CELLULAR AND MOLECULAR MECHANISMS OF DIABETIC CARDIOMYOPATHY Release Date: January 18, 2000 RFA: HL-00-009 National Heart, Lung, and Blood Institute National Institute of Diabetes and Digestive and Kidney Diseases National Institute on Aging Letter of Intent Receipt Date: March 3, 2000 Application Receipt Date: April 21, 2000 THIS RFA 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 RFA. PURPOSE The objective of this initiative is to support research to elucidate the cellular and molecular mechanisms that underlie the pathogenic processes occurring in the heart leading to diabetic cardiomyopathy. The overall goal is to stimulate innovative multidisciplinary research to develop new strategies that effectively prevent or treat cardiac myopathic disease progression in diabetic patients. HEALTHY PEOPLE 2000 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 Request for Applications (RFA), CELLULAR AND MOLECULAR MECHANISMS OF DIABETIC CARDIOMYOPATHY is related to one or more of the priority areas. Potential applicants may obtain a copy of "Healthy People 2010" at http://odphp.osophs.dhhs.gov/pubs/hp2000. 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 RFA will use the National Institutes of Health (NIH) research project grant (R01) award mechanism. Responsibility for the planning, direction, and execution of the proposed project will be solely that of the applicant. The total project period for an application submitted in response to this RFA may not exceed 4 years. This RFA is one-time solicitation. Future unsolicited competing continuation applications will compete with all investigator-initiated applications and be reviewed according to the customary peer review procedures. The anticipated award date is September 29, 2000. FUNDS AVAILABLE For FY 2000, the NHLBI intends to commit approximately $4,000,000 and the NIDDK and NIA intend to commit approximately $250,000 and $500,000, respectively to fund 12 to 16 new grants in response to this RFA. An applicant may request a project period of up to 4 years and a budget for direct costs for up to 10 modules of $25,000 each (maximum $250,000 direct costs) per year, including Facilities and Administrative Costs on consortium arrangements. Because the nature and scope of the research proposed may vary, it is anticipated that the size of each award will also vary. Although the financial plans of the NHLBI, NIDDK and NIA provide support for this program, awards pursuant to this RFA are contingent upon the availability of funds and the receipt of a sufficient number of meritorious applications. At this time, it is not known if competing renewal applications will be accepted and/or if this RFA will be reissued. RESEARCH OBJECTIVES Background Cardiovascular disease represents the major cause of morbidity and mortality in diabetic patients. Patients with diabetes also have fewer warning signs of heart attack, increased mortality during the first year after a heart attack, poorer response to angioplasty, and higher rates of congestive heart failure. Increased risks for heart failure and death in patients with diabetes mellitus are especially pronounced in women, African-Americans, certain Native Americans and the elderly. One reason for the poor prognosis in patients with both diabetes and ischemic heart disease seems to be an worsened myocardial function leading to accelerated heart failure (diabetic cardiomyopathy). Despite the obvious importance of diabetic cardiomyopathy, a better understanding of this complex and very likely multi-factorial problem at the cellular and molecular levels is lacking. Also, there has been very little progress in understanding its underlying pathophysiology, specific manifestations and natural history in patients, and treatment. Prior to 1972, the increased cardiovascular morbidity and mortality that diabetics endure had been attributed to vascular disease. In 1972, Rubler et al. first described a specific type of cardiomyopathy related to diabetes, suggesting that this myocardial disease exists as an independent clinical entity. The term "diabetic cardiomyopathy" was proposed. This work has subsequently been followed by numerous investigations reporting cardiac dysfunction in diabetic patients which occurred in either the absence or presence of coronary artery disease. Diabetic cardiomyopathy, as an early complication of diabetes, is manifested by diastolic dysfunction followed by abnormalities in systolic function. When presenting with other cardiovascular complications (i.e., ischemic heart disease or hypertension), diabetic patients have a much worse prognosis than non-diabetic patients and are more prone to progress to congestive heart failure . The underlying diabetic cardiomyopathy appears to contribute to accelerated heart failure. Although several mechanisms have been proposed for diabetic cardiomyopathy, the pathogenesis of this disease is unknown. Common histopathologic abnormalities of diabetic cardiomyopathy include small vessel disease, interstitial fibrosis and myocardial hypertrophy. However, there is conflicting evidence regarding the relative role of these derangements in the development of diabetic cardiomyopathy. Also unsettled is the relationship of these cardiac changes to the type of diabetes, its duration and its severity. Much of what is known about the pathogenesis of diabetic complications has been gleaned from studies using animal models. By far the most extensively employed animal model is the streptozotocin (STZ)-induced diabetes mellitus in the rat. Rats given STZ for weeks to months develop hypoinsulinemic diabetes mellitus, with consistent depression of myocardial contraction, and, most especially, relaxation. Effects on "passive" diastolic compliance have been variable. These contractile abnormalities are correlated with several alterations in excitation-contraction coupling, ion transport and exchange, including prolongation of the action potential, and depressed sarcoplasmic reticular calcium pumping and sarcolemmal Na/Ca exchange. Abnormalities of the contractile machinery have also been detected in mechanical studies in skinned strips, in addition to a V1 to V3 isomyosin switch. While the STZ-diabetes mellitus rat is a reliable, well-characterized model, it may not be the most relevant model for human disease, particularly Type II diabetes. Clinical and experimental studies have provided only limited insights into the mechanism(s) of diabetic cardiomyopathy. Free radical production with altered lipid content of membranes is one postulated mechanism. The direct effects of abnormal carbohydrate metabolism and excessive fatty acid oxidation have been implicated as an important proximate cause of diabetic cardiomyopathy in STZ treated rats. However, several other consequences of abnormal carbohydrate metabolism, for example, depressed pyruvate dehydrogenase activity and inadequate energy availability, have also been proposed to account for diabetic cardiomyopathy. Possible molecular/genetic mechanisms involved in diabetic cardiomyopathy in animal models have in general not been well characterized. Microvascular disease and protein glycation/glycosylation, important mechanisms of complications in patients with diabetes mellitus, do not have particularly good counterparts in experimental models. The direct effects of hyperglycemia are also difficult to characterize in intact animals. Thus, the roles of these major components of diabetes mellitus in causation of diabetic cardiomyopathy are particularly difficult to evaluate. There has been little progress in characterizing the cellular and molecular features of diabetic cardiomyopathy in patients, much less their mechanisms. It remains unclear whether there are differences between insulin dependent and non-insulin dependent forms of diabetes mellitus with respect to the development of diabetic cardiomyopathy. Defining cardiac changes in diabetic humans is obviously extremely important in light of the fact that diabetes is a chronic disease not well represented by animal models. Proposed Research This initiative is directed at elucidation of processes influencing diabetic cardiomyopathy at the molecular, cellular, tissue, and organ levels. Studies focusing on cellular and molecular mechanisms, genetic susceptibility, pharmacologic intervention, and development of novel strategies to treat and prevent progression of diabetic cardiomyopathy are sought. The following aims are examples of the scope of the solicitation. They are not exclusive and other innovative approaches are encouraged based on the applicant=s expertise and knowledge. o Develop and utilize experimental models with high relevance to human diabetic cardiomyopathy to answer specific, mechanistic questions o Delineate connections between altered intracellular signaling, including those related to glucose transport and protein kinase C activation, and altered contractile function and cell death in disease states o Examine the relation between altered energy metabolism and myocardial function in diabetes mellitus o Elucidate the mechanisms contributing to the modification of cardiac responses to ischemia-reperfusion and oxidative stress in diabetes mellitus. o Elucidate myocardial cellular/molecular alterations in patients with diabetes mellitus. o Apply noninvasive imaging technologies to define alterations in the myocardium of diabetic patients o Examine the fundamental reasons for gender, racial and ethnic variations in diabetes mellitus associated cardiomyopathy. o Develop novel therapeutic interventions using innovative genetic, molecular and cellular approaches 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 was 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: https://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: https://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. LETTER OF INTENT Prospective applicants are asked to submit a letter of intent that includes a descriptive title of the proposed research, the name, address, and telephone number of the Principal Investigator, the identities of other key personnel and participating institutions, and the number and title of the RFA in response to which the application may be submitted. 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 NHLBI, NIDDK and NIA staff to estimate the potential review workload and avoid conflict of interest in the review. The letter of intent is to be mailed, or faxed, by March 3, 2000 to: Dr. C. James Scheirer Division of Extramural Affairs National Heart, Lung, and Blood Institute 6701 Rockledge Drive, Room 7220, MSC 7924 Bethesda, MD 20892-7924 Telephone: (301) 435-0266 FAX: (301) 480-3541 Email: js110j@nih.gov. APPLICATION PROCEDURES 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 Grant applications can be found at https://grants.nih.gov/grants/funding/modular/modular.htm 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. The research grant application form PHS 398 (rev. 4/98) is to be used in applying for these grants. These forms are available at most institutional offices of sponsored research and 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. The RFA label available in the PHS 398 (rev. 4/98) application form 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 of the face page of the application for and the YES box must be marked. The sample RFA label available at: https://grants.nih.gov/grants/funding/phs398/label-bk.pdf has been modified to allow for this change. Please note this is in pdf format. 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 BETHESDA, MD 20817 (for express/courier service) At the time of submission, two additional copies of the application must be sent to: Dr. C. James Scheirer Division of Extramural Affairs National Heart, Lung, and Blood Institute 6701 Rockledge Drive, Room 7220, MSC 7924 Bethesda, MD 20892-7924 Telephone: (301)435-0266 FAX: (301)480-3541 Email: js110j@nih.gov. Applications must be received by the application receipt date listed in the heading of this RFA. If an application is received after that date, it will be returned to the applicant without review. The Center for Scientific Review (CSR) will not accept any application in response to this RFA 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. 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. 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 https://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 subsequent years 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: https://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. REVIEW CONSIDERATIONS Upon receipt, applications will be reviewed for completeness by the CSR and responsiveness by the NHLBI, NIDDK and NIA. Incomplete and/or non-responsive applications will be returned to the applicant without further consideration. 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 NHLBI in accordance with the review criteria stated below. 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 the applications under review, will be discussed, assigned a priority score, and receive a second level review by the NHLBI and NIDDK and NIA National Advisory Councils. 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. Schedule Letter of Intent Receipt Date: March 3, 2000 Application Receipt Date: April 21, 2000 Peer Review Date: June/July 2000 Council Review: September 7-8, 2000 Earliest Anticipated Start Date: September 29, 2000 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 concerning this RFA are encouraged. The opportunity to clarify any issues or questions from potential applicants is welcome. Direct inquiries regarding programmatic issues to: Isabella Liang, Ph.D. Division of Heart and Vascular Diseases National Heart, Lung, and Blood Institute Two Rockledge Center, Suite 9142 6701 Rockledge Drive Bethesda, MD 20892-7940 Telephone: (301)435-0520 FAX: (301) 480-1335 Email: liangi@nih.gov Barbara Linder, M.D., Ph.D. Division of Diabetes. Endocrinology and Metabolic Diseases National Institute of Diabetes and Digestive and Kidney Diseases Building 45, Room 5AN18A Bethesda, MD 20892 Telephone: (301) 594-0021 FAX: (301) 480-3503 Email: linderb@extra.niddk.nih.gov David B. Finkelstein, Ph.D. Biology of Aging Program National Institute on Aging 7201 Wisconsin Avenue, Suite 2C231 Bethesda, MD 20892 Telephone: (301) 496-6402 FAX: (301) 480-0010 Email: finkelsd@nia.nih.gov Direct inquiries regarding fiscal matters to: Ms. Carol Dangel Grants Operations Branch National Heart, Lung, and Blood Institute Two Rockledge Center, Suite 7140 6701 Rockledge Drive, MSC 7926 Bethesda, MD 20892-7926 Telephone: (301)435-0177 FAX: (301)480-3310 Email: dangelc@nih.gov Ms. Charlette Kenley Grants Management Branch National Institute of Diabetes and Digestive and Kidney Diseases Building 45, Room 6AS49D Bethesda, MD 20892 Telephone: (301) 594-8847 FAX: (301) 480-3504 Email: kenleyc@extra.niddk.nih.gov Ms. Crystal Ferguson Grants and Contract Management Office National Institute on Aging 7201 Wisconsin Avenue, Suite 2N212 Bethesda, MD 20892 Telephone: (301) 496-1472 FAX: (301) 402-3672 Email: fergusoc@nia.nih.gov AUTHORITY AND REGULATIONS This program is described in the Catalog of Federal Domestic Assistance No. 93.837, 93.847 and 93.866. 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 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 PHS mission to protect and advance the physical and mental health of the American people.
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