Full Text HL-95-006 SPECIALIZED CENTERS OF RESEARCH IN MOLECULAR MEDICINE AND ATHEROSCLEROSIS NIH GUIDE, Volume 23, Number 35, October 7, 1994 RFA: HL-95-006 P.T. 04 Keywords: Cardiovascular Diseases Biology, Molecular Pathophysiology Disease Model Gene Therapy+ National Heart, Lung, and Blood Institute Letter of Intent Receipt Date: October 9, 1995 Application Receipt Date: December 8, 1995 PURPOSE This solicitation invites new grant applications to enter into a single open competition for Specialized Centers of Research (SCOR) in Molecular Medicine and Atherosclerosis. The goals of the program are to advance the understanding of the etiology and pathobiology of the atherosclerotic lesion at the molecular level through the modern methods and approaches of molecular medicine. Molecular medicine represents a paradigm shift to more systematic targeting and design of clinical interventions based upon detailed and sophisticated molecular information. It embraces strategies aimed at understanding the molecular basis of disease, and at studying how the structure and activity of living cells are controlled by molecules such as DNA and proteins. A SCOR provides the opportunity for investigators to engage in interdisciplinary and collaborative research that is focused on a specific disease or an area within a disease category. It is required that SCOR applications include studies of human subjects and/or human materials as well as basic studies clearly related to a disease area. The foundation of the clinical component should be strongly linked to the basic science projects; the basic science studies should be driven by the needs of the clinical projects. Thus, a SCOR has a central theme to which all research projects pertain. In addition, a SCOR may include core units to provide services to the various research projects and to support the organizational and administrative aspects of the program. Previous generations of the SCOR in Arteriosclerosis have contributed significantly to the understanding of the basic mechanisms responsible for the development of atherosclerosis, and clarified the role of major risk factors such as blood cholesterol and specific lipoproteins and apoproteins in atherogenesis. The objectives of this new cycle of SCORs are to focus on studies on the pathobiology of the atherosclerotic lesion specially at the level of the arterial wall. Such studies may include investigations of the mechanisms for lesion susceptibility and initiation; the mechanisms of lesion progression, complication, and regression; and the interactions of the vessel wall with lipoproteins and other systemic factors promoting atherogenesis. The new program emphasizes a shift away from studies with an exclusive focus on the structure and function of lipids and lipoproteins. The means for acquiring this new knowledge would involve exploitation of new techniques and strategies of molecular medicine such as gene transfer and gene mapping and identification, three-dimensional structural biology, vascular imaging, genetically modified animal models, and gene therapy, which can yield information that heretofore was inaccessible. All these techniques are complemented by clinical research disciplines as appropriate. Coronary Heart Disease (CHD) accounts for the largest share of deaths from diseases of the heart. CHD rates are particularly high in blacks, perhaps due to the higher prevalence of major CHD risk factors such as hypertension, diabetes and obesity. Differences in the nature of the atherosclerotic process leading to CHD in blacks may also be a contributory factor. The National Heart, Lung, and Blood Institute (NHLBI) wishes to encourage research into the pathogenesis of the atherosclerotic lesion in blacks as part of this SCOR program. To chart a course for future research, the NHLBI convened a working group, which released a report in March 1994 on RESEARCH IN CORONARY HEART DISEASE IN BLACKS. This report provides specific recommendations for future research in black populations. The NHLBI wishes to strongly encourage research into the pathogenesis of the atherosclerotic lesion in women, Blacks and other minorities as part of this SCOR program and recommends that this report, in particular, be consulted. In addition, to encourage women and underrepresented minority investigators to work within a SCOR project, to facilitate recruitment of new scientists to this area of research, and to foster cutting edge and innovative research directions, each SCOR program may support up to two investigators by utilizing up to $50,000 per year per investigator to fund pilot and feasibility projects. This will allow underrepresented minority investigators to acquire the skills and data to become more competitive in seeking independent research support (e.g., R01, R29). These funds will not be supplements, but rather specific dollars identified in the SCOR budget and restricted to be used for this purpose. The recipients would be chosen based on a proposal written by a SCOR investigator and reviewed by an internal review committee at the parent institution. HEALTHY PEOPLE 2000 The Public Health Service (PHS) is committed to achieving the health promotion and disease prevention objectives of "Healthy People 2000," a PHS-led national activity for setting priority areas. This RFA, Specialized Centers of Research in Molecular Medicine and Atherosclerosis, is related to the priority area of heart disease and stroke. Potential applicants may obtain a copy of Healthy People 2000" (Full Report: Stock No. 017-001-00474-0 or Summary Report: Stock No. 017-001-00473-1) through the Superintendent of Documents, Government Printing Office, Washington, DC 20402-9325 (telephone 202-783-3238). ELIGIBILITY REQUIREMENTS Applications may be submitted by for-profit and non-profit domestic institutions, public and private, such as universities, colleges, hospitals, laboratories, units of State and local goverrnments, and eligible agencies of the Federal government. Racial/ethnic minority individuals, women, and persons with disabilities are encouraged to apply as Principal Investigators. Awards will not be made to foreign institutions. However, under exceptional circumstances, a foreign component critical to a project may be included as a part of that project. MECHANISM OF SUPPORT This RFA will use the National Institutes of Health (NIH) specialized center of research (P50) grant mechanism. Responsibility for planning the proposed project will be solely that of the applicant. The total project period of applications submitted in response to the present RFA may not exceed five years. The anticipated date of award is December 1, 1996. Upon initiation of the program, there will be required communications between SCORs, usually in the setting of a biennial combined meeting of SCOR participants. Applicants should request travel funds for this purpose in fiscal years 1997, 1999, and 2001 of the budget. Applicants should also include a statement in their applications indicating their willingness to participate in these meetings. The principal investigator should be an established research scientist with the ability to ensure quality control and the experience to administer effectively and integrate all components of the program. A minimum time commitment of 25 percent is expected for this individual. The principal investigator must also be the project leader of one of the component research projects. If, through peer review, this project is not recommended for further consideration, the overall SCOR application will not be considered further. If this project is judged by peer review to be of low scientific merit, it will markedly reduce the overall scientific merit ranking assigned to the entire application by the review committee. Project leaders must agree to commit at least 20 percent effort to each project for which they are responsible. This RFA is intended to support Specialized Centers of Research grants. Therefore, applications that include only basic or only clinical research will not be responsive to this RFA. In addition, clinical research projects focused on large epidemiological studies or large clinical trials will be considered unresponsive to this RFA. This new SCOR program focuses on studies of the atherosclerotic lesion at the level of the arterial wall. Thus, studies with exclusive focus on the structure and function of lipoproteins will be considered unresponsive to this RFA. Applicants should be aware that applications for supplemental funds will be accepted only under unusual and well defined circumstances. For example, the NHLBI may provide supplements to Centers to continue a project not funded for the entire project period. NHLBI staff should be consulted prior to submission of an application. Supplemental grants for these purposes will not be awarded for the first 18 months or the last 12 months of a total project period. Length of SCOR Programs Each NHLBI SCOR program be limited to ten years of support. Exceptions to this policy will be made only if a thorough evaluation of needs and opportunities, conducted by a committee composed of non-federal experts, determines that there are extraordinarily important reasons to continue a specific SCOR program. Under this policy, a given SCOR grant is awarded for a five-year project period following an open competition. Only one five-year competing renewal is permitted, for a total of ten years of support, unless the SCOR program is recommended for extension. The NHLBI comprehensive evaluation of the SCOR program in Molecular Medicine and Atherosclerosis will be conducted during the second project period according to the following timetable. Announcement SCOR competition FY 1995 Project Period (First Competition) FY 1997 to FY 2001 Program Re-announcement FY 1999 Project Period (Second Competition) FY 2002 to FY 2006 Letters to SCOR Directors regarding SCOR evaluation Plans FY 2004 (mid-way through year 02 of 2nd project period) SCOR Evaluation Meeting FY 2004 (Late in year 02 of project period) Notification of SCOR Directors of NHLBI decision FY 2004 (mid-way through year 03 of 2nd project period) The NHLBI does not limit the number of SCOR applications in a given SCOR program from one institution provided there is a different SCOR principal investigator for each application and each application is self-contained and independent of the other(s). This does not preclude cooperation planned or possible among participants of SCORs after awards are made. Scientific overlap among applications will not be accepted. If more than one application is envisioned from an institution, the institution is encouraged to discuss its plans with the NHLBI SCOR program administrator. Consortium Arrangements If a grant application includes research activities that involve institutions other than the grantee institution, the program is considered a consortium effort. Such activities may be included in a SCOR grant application, but it is imperative that a consortium application be prepared so that the programmatic, fiscal, and administrative considerations are explained fully. The published policy governing consortia is available in the business offices of institutions that are eligible to receive Federal grants-in- aid. Consult the latest published policy governing consortia before developing the application. If clarification of the policy is needed, contact Mr. William Darby, Section Chief, Grants Operation Branch, NHLBI, (301)594-7458. Applicants should exercise great diligence in preserving the interactions of the participants and the integration of the consortium project(s) with those of the parent institution, because synergism and cohesiveness can be diminished when projects are located outside the group at the parent institution. Indirect costs paid as part of a consortium agreement are excluded from the limit on the amount of direct costs that can be requested. FUNDS AVAILABLE Applicants may request up to $1,170,000 direct costs, not including indirect costs for collaborating institutions, in the first year, with a maximum increase of no more than four percent in each future year requested in the application. It is anticipated that seven SCOR grants, for a five year project period, at an estimated first year total cost of $12.285 million, will be supported. Award of grants pursuant to this RFA is contingent upon receipt of funds for this purpose. Designated funding levels are subject to change at any time prior to final award, due to unforeseen budgetary, administrative, and/or scientific developments. Equipment is included in the budget limitation. However, requests for expensive special equipment that cause an application to exceed this limit may be permitted on a case-by-case basis following staff consultation. Such equipment requires justification. Final decisions will depend on the nature of the justification and the availability of funds. RESEARCH OBJECTIVES Background Atherosclerosis underlies most coronary heart disease, a major cause of death (500,000 per year) and disability, as well as much peripheral vascular disease, many cases of stroke, and several other diseases. Atherosclerosis is a multifactorial process with a complex and incompletely understood etiology. An interdisciplinary approach integrating basic sciences with the clinical aspects of the disease is required to study this disorder, and the NHLBI adopted the SCOR mechanism in 1971 for that purpose. Since their inception, the SCORs in Arteriosclerosis have promoted multidisciplinary research on the relationships of hyperlipidemia, hypertension, thrombosis, diabetes, smoking, and other systemic risk factors to the etiology and pathogenesis of atherosclerosis. The SCORs have advanced our understanding of the structure and function of lipoproteins and apolipoproteins at the systemic and cellular levels and their role in atherogenesis. The program contributed greatly to the development of the concept of the oxidative modification hypothesis for atherosclerosis, and demonstrated that cholesterol lowering in Familial Hypercholesterolemia retarded the progression and promoted the regression of human coronary atherosclerotic lesions. The SCORs pioneered research on nutrition, lesion dynamics, and the relationship of hemodynamics to atherogenesis, and led to the establishment of nonhuman primate resources. The SCORs made important contributions to the pediatric aspects of atherosclerosis, and conducted behavioral and psychosocial research, and demonstration and education projects. Many of these studies have advanced sufficiently so as to no longer warrant a "special" program and are now supported by other mechanisms. Despite the significant progress achieved, however, there remain many unresolved questions in atherosclerosis research that are well suited for the comprehensive and multidisciplinary nature of the SCOR mechanism. The past accomplishments of the SCOR/A program and the potential for continued advances in understanding and averting atherosclerosis and coronary artery disease through an integrated program of clinical and basic research are the basis for continuation of this avenue of support. Atherosclerosis research is evolving; a shift of emphasis has gradually occurred from a predominant interest in the role of lipids and lipoproteins, towards defining the role of the arterial wall and its interactions with systemic factors. This shift has led to a change in the direction of the current solicitation. Significant progress has been made in elucidating the structure and function of lipoproteins and apoproteins, the generation of useful animal models for nutrition and metabolic studies, and the definition of factors influencing localization of atherosclerotic lesions. Other ongoing activities over the last decade have considerably expanded insight into relevant processes in the arterial wall. An explicit pathogenesis is emerging and the development of new modes of intervention to show the progression of the disease is now possible. However, much of the pathobiology involving the arterial wall is incompletely defined, and this is believed to be especially important in the clinical expression of atherosclerosis. Critical Areas of Research Opportunity To optimize the impact of the new SCOR program in the next decade, emphasis needs to be placed on the pathobiology of the arterial wall that results in the initiation, progression, complication, and regression of atherosclerosis. Studies on systemic factors promoting atherogenesis and its complications acting at the level of the vessel wall also need to be addressed. To delineate the mechanisms responsible for atherosclerosis and its complications in humans, sophisticated, state-of-the-art methodologies and approaches of molecular medicine such as gene regulation, gene transfer, three-dimensional structural biology, vascular imaging techniques, gene mapping and identification, and genetically modified animal models are required, as well as the more standard research approaches. Because of the interdisciplinary nature of the research, collaboration among investigators of varied expertise within the same or different institution is strongly encouraged. Specifically, Networking (i.e., shared biologic and information resources, reagents, patients, genetically altered animals, and the like), will be established to prevent duplication of efforts and to maximize benefits in the most cost-efficient manner possible. The following are examples of methods, approaches, and areas of opportunities for research into lesion susceptibility and initiation; progression, complication, and regression of atherosclerotic lesions; and systemic factors promoting atherogenesis and its complications acting at the level of the arterial wall. The list is not to be regarded as complete or exclusive and other research proposed by applicants that meet the objectives of this program will be considered by the NHLBI. It includes examples of several questions pertaining to blacks. Mechanisms Involved in Lesion Susceptibility and Initiation Hemodynamic factors influence the localization of the atherosclerotic lesion. The role of sheer stress in affecting the site of early lesions is controversial in view of the demonstrated existence of selective ion channels that may signal changes in the local hemodynamic environment in vascular cells. In addition, there exists a newly discovered Shear Stress Response Element and DNA binding proteins in the promoter regions of certain genes that encode growth factors or adhesion molecules that are thought to play a role in lesion initiation. This type of work provides a framework for novel molecular approaches to the study of atherosclerotic lesion initiation that promise to provide insight into the critical links among well-defined risk factors, hemodynamics, and locally altered arterial wall biology. Another important gap in our knowledge of lesion initiation in humans relates to the formation of the arterial intima and the heterogeneity of smooth muscle and endothelial cells in the human arterial wall. New concepts of vascular developmental biology and molecular tools for distinguishing subpopulations of arterial cells are currently emerging. An opportunity thus exists to approach key issues in the initiation of human atherogenesis that previously have remained elusive. The effects of the well established risk factors on CHD events in the population at large have been shown to apply also to blacks, and most studies show that hypertension, glucose intolerance, and obesity may contribute disproportionately to CHD in black populations. The contribution of these risk factors to lesion initiation and acceleration would shed light on devising approaches for interventions targeted to black populations. Mechanisms Involved in Lesion Progression, Complication, and Regression Recent clinical and pathological data show that, in human coronary atherosclerosis, rupture of the plaque, rather than gradual closure, underlies many acute myocardial infarctions and episodes of unstable angina, and that non-occlusive plaque rupture may constitute an important mode of episodic lesion progression. Arterial calcification is a prominent feature of coronary atherosclerosis and correlates with increased risk of myocardial infarction and may play an important role in plaque rupture. Calcification of the arterial wall has been shown to result from the expression of the same genes that are involved in bone formation. When calcium and vitamin D are prescribed to prevent osteoporosis, the potential for enhancing arterial calcification exists. Further research into the molecular mechanisms of arterial calcification may yield new insights into the aging of the vasculature and present new targets for clinical intervention. Normal hemostasis and vascular patency are maintained by a dynamic equilibrium between the fibrinolytic and coagulation systems. Endothelial cells play a central role in hemostatic regulation by producing components of the coagulation and the fibrinolytic systems and inhibitors of platelet aggregation. Hence, several issues implicating the hemostatic system in atherogenesis merit consideration. These may include interactions of the coagulation factors with blood lipids and their impact on the function of the endothelial cells and blood cells; mechanisms regulating the interaction of the blood components with the vascular endothelium in thrombosis and atherogenesis; factors regulating endothelial functions such as macromolecular transport, abnormal permeability, and endothelial cell relaxing factor; and mechanisms controlling arterial endothelial thrombo-resistance processes. Potential specific areas of new research might include studies of apoptosis of cells within plaques, matrix accretion and dissolution, studies on the origin of the calcifying cells of the arterial wall, regulation of prothrombotic factors such as tissue factor within complex lesions, and formation of plaques in microvessels which are sources of intraplaque hemorrhage. Emerging vascular imaging modalities provide a major opportunity to probe, in vivo, the nontraditional mechanisms of plaque progression and complication. Human tissue, such as that obtained at atherectomy from black and white male and female patients, can be utilized to shed light on the alterations in cellular and molecular regulatory mechanisms, as well as on possible differences among races. The use of these technologies may provide information on the structure of the intima, media, and adventitia of coronary arteries, which may elaborate on the vascular remodeling and compensatory responses to atheroma. Such observations may provide insight into how profiles of risk factors in blacks and whites influence these pathophysiological mechanisms. Plaque rupture and acute thrombosis have been identified as major substrates for acute coronary syndromes in the general population. However, it is not known whether current concepts about lipid content and structure of the fibrous cap of atheroma are directly applicable to blacks, or whether these characteristics have a more pronounced influence on the development of acute coronary syndromes owing to the high prevalence of hypertension, thrombotic diathesis and high levels of lipoprotein (a) [Lp(a)] in blacks. As stenotic but stable plaques seldom cause lethal clinical manifestations, a biological approach to understanding the mechanisms of plaque destabilization should suggest novel therapies aimed at reversing this process, a target newly envisioned in cardiovascular therapeutics. One potential avenue to this end could involve local gene therapy using newly developed vectors and endovascular delivery systems. Systemic Factors Promoting Atherogenesis and its Complications Acting at the Level of the Arterial Wall Many systemic factors associated with atherosclerosis have been identified. However, understanding how these risk factors interact with vascular cells has lagged. One high priority area in this regard involves the complex interactions of insulin resistance, dyslipidemia, hypertension, and central obesity with coronary heart disease. These risk factors are particularly prevalent in the black population where studies of these complex interactions and their association with race would be desirable. The advent of genetically altered animals such as mice provides a new avenue to explore the integrative metabolic and local arterial wall aspects of such systemic factors that promote atherogenesis. For example, an area of interest that could be used to probe the link of systemic factors with atherosclerotic lesions would be the generation of compound mutants of insulin-resistant mice with apo-E- or LDL receptor-deficient animals on different diets. Once established, such newly created animal models could be used for systematic evaluation of the effect of dietary and other environmental variables on atherogenesis. Likewise, such compound mutant animal strains could be used to test potential preventive and therapeutic measures. Various compound mutant animals could be applied to advantage to probe polygenic risk factors that promote atherogenesis (e.g., crosses with animals over-expressing or with gene knockouts involving growth factors, cytokines, coagulation factors, and apolipoproteins). Molecular Medicine Methods and Approaches Responses to this RFA should apply modern methods and approaches of molecular medicine to studies of the pathogenesis of atherosclerosis in the arterial wall and should emphasize the molecular and cellular bases of atherogenesis and the molecular genetics of atherosclerosis. The methodology to be used may include, among others, the following approaches: Genetics/Gene Manipulation The power to map and identify genes responsible for disease, the capability of delivering exogenous genes to cells and organs, and the ability to manipulate gene expression and regulation all provide opportunities to investigate the role of various factors on vessel wall biology. Examples of methods and approaches include: o Methods to Prevent Specific Gene Expression (e.g., antisense) o Understanding Gene Expression in the Developing Animal. o Gene Transfer and Therapy. o Generation of Genetically Altered Animals. o Gene Mapping and Identification. Structural Biology Elucidation of the fine structure of the key enzymes, receptors, growth factors, cytokines, etc., at the three-dimensional level is an important step toward understanding their mechanisms of action on the vessel wall and designing agonists or antagonists to perturb their activity. Examples of the methodology to be used include: o X-Ray Crystallography o NMR o New Electron and Laser Microscopy Techniques Vascular Imaging Techniques The imaging of arterial lesions can be used to investigate the pathophysiological basis for the development and progression/ regression of atherosclerosis and to predict the impact of intervention on progression/ regression. The use of improved methods for invasive and noninvasive imaging of lesions, especially plaque rupture and acute occlusion, is a high priority. Examples of the methods that can be used include: o Quantitative Angiography o B-Mode Ultrasound o Intravascular Ultrasound o NMR Basic and Clinical Research The overall concept of a SCOR program focuses on scientific issues related to diseases relevant to the mission of the NHLBI. It is essential, therefore, that all applications include both basic and clinical research projects. In the ideal SCOR, the clinical research derives from, or is otherwise intimately linked to, the basic research proposed by the investigators. Interactions between basic and clinical scientists are expected to strengthen the research, enhance transfer of fundamental research findings to the clinical setting, and identify new research directions. Plans for transfer of findings from basic to clinical studies should be described. Each SCOR grant application and award must include research involving human/patient subjects. Support may be provided for human biomedical and behavior studies of etiology, pathogenesis, prevention and prevention strategies, diagnostic approaches, and treatment of diseases, disorders or conditions. Small population-based studies, where the research can be completed within five years, may also be proposed. In addition, basic research projects must be included that relate to the clinical focus. A SCOR may also contain one or more core units that support the research projects. Special instructions pertaining to the regulations regarding inclusion of human subjects in research are detailed under the section STUDY POPULATION. 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 new policy results from the NIH Revitalization Act of 1993 (Section 492B of Public Law 103-43) and supersedes and strengthens the previous policies (Concerning the Inclusion of Women in Study Populations, and Concerning the Inclusion of Minorities in Study Populations), which have been in effect since 1990. The new policy contains some provisions that are substantially different from the 1990 policies. 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 reprinted in the NIH Guide for Grants and Contracts, Volume 23, Number 11, March 18, 1994. Investigators also may obtain copies of the policy 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, by October 9, 1995 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 subsequent applications, the information that it contains is helpful in planning for the review of applications. The letter of intent is to be sent to: Dr. C. James Scheirer Division of Extramural Affairs National Heart, Lung, and Blood Institute Westwood Building, Room 553 A Bethesda, MD 20892-9070 Upon receipt of the letter of intent, applicants will be contacted by program staff to discuss their proposed applications and to provide guidance to applicants not familiar with the SCOR concept. APPLICATION PROCEDURES The research grant application for PHS 398 (rev. 9/91) is to be used in applying for these grants. These forms are available at most institutional offices of sponsored research and may be obtained from the Office of Grants Information, Division of Research Grants, National Institutes of Health, Westwood Building, Room 449, Bethesda, MD 20892-9070, telephone 301/710-0267. Applicants must follow the instructions provided in the supplement to the RFA. Applicants from institutions that have a General Clinical Research Center (GCRC) funded by the NIH National Center for Research Resources may wish to identify the GCRC as a resource for conducting the proposed research. If so, a letter of agreement from either the GCRC program director or principal investigator could be included with the application. The RFA label available in the PHS 398 application form must be affixed to the bottom of the face page of the application. 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, to identify the application as a response to this RFA, check "YES," enter the title "Specialized Center of Research in Molecular Medicine and Atherosclerosis," and the RFA number HL-95-006 on Line 2a of the face page of the application. Send or deliver a signed, typewritten original of the application, including the checklist, and three signed photocopies, in one package to: Division of Research Grants National Institutes of Health Westwood Building, Room 240 Bethesda, MD 20892-9070** Send two additional copies of the application to Dr. C. James Scheirer, Chief, Review Branch, Centers and Special Projects Section at the address listed under LETTER OF INTENT. It is important to send these two copies at the same time as the original and three copies are sent to the Division of Research Grants, otherwise the NHLBI cannot guarantee that the application will be reviewed in competition for this RFA. Applications must be received by December 8, 1995. If an application is received after that date, it will be returned to the applicant. The Division of Research Grants (DRG) will not accept any application in response to this RFA that is essentially the same as one currently pending initial review, or 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. REVIEW CONSIDERATIONS Upon receipt, applications will be reviewed for completeness by DRG and for responsiveness by the NHLBI. Incomplete applications will be returned to the applicant without further consideration. If NHLBI staff find that the application is not responsive to the RFA, it will be returned without further consideration. Applications that are complete and responsible to the RFA will be evaluated for scientific and technical merit by an appropriate peer group convened by the NHLBI in accordance with the review criteria stated below. As part of the initial merit review, a process (triage) may be used by the initial review group in which applications will be determined to be competitive or non-competitive based on their scientific merit relative to other applications received in response to the RFA. Applications judged to be competitive will be discussed and be assigned a priority score. Applications determined to be non-competitive will be withdrawn from further consideration and the principal investigator/program director and the official signing for the applicant organization will be notified. Neither site visits nor reverse site visits are planned as a part of the review process, therefore each application should be complete on submission. Review criteria for RFAs are generally the same as those for unsolicited interdisciplinary research grant applications. o the scientific merit of each proposed project in the application, including originality, feasibility of the approach, and adequacy of the experimental design; o the integration of the clinical and fundamental research into a coherent enterprise with adequate plans for interaction and communication of information and concepts among the collaborating investigators; o the technical merit and justification of each core unit; o the qualifications, experience, and commitment of the SCOR Director and his/her ability to devote adequate time and effort to provide effective leadership; o the competence of the investigators to accomplish the proposed research goals, their commitment, and the time they will devote to the program; o the adequacy of facilities to perform the proposed research including the laboratory and clinical facilities, access to subjects, instrumentation, and data management systems when needed; o the scientific and administrative structure of the program, including adequate internal and external arrangements and procedures for monitoring and evaluating the proposed research and for providing ongoing quality control and scientific review; o the institutional commitment to the program and the appropriateness of the institutional resources and policies for the administration of a research program of the type proposed; and o the appropriateness of the budget for the proposed program. o Adequacy of plans to include both genders and minorities and their subgroups as appropriate for the scientific goals of the research. Plans for the recruitment and retention of subjects will also be evaluated. AWARD CRITERIA Applications must fulfill all eligibility criteria in order to be considered for funding. Since a variety of approaches would represent valid responses to this RFA, it is anticipated that there will be a range of costs among individual grants awarded. The most important criterion in selecting awardees will be the scientific merit as reflected in the priority score. However, factors such as program balance and available funds may enter into selection from among meritorious applications. Schedule Letter of Intent Receipt Date: October 9, 1995 Application Receipt Date: December 8, 1995 Review by NHLBI Advisory Council: September 1996 Anticipated Award Date: December 1, 1996 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: Dr. Momtaz K. Wassef Division of Heart and Vascular Diseases National Heart, Lung, and Blood Institute Federal Building, Room 4A12 7550 Wisconsin Avenue MSC 9050 Bethesda, MD 20892-9070 Telephone: (301) 496-1978 FAX: (301) 480-9882 Email: momtaz_wassef%nihhfed1.bitnet@cu.nih.gov Inquiries regarding fiscal and administrative matters may be directed to: Mr. William Darby Division of Extramural Affairs National Heart, Lung, and Blood Institute Westwood Building, Room 4A11 Bethesda, MD 20892-9070 Telephone: (301) 594-7458 FAX: (301) 594-7492 AUTHORITY AND REGULATIONS This program is described in the Catalog of Federal Domestic Assistance No. 93.837, Heart and Vascular Diseases. Awards will be made under the 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 PHS grants policies and Federal Regulations 42 CFR 52 and 45 CFR Part 74. This program is not subject to the intergovernmental review requirement of Executive Order 12372 or Health Systems Agency review. .
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