PA-01-112: THE ROLE OF ANTIOXIDANTS IN THE PREVENTION OF DIABETIC COMPLICATIONS

Department of Health
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The final receipt date for applications submitted in response to this Program Announcement will be October 1, 2004 unless reissued. THE ROLE OF ANTIOXIDANTS IN THE PREVENTION OF DIABETIC COMPLICATIONS Release Date: June 27, 2001 PA NUMBER: PA-01-112 National Institute of Diabetes and Digestive and Kidney Diseases National Eye Institute National Heart, Lung and Blood Institute National Institute on Aging National Institute of Neurological Disorders and Stroke Office of Dietary Supplements THIS PA USES THE "MODULAR GRANT" AND "JUST-IN-TIME" CONCEPTS. IT INCLUDES DETAILED MODIFICATIONS TO STANDARD APPLICATION INSTRUCTIONS THAT MUST BE USED WHEN PREPARING APPLICATIONS IN RESPONSE TO THIS PA. PURPOSE The National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), the National Eye Institute (NEI), the National Heart, Lung and Blood Institute (NHLBI), the National Institute on Aging (NIA), the National Institute of Neurological Disorders and Stroke (NINDS) and the Office of Dietary Supplements (ODS) seek basic and clinical research applications to study the use of vitamin E and other antioxidants in the prevention or amelioration of diabetic complications. Prevention and treatment of long-term micro- and macrovascular complications remain critical problems in the management of type 1 or type 2 diabetes mellitus. A growing body of in vitro and in vivo research indicates that hyperglycemia leads to increased oxidative stress and endothelial dysfunction. In addition, numerous studies have suggested that patients with diabetes appear to have decreased antioxidant defense capability, measured as lower levels of specific antioxidants, such as ascorbic acid (vitamin C) or vitamin E, or reduced activities of antioxidant enzymes, such as catalase, superoxide dismutase or glutathione peroxidase. This Program Announcement solicits applications to 1) determine the efficacy of vitamin E or other antioxidants in preventing, delaying or ameliorating the micro- or macrovascular complications of diabetes, and 2) provide insight into the mechanism(s) by which antioxidants might prevent or influence the development of diabetic vascular disease. 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 ed national activity for setting priority areas. This Program Announcement PA), The Role of Antioxidants in the Prevention of Diabetic Complications, 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/. ELIGIBILITY REQUIREMENTS Applications may be submitted by domestic and foreign, for-profit and non- profit organizations, public and private, such as universities, colleges, hospitals, laboratories, units of State and local governments, and eligible agencies of the Federal government. Racial/ethnic minority individuals, women, and persons with disabilities are encouraged to apply as principal investigators. MECHANISM OF SUPPORT This PA will use the National Institutes of Health (NIH) research project grant (R01) and the Exploratory/Development Research Grant (R21) award mechanisms. Responsibility for the planning, direction, and execution of the proposed project will be solely that of the applicant. The total project period for an R01 application submitted in response to this PA may not exceed 5 years. The R21 awards are to demonstrate feasibility and to obtain preliminary data testing innovative ideas that represent clear departure from ongoing research interests. These grants are intended to 1) provide initial support for new investigators, 2) allow exploration of possible innovative new directions for established investigators, and 3) stimulate investigators from other areas to lend their expertise to research within the scope of this solicitation. Applicants for the R21 must limit their requests to $125,000 direct costs per year and are limited to two years. These R21 grants will not be renewable, continuation of projects developed under this program will be through the regular research grant (R01) program. Specific application instructions have been modified to reflect "MODULAR GRANT" and "JUST-IN-TIME" streamlining efforts being examined by the NIH. Complete and detailed instructions and information on Modular Grants can be found at http://grants.nih.gov/grants/funding/modular/modular.htm. RESEARCH OBJECTIVES Background Prevention and treatment of long-term micro- and macrovascular complications remain a critical problem in the management of type 1 or type 2 diabetes mellitus. In the United States, diabetes is the leading cause of new blindness in working-age adults, of new cases of end stage renal disease and of non-traumatic lower leg amputations. In addition, cardiovascular complications are now the leading cause of diabetes-related morbidity and mortality, particularly among women and the elderly. In adult patients with diabetes, the risk of cardiovascular disease (CVD) is three to five fold greater than in the general population. A growing body of in vitro and in vivo research indicates that hyperglycemia leads to increased oxidative stress and endothelial dysfunction. Evidence of oxidative damage has been demonstrated in arterial samples obtained from animal models of experimental diabetes and from human diabetic subjects. It has been recognized that oxidation of glucose can generate oxygen free radicals and excess reactive oxygen species such as superoxides. These molecules can promote lipid peroxidation, leading to excessive oxidative burden in patients with diabetes. Oxidative stress can also influence the expression of multiple genes in vascular cells, including signaling molecules such as PKC, NFkB and ERK, overexpression of these genes may lead to endothelial dysfunction and, ultimately, to micro- and macrovascular disease. Molecules in the arterial wall can also be modified by glycation, which usually is associated with oxidation. The formation of advanced glycation end-products (AGEs) can occur on proteins, lipids and nucleic acids. AGEs can lead to increased production of oxygen free radicals and may, therefore, play a role in the development of microvascular disease and atheroscerosis Numerous studies have also suggested that patients with diabetes appear to have decreased antioxidant defense capability, measured as lower levels of specific antioxidants, such as ascorbic acid (vitamin C) or vitamin E, or reduced activities of antioxidant enzymes, such as catalase, superoxide dismutase or glutathione peroxidase. In diabetic animals, many, but not all, studies support the use of antioxidant supplementation in reducing various parameters of oxidative stress and in slowing or preventing the development of microvascular complications. Studies in humans have also been promising. Recently, particular interest has focused on the use of vitamin E for the prevention of microvascular complications. Several studies of vitamin E supplementation in diabetic individuals have demonstrated a decrease in biochemical markers of oxidative stress. One small, short-term study of vitamin E supplementation in patients with diabetes showed improvement in some surrogate markers for retinopathy and nephropathy. A limiting feature of the published studies is that the preparation and dose of vitamin E used has been widely variable. In addition, little data is available regarding potential toxicity of high doses of vitamin E, nor is there data on potential interactions of vitamin E with other nutrients or other antioxidants. Furthermore, interest in mounting a large clinical trial to study the efficacy of vitamin E in preventing diabetic vascular disease has been tempered by the recent negative results of several large, randomized, prospective trials of vitamin E in the prevention of cardiovascular disease and cancer. These large trials were undertaken based on the results of animal studies and a wealth of epidemiologic data suggesting that increased antioxidant consumption is associated with protection from cancer and atherosclerosis. The reason for the discrepancy between the epidemiologic and intervention data is not clear. Nevertheless, given the enormous public health cost of diabetes, the prospect of being able to use a relatively low-cost vitamin supplement to lower the risk of diabetic complications merits further study. The ODS, the NIDDK, the NHLBI, the NEI, the National Cancer Institute (NCI) and the Juvenile Diabetes Research Foundation International (JDRF) sponsored a workshop on Vitamin E and Diabetic Complications in October 2000. Participants highlighted a number of critical gaps in knowledge, which merit further investigation. This Program Announcement seeks to address some of these important issues. Objectives and Scope This Program Announcement solicits basic or clinical applications to 1) determine the efficacy and safety of vitamin E or other antioxidants in preventing, delaying or ameliorating the micro- or macrovascular complications of diabetes, and 2) provide insight into the mechanism(s) by which antioxidants might prevent or influence the development of diabetic vascular disease. Epidemiologic or descriptive studies which assess diet or nutritional supplementation, or which simply measure blood levels of oxidants/antioxidants in patients with diabetes will not be considered responsive to this solicitation. Appropriate topics for investigation under this PA would include but are not limited to: o Preclinical studies to determine the mechanism(s) by which antioxidant(s) prevent or influence the development of diabetic vascular disease, including neurovascular and cerebrovascular disease, o Studies to define interactions between oxidative pathways and free radical formation and the signaling pathways by which insulin, glucose and other factors affect the endothelium, o Studies to investigate genetic factors that may affect susceptibility to oxidative damage and response to anti-oxidant therapies in people with diabetes, o Studies to define similarities and differences in the mechanisms by which oxidative stress and anti-oxidant therapies affect microvascular and macrovascular disease in diabetes, o Phase II studies to assess metabolism and tissue distribution, determine kinetics, and establish optimal dosing regimens for vitamin E or other antioxidants in patients with diabetes and/or diabetic complications, o Studies to establish valid surrogate markers or clinical endpoints of diabetic complications that could be used in phase III trials of antioxidants, o Studies to determine clinically meaningful, state-of-the art measures of oxidant/antioxidant status of patients with diabetes, o Small trials to compare antioxidants to establish which one(s) is most likely to be efficacious in diabetic complications, or to define specific subpopulations who are most likely to benefit from antioxidant intervention, o Studies to develop new strategies to inhibit oxidation/glycoxidation and examine the effect of these strategies on microvascular or cardiovascular disease. INCLUSION OF WOMEN AND MINORITIES IN RESEARCH INVOLVING HUMAN SUBJECTS 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 biomedical and behavioral research projects involving human subjects, unless a clear and compelling rationale and justification are 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 research involving human subjects should read the UPDATED "NIH Guidelines for Inclusion of Women and Minorities as Subjects in Clinical Research," published in the NIH Guide for Grants and Contracts on August 2, 2000 (http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-048.html), a complete copy of the updated Guidelines are available at http://grants.nih.gov/grants/funding/women_min/guidelines_update.htm: The revisions relate to NIH defined Phase III clinical trials and require: a) all applications or proposals and/or protocols to 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) all investigators to report accrual, and to conduct and report analyses, as appropriate, by sex/gender and/or racial/ethnic group differences. INCLUSION OF CHILDREN AS PARTICIPANTS IN RESEARCH INVOLVING HUMAN SUBJECTS It is the policy of NIH that children (i.e., individuals under the age of 21) must be included in all human subjects research, conducted or supported by the NIH, unless there are scientific and ethical reasons not to include them. This policy applies to all initial (Type 1) applications submitted for receipt dates after October 1, 1998. 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" that was published in the NIH Guide for Grants and Contracts, March 6, 1998, and is available at the following URL address: http://grants.nih.gov/grants/guide/notice-files/not98-024.html Investigators also may obtain copies of these policies from the program staff listed under INQUIRIES. Program staff may also provide additional relevant information concerning the policy. 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. Reviewers are cautioned that their anonymity may be compromised when they directly access an Internet site. 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. APPLICATION PROCEDURES Applications are to be submitted on the grant application form PHS 398 (rev. 4/98) at http://grants.nih.gov/grants/funding/phs398/phs398.html and will be accepted at the standard application deadlines (http://grants.nih.gov/grants/dates.htm) as indicated in the application kit. Application kits are available at most institutional offices of sponsored research and may be obtained from the Division of Extramural Outreach and Information Resources, National Institutes of Health, 6701 Rockledge Drive, MSC 7910, Bethesda, MD 20892-7910, telephone 301/710-0267, email: GrantsInfo@nih.gov Applicants planning to submit an investigator-initiated new (type 1), competing continuation (type 2), competing supplement, or any amended/revised version of the preceding grant application types requesting $500,000 or more in direct costs for any year are advised that he or she must contact the Institute or Center (IC) program staff before submitting the application, i.e, as plans for the study are being developed. Furthermore, the application must obtain agreement from the IC staff that the IC will accept the application for consideration for award. Finally, the applicant must identify, in a cover letter sent with the application, the staff member and Institute or Center who agreed to accept assignment of the application. This policy requires an applicant to obtain agreement for acceptance of both any such application and any such subsequent amendment. Refer to the NIH Guide for Grants and Contracts, March 20, 1998 at http://grants.nih.gov/grants/guide/notice-files/not98-030.html The Research Plan for R21 applications cannot exceed 15 pages and appendix material will not be accepted. Further details regarding the purpose and format of R21 applications can be found by reading the NINDS guidelines describing the R21 program (http://www.ninds.nih.gov/funding/r21guidelines.htm). All R21 applications submitted in response to this Program Announcement should follow the NINDS guidelines, regardless of Institute assignment. Applicants may also contact one of the Program Officials listed under Inquiries for further information. If there is other important information it should be included in the PA. SPECIFIC INSTRUCTIONS FOR MODULAR GRANT APPLICATIONS The modular grant concept establishes specific modules in which direct costs may be requested as well as a maximum level for requested budgets. Only limited budgetary information is required under this approach. The just-in-time concept allows applicants to submit certain information only when there is a possibility for an award. It is anticipated that these changes will reduce the administrative burden for the applicants, reviewers, and Institute staff. The research grant application form PHS 398 (rev. 4/98) is to be used in applying for these grants, with the modifications noted below. BUDGET INSTRUCTIONS Modular Grant applications will request direct costs in $25,000 modules, up to a total direct cost request of $250,000 per year for an R01 and up to $125,000 per year for an R21. Applications that request more than $250,000 direct costs in any year must follow the traditional PHS 398 application instructions. The total direct costs must be requested in accordance with the program guidelines and the modifications made to the standard PHS 398 application instructions described below: PHS 398 o FACE PAGE: Items 7a and 7b should be completed, indicating Direct Costs (in $25,000 increments up to a maximum of $250,000) and Total Costs [Modular Total Direct plus Facilities and Administrative (F&A) costs] for the initial budget period. Items 8a and 8b should be completed indicating the Direct and Total Costs for the entire proposed period of support. o DETAILED BUDGET FOR THE INITIAL BUDGET PERIOD: Do not complete Form Page 4 of the PHS 398. It is not required and will not be accepted with the application. o BUDGET FOR THE ENTIRE PROPOSED PERIOD OF SUPPORT: Do not complete the categorical budget table on Form Page 5 of the PHS 398. It is not required and will not be accepted with the application. o NARRATIVE BUDGET JUSTIFICATION: Prepare a Modular Grant Budget Narrative page. (See http://grants.nih.gov/grants/funding/modular/modular.htm for sample pages.) At the top of the page, enter the total direct costs requested for each year. This is not a Form page. o Under Personnel, list all project personnel, including their names, percent of effort, and roles on the project. No individual salary information should be provided. However, the applicant should use the NIH appropriation language salary cap and the NIH policy for graduate student compensation in developing the budget request. For Consortium/Contractual costs, provide an estimate of total costs (direct plus facilities and administrative) for each year, each rounded to the nearest $1,000. List the individuals/organizations with whom consortium or contractual arrangements have been made, the percent effort of all personnel, and the role on the project. Indicate whether the collaborating institution is foreign or domestic. The total cost for a consortium/contractual arrangement is included in the overall requested modular direct cost amount. Include the Letter of Intent to establish a consortium. Provide an additional narrative budget justification for any variation in the number of modules requested. o BIOGRAPHICAL SKETCH: The Biographical Sketch provides information used by reviewers in the assessment of each individual"s qualifications for a specific role in the proposed project, as well as to evaluate the overall qualifications of the research team. A biographical sketch is required for all key personnel, following the instructions below. No more than three pages may be used for each person. A sample biographical sketch may be viewed at: http://grants.nih.gov/grants/funding/modular/modular.htm. - Complete the educational block at the top of the form page, - List position(s) and any honors, - Provide information, including overall goals and responsibilities, on research projects ongoing or completed during the last three years. - List selected peer-reviewed publications, with full citations, o CHECKLIST: This page should be completed and submitted with the application. If the F&A rate agreement has been established, indicate the type of agreement and the date. All appropriate exclusions must be applied in the calculation of the F&A costs for the initial budget period and all future budget years. o The applicant should provide the name and phone number of the individual to contact concerning fiscal and administrative issues if additional information is necessary following the initial review. The Program Announcement 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 title and number of the program announcement must be typed on line 2 of the face page of the application form and the YES box must be marked. Submit a signed, typewritten original of the application, including the Checklist, and five 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 BETHESDA, MD 20817 (for express/courier service) REVIEW CONSIDERATIONS Applications will be assigned on the basis of established PHS referral guidelines. Applications will be evaluated for scientific and technical merit by an appropriate scientific review group convened in accordance with the standard NIH peer review procedures. As part of the initial merit review, all applications will receive a written critique and undergo a process in which only those applications deemed to have the highest scientific merit, generally the top half of applications under review, will be discussed, assigned a priority score, and receive a second level review by the appropriate national advisory council or board. Review Criteria The goals of NIH-supported research are to advance our understanding of biological systems, improve the control of disease, and enhance health. In the written comments reviewers will be asked to discuss the following aspects of the application 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 the 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 be advanced? What will be the effect of these studies on the concepts or methods that drive this field? (2) Approach: Are the conceptual framework, design, methods, and analyses adequately developed, well-integrated, and appropriate to the aims of the project? Does the applicant acknowledge potential problem areas and consider alternative tactics? (3) Innovation: Does the project employ novel concepts, approaches or method? Are the aims original and innovative? Does the project challenge existing paradigms or develop new methodologies or technologies? (4) Investigator: Is the investigator appropriately trained and well suited to carry out this work? Is the work proposed appropriate to the experience level of the principal investigator and other researchers (if any)? (5) Environment: Does the scientific environment in which the work will be done contribute to the probability of success? Do the proposed experiments take advantage of unique features of the scientific environment or employ useful collaborative arrangements? Is there evidence of institutional support? In addition to the above criteria, in accordance with NIH policy, all applications will also be reviewed with respect to the following: o The adequacy of plans to include both genders, minorities and their subgroups, and children as appropriate for the scientific goals of the research. Plans for the recruitment and retention of subjects will also be evaluated. o The reasonableness of the proposed budget and duration in relation to the proposed research o The adequacy of the proposed protection for humans, animals or the environment, to the extent they may be adversely affected by the project proposed in the application. AWARD CRITERIA Award criteria that will be used to make award decisions include: o scientific merit (as determined by peer review) o availability of funds o programmatic priorities. INQUIRIES Inquiries are encouraged. The opportunity to clarify any issues or questions from potential applicants is welcome. Direct inquiries regarding programmatic issues to: Barbara Linder, M.D, Ph.D. Division of Diabetes, Endocrinology and Metabolic Diseases National Institute of Diabetes and Digestive And Kidney Diseases 6707 Democracy Boulevard, Rm. 699 MSC 5460 Bethesda, MD 20892-5460 Telephone: (301) 594-0021 FAX: (301) 480-3503 E-mail: bl99n@nih.gov Peter Dudley, Ph.D. Vision Research Program National Eye Institute Executive Plaza South, Rm. 350 Bethesda, MD 20892 Telephone: (301) 496-0484 FAX: (301) 402-0528 E-mail: pd8n@nih.gov Momtaz Wassef, Ph.D. Division of Heart and Vascular Diseases National Heart, Lung, and Blood Institute 6701 Rockledge Drive, Suite 10186 Bethesda, MD 20892-7956 Telephone: (301) 435-0550 FAX: (301) 480-2848 E-mail: mw47d@nih.gov David B. Finkelstein, Ph.D. Biology of Aging Program National Institute on Aging 7201 Wisconsin Avenue, Suite 2C231, MSC 9205 Bethesda, MD 20892-9205 Telephone: (301) 496-6402 FAX: (301) 402-0010 Email: df18s@nih.gov Paul Nichols, Ph.D. National Institute of Neurological Disorders and Stroke Neuroscience Center, Room2118 6001 Executive Blvd. Bethesda, MD 20892 Telephone: (301) 496-9964 FAX: (301) 401-2060 E-mail: pn13w@nih.gov Rebecca B. Costello, Ph.D. Office of Dietary Supplements Office of Disease Prevention Building 31, 1B29 Bethesda, MD 20892 Telephone: (301) 435-2920 FAX: 301-480-1845 Email: bc135d@nih.gov Direct inquiries regarding fiscal matters to: Charlette Kenley Division of Extramural Activities Grants Management Branch National Institute of Diabetes and Digestive And Kidney Diseases 6707 Democracy Boulevard Rm. 640 MSC 5456 Bethesda, MD 20892-5456 Telephone: (301) 594-8847 FAX: (301) 480-3504 E-mail: ck128k@nih.gov Margie Baritz Division of Extramural Activities National Eye Institute Executive Plaza South, Rm. 350 Bethesda, MD 20892-6600 Telephone: (301) 496-5884 FAX: (301) 496-9997 E-mail: mb41k@nih.gov Owen Bobbitt Grants Operations Branch National Heart, Lung, and Blood Institute 6701 Rockledge Drive, Suite 7156 Bethesda, MD 20892-7926 Telephone: (301) 435-0177 FAX: (301)480-3310 E-mail: ob5i@nih.gov Linda Whipp Grants and Contracts Management Office National Institute on Aging 7201 Wisconsin Avenue, Suite 2N212, MSC 9205 Bethesda, MD 20892 Telephone: (301) 496-1472 FAX: (301) 402-3672 Email: lw17m@nih.gov Denise Chatman Grants Management Branch National Institute of Neurological Disorders and Stroke Neuroscience Center, Room 3290 6001 Executive Blvd. Bethesda, MD 20892 Telephone: (301) 496-9231 FAX: (301) 402-0129 E-mail: dc55g@nih.gov AUTHORITY AND REGULATIONS This program is described in the Catalog of Federal Domestic Assistance No. 93.847, 93.867, 93.121, 93.866, and 93.853. Awards are made under authorization of sections 301 and 405 of the Public Health Service Act as amended (42 USC 241 and 284) and administered under NIH grants policies and Federal Regulations 42 CFR 52 and 45 CFR Parts 74 and 92. This program is not subject to the intergovernmental review requirements of Executive Order 12372 or Health Systems Agency review. The PHS strongly encourages all grant and contract recipients to provide a smoke-free workplace and promote the non-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, and 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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