow the instructions for non-modular research grant applications.

2. Funds Available

The participating ICs, NIDDK and NCI, intend to commit approximately $2.5 million dollars in FY 2005 to fund 5-10 new and/or competing continuation grant applications in response to this RFA. For R01 grant applications, an applicant may request a project period of up to 4 years and a budget for direct costs up to $300,000 dollars per year. For R21 grant applications, an applicant may request a project period of up to 2 years and total budget of direct costs of $275,000 for the 2 years. The earliest project start dates for these grants would be in September 30, 2005.

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. Fiscal and administrative costs are not included in the direct cost limitation, see NOT-OD-04-040.

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:

Foreign institutions/organizations considering applying to this RFA must demonstrate an ability to conduct the proposed study in the designated setting(s), as well as an ability to meet government clearance requirements. 

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 programs.

2. Cost Sharing
Cost sharing is not required.

3. Other-Special Eligibility Criteria
Applicants may submit more than one application, providing there is no scientific or budgetary overlap.

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. For further assistance contact GrantsInfo, Telephone (301) 435-0714, Email: GrantsInfo@nih.gov.

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

2. Content and Form of Application Submission

Applications must be prepared using the PHS 398 research grant application instructions and forms (rev. 5/2001; 9/2004 version after May 10). Applications must have a Dun and Bradstreet (D&B) Data Universal Numbering System (DUNS) number as the universal identifier when applying for Federal grants or cooperative agreements. The D&B number can be obtained by calling (866) 705-5711 or through the web site at http://www.dnb.com/us/. The D&B number should be entered on line 11 of the face page of the PHS 398 form.

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

3. Submission Dates

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

3.A. Receipt, Review and Anticipated Start Dates

Letter of Intent Receipt Date: January 27, 2005
Application Receipt Date(s): February 24, 2005
Peer Review Date: June – July, 2005
Council Review Date: September 14 – 15, 2005
Earliest Anticipated Start Date: September 30, 2005

3.A.1. Letter of Intent

Prospective applicants are asked to submit a letter of intent that includes the following information:

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

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

The letter of intent should be sent to:

Francisco O. Calvo, Ph.D.
Chief, Review Branch
National Institute of Diabetes and Digestive and Kidney Diseases
6707 Democracy Boulevard, Rm. 752
Bethesda, MD 20892-5452
(for express/courier service: Bethesda, MD 20817)
Telephone: (301) 594-8897)
Email: fc15y@nih.gov

3.B. Sending an Application to the NIH

Applications must be prepared using the PHS 398 research grant application instructions and forms as described above. 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)

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

Francisco O. Calvo, Ph.D.
Chief, Review Branch
National Institute of Diabetes and Digestive and Kidney Diseases
6707 Democracy Boulevard, Rm. 752
Bethesda, MD 20892-5452
(for express/courier service: Bethesda, MD 20817)
Telephone: (301) 594-8897)
Email: fc15y@nih.gov

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

3.C. Application Processing

Applications must be received on or before the application receipt date listed in the heading of this funding opportunity. If an application is received after that date, it will be returned to the applicant without review.

Upon receipt, applications will be reviewed for completeness by the CSR and responsiveness by the NIDDK Review Branch . Incomplete and non-responsive applications will not be reviewed.

The NIH will not accept any application in response to this funding opportunity that is essentially the same as one currently pending initial review, unless the applicant withdraws the pending application. However, if a previously unfunded application, originally submitted as an investigator-initiated application, is to be submitted in response to this RFA, it is to be prepared as a NEW application. That is, the application 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.

Although there is no immediate acknowledgement of the receipt of an application, applicants are generally notified of the review and funding assignment within eight (8) weeks.

4. Intergovernmental Review
This initiative is not subject to intergovernmental review.

5. Funding Restrictions

All 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 (see also Section VI.3. Award Criteria).

6. Other Submission Requirements

Supplementary Instructions: All instructions for the PHS 398 must be followed with these exceptions:

For R21 grant applications, Items a – d of the Research Plan (Specific Aims, Background and Significance, Preliminary Studies, Research Design and Methods) may not exceed a total of 15 pages. No preliminary data are required, but should be included if it is available.

For all applications, no more than five manuscripts, previously accepted for publication, may be included in the appendix.

Specific Instructions for Modular Grant applications:

Applications requesting up to $250,000 per year in direct costs must be submitted in a modular budget format. The modular budget format simplifies the preparation of the budget in these applications by limiting the level of budgetary detail. Applicants request direct costs in $25,000 modules. Section C of the research grant application instructions for the PHS 398 at http://grants.nih.gov/grants/funding/phs398/phs398.html includes step-by-step guidance for preparing modular budgets. Additional information on modular budgets is available at http://grants.nih.gov/grants/funding/modular/modular.htm.

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).

Section V. Application Review Information

1. Criteria

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 the NIDDK Review Branch in accordance with the review criteria stated below.

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

3. Merit Review Criteria

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.

1. 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?

2. 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?

3. 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?

4. 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)?

5. 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?

3.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.

3.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.

3.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).

Section VI. Award Administration Information

1. Award Notices

After the peer review of the application is completed, the Principal Investigator will also receive a written critique called a Summary Statement.

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 Grant Award (NGA) will be provided to the applicant organization. The NGA signed by the grants management officer is the authorizing document.

Selection of an application for award is not an authorization to begin performance. Any costs incurred before receipt of the NGA are at the recipient's risk. These costs may be reimbursed only to the extent considered allowable pre-award costs.

The NGA will be sent by email to the Business Official with a copy to the Principal Investigator.

2. Administrative Requirements

All NIH grant and cooperative agreement awards include the NIH Grants Policy Statement as part of the notice of grant award. 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.

3. Award Criteria

The following will be considered in making funding decisions:

4. 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:

Teresa L. Z. Jones, M.D.
Division of Diabetes, Endocrinology and Metabolism
National Institute of Diabetes and Digestive and Kidney Diseases
6707 Democracy Blvd., Room 609 
Bethesda, MD 20892-5458
Telephone: (301) 435-2996 
Email: tj104e@nih.gov

Edward Doo, M.D.
Division of Digestive Diseases and Nutrition
National Institute of Diabetes and Digestive and Kidney Diseases
6707 Democracy Blvd., Room 651 
Bethesda, MD 20892-5450
Telephone: (301) 451-4524 
Email: ed56o@nih.gov

Sharon Ross, PhD, MPH
Nutritional Sciences Research Group
Division of Cancer Prevention
National Cancer Institute
6130 Executive Boulevard, Room 3157
Bethesda, MD 20892
Telephone: (301) 594-7547
Email: rosssha@mail.nih.gov

Rebecca B. Costello, Ph.D., F.A.C.N.
Deputy Director
Office of Dietary Supplements
National Institutes of Health
6100 Executive Blvd., Room 3B01
Bethesda, Maryland 20892-7517
Telephone: (301) 435-2920
Email: bc135d@nih.gov

2. Peer Review Contacts:

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

3. Financial or Grants Management Contacts:

Millissa Lee
Grants Management Branch
National Institute of Diabetes and Digestive and Kidney Diseases
6707 Democracy Boulevard, Rm. 721
Bethesda, MD 20892-5456
Telephone: (301) 594-0417
Email: ml306e@nih.gov

Marie Moyer
Grants Administration Branch
National Cancer Institute
1003 West 7th Street, Suite 300
Frederick, MD 21701
Telephone: (301) 846-1007
Email: mm116d@nih.gov

Section VIII. Other Information

Required Federal Citations

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

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

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

Sharing 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.

Public 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 public 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 PA 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.

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 web site (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.


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