PA-00-026: THE ROLE OF ENDOTHELIAL DYSFUNCTION IN DIABETIC COMPLICATIONS

Department of Health
and Human Services (HHS)

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THE ROLE OF ENDOTHELIAL DYSFUNCTION IN DIABETIC COMPLICATIONS Release Date: December 13, 1999 PA NUMBER: PA-00-026 National Institute of Diabetes and Digestive and Kidney Diseases 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) invites investigator-initiated research grant applications to study the role of endothelial alteration or dysfunction in the etiology and pathogenesis of the micro- and macrovascular complications of diabetes. Endothelial function is known to be abnormal in diabetes and may be an early step in the development of atherosclerotic lesions. Recent work has also focused attention on the role of endothelial function in the pathogenesis of microvascular complications. This PA, with a $1 million dollar annual set- aside, is intended to stimulate the application of new molecular technologies to this area. Understanding the pathogenesis of endothelial dysfunction in diabetes at the molecular and cellular level will provide new targets for pharmacologic or genetic manipulations to prevent complications of diabetes. HEALTHY PEOPLE 2000 The Department of Health and Human Services (DHHS) is committed to achieving the health promotion and disease prevention objectives of "Healthy People 2000," a DHHS-led national activity for setting priority areas. This PA, The Role of Endothelial Dysfunction in Diabetic Complications, is related to the priority area of diabetes and chronic disabling conditions. Potential applicants may obtain a copy of "Healthy People 2000" at http://odphp.osophs.dhhs.gov/pubs/hp2000 ELIGIBILITY REQUIREMENTS Applications may be submitted by domestic and foreign for-profit and nonprofit 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 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 $100,000 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 FUNDS AVAILABLE $1 million will be set aside by NIDDK in FY 2001, 2002, and 2003 to fund competing applications relevant to this PA. Funding is dependent on the receipt of a sufficient number of applications of high scientific merit and on the availability of funds for this purpose. RESEARCH OBJECTIVES Background Diabetes is the leading cause of end stage renal disease, blindness in adults, and non-traumatic lower leg amputations. In addition, individuals with diabetes have a 2- to 4-fold increased risk of developing, and dying from, cardiovascular disease. One in ten health care dollars in the United States is spent on diabetes, most of these health care costs are incurred in the treatment of macro- and microvascular complications. Endothelial dysfunction is a key feature of diabetes and is thought to be a major cause of the associated vascular complications. Endothelial cell damage, with loss of the vascular protective effects of nitric oxide (NO), is a likely early step in the accelerated atherosclerosis of diabetes. Impaired endothelial-dependent vasodilatation has been described in patients with type 1 and type 2 diabetes, and the degree of impairment may correlate with glycemic control. Hyperglycemia itself appears to affect multiple mechanisms that increase atherosclerosis. Hyperglycemia enhances oxidation, thrombosis, inflammation, matrix production, and the formation of advanced glycation end products and other metabolites that can potentially damage the vasculature. Insulin may also play an important role in atherogenesis. Even in the absence of diabetes, patients with insulin resistance are at significantly increased risk for atherosclerosis. Insulin resistance is associated with hypertriglyceridemia and a preponderance of small, dense low density lipoprotein (LDL). This LDL phenotype may be more susceptible to oxidative modification, a process that promotes atherosclerosis by impairing endothelial cell function, stimulating inflammation and adhesion, and promoting vascular smooth muscle cell changes. Insulin itself stimulates vascular smooth muscle cell migration, growth and matrix production, and enhances clot formation. Insulin resistance is also associated with impaired NO production. Endothelial dysfunction may also contribute substantially to the pathogenesis of microvascular complications. Diabetic nephropathy results from changes in blood flow in small vessels with an increase in mesangial cells and excess accumulation of extracellular matrix. The earliest retinal abnormalities induced by hyperglycemia are impaired autoregulation of retinal blood flow and decreased retinal blood flow, associated with loss of endothelial- supporting pericytes from retinal capillaries. These changes are followed by endothelial cell permeability changes and retinal capillary occlusion. In diabetic peripheral sensory neuropathy, capillary closure is frequently observed in the vasa nervorum, and endoneurial blood flow and oxygen tension are reduced. The molecular basis of endothelial cell dysfunction in diabetes is not well understood. Mechanisms by which hyperglycemia may cause microvascular damage include: increased polyol pathway activity and associated changes in intracellular redox state, increased diacylglycerol synthesis with consequent activation of protein kinase C, increased nonenzymatic glycation of both intracellular and extracellular proteins, and increased formation of reactive oxygen species. Increased free radical generation, increased oxidative stress and abnormal plasma lipid composition have all been implicated in macrovascular endothelial cell dysfunction. Determining the effects of hyperglycemia on endothelial function and the subsequent role of endothelial abnormalities in the development of diabetic vascular lesions is critical to understanding the etiology and pathogenesis of the micro- and macrovascular complications of diabetes. Dissecting these pathways will provide new targets for effective therapeutic or prevention strategies. Objectives and Scope Recent advances in understanding endothelial cell biology, coupled with new molecular technologies, provide powerful tools for studying endothelial function in diabetes. In addition, there is clearly a need for the development of good animal models of diabetic complications, as well as of surrogate markers that would be useful for monitoring the development and progression of complications. The use of such markers would also facilitate the study of potential pharmacologic agents that could be developed, based on a better understanding of the etiology and pathogenesis of diabetic complications. Appropriate topics for investigation would include, but are not limited to: o Studies to determine how hyperglycemia alters endothelial and/or vascular smooth muscle cell function, including changes in gene expression. o Studies to determine what genes modulate susceptibility of tissues to hyperglycemia-induced injury. o Studies to understand the sequence of events in the pathogenesis of hyperglycemia-induced vascular injury. o Studies to determine how vascular inflammation is altered in diabetes. o Studies to determine the effects of insulin in vascular cells at the molecular and physiologic levels. o Studies to determine how specific alterations in circulating lipids in patients with diabetes affect the development and expansion of atherosclerotic lesions. o Studies to determine how hyperglycemia or hyperinsulinemia alter hemostasis and cellular interactions at the surface of unstable atherosclerotic plaques. o Studies to evaluate how antidiabetic drugs affect the vasculature and the coagulation system, and determine what impact they may have on atherosclerosis development and progression. 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 subpopulations must be included in all NIH supported biomedical and behavioral research projects involving human subjects, unless a clear and compelling rationale and justification is provided 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 "NIH Guidelines For Inclusion of Women and Minorities as Subjects in Clinical Research," which have been published in the Federal Register of March 28, 1994 (FR 59 14508-14513) and in the NIH Guide For Grants and Contracts, Vol. 23, No. 11, March 18, 1994, available on the web at http://grants.nih.gov/grants/guide/notice-files/not94-100.html 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 may also obtain copies of these policies from the program staff listed under INQUIRIES. Program staff may also provide additional relevant information concerning the policy. APPLICATION PROCEDURES Applications are to be submitted on the grant application form PHS 398 (rev. 4/98) and will be accepted at the standard application deadlines as indicated in the application kit. Application kits are available at most institutional offices of sponsored research, or 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: [email protected]. 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 NIDDK program staff before submitting the application, i.e., as plans for the study are being developed. Furthermore, the applicant must obtain agreement from the staff that the NIDDK 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 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. (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 key 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 key 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. Submit the signed, original, single-sided application, including the Checklist, along with five signed photocopies and five collated sets of appendix materials 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) The Center for Scientific Review (CSR) will not accept any application in response to this PA that is essentially the same as one currently pending initial review, unless the applicant withdraws the pending application. The CSR will not accept any application that is essentially the same as one already reviewed. This does not preclude the submission of substantial revisions of applications already reviewed, but such applications must include an introduction addressing the previous critique. The goal of this PA is to stimulate investigations of endothelial alteration or dysfunction in the etiology and pathogenesis of the complications of diabetes. Applications that deal primarily with the macrovascular complications of diabetes may also be assigned to the National Heart, Lung and Blood Institute based on current CSR referral guidelines. REVIEW CONSIDERATIONS Applications will be assigned on the basis of established NIH 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, reviewer 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. o 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? o 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? o 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? o 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)? o 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 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 to the proposed research. o The adequacy of the proposed protection of humans, animals, or the environment, to the extent that they may be adversely affected by the project proposed in the application. o Availability of special opportunities for furthering research programs through the use of unusual talent resources, populations, or environmental conditions in other countries which are not readily available in the United States or which provide augmentation of existing U.S. resources. AWARD CRITERIA Applications will compete for available funds with all other recommended applications. The following will be considered in making funding decisions: o Quality of the proposed project as determined by peer review, o Availability of funds, o Program priority. 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 NIDDK 45 Center Drive MSC 6600 Bethesda, MD 20892-6600 Telephone: (301) 594-0021 FAX: (301) 480-3503 E-mail: [email protected] Direct inquiries regarding fiscal and administrative matters to: Florence Danshes Division of Extramural Activities NIDDK 45 Center Drive MSC 6600 Bethesda, MD 20892-6600 Telephone: (301) 594-8861 AUTHORITY AND REGULATIONS This program is described in the Catalog of Federal Domestic Assistance No. 93.847. Awards are made under authorization of the Public Health Service Act, Title IV, Part A (Public Law 78-410, as amended by Public Law 99-158, 42 USC 241 and 285) 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 NIH 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, 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 NIH mission to protect and advance the physical and mental health of the American people.

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