RFA-HL-00-015: SCOR: MOLECULAR MEDICINE AND ATHEROSCLEROSIS

Department of Health
and Human Services (HHS)

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SCOR: MOLECULAR MEDICINE AND ATHEROSCLEROSIS Release Date: July 17, 2000 RFA: HL-00-015 National Heart, Lung, and Blood Institute http://www.nhlbi.nih.gov/index.htm Letter of Intent Receipt Date: March 16, 2001 Application Receipt Date: June 15, 2001 PURPOSE The objective of this initiative is to establish new or to continue to support closely interacting, multiproject Specialized Centers of Research (SCORs) to study the etiology and pathophysiology of atherosclerosis at the molecular level. The goals of this second cycle of the SCORs are to focus on studies on the pathobiology of the atherosclerotic lesion 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 systemic factors promoting atherogenesis. The current SCOR program was funded in 1997 and therefore, this initiative represents the recompetition of an existing SCOR program and covers the second five-year funding period of a ten- year program. A SCOR provides the opportunity for investigators to engage in interdisciplinary and collaborative research which 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. 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. In addition, to encourage women, under represented minority investigators, and persons with disabilities to work within a SCOR project, to facilitate recruitment of new women and under represented minority scientists and those with disabilities 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 women, under-represented minority investigators and those with disabilities to acquire skills and data to make them more competitive in seeking independent research support (e.g. R01). 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 2010 The Public Health Service (PHS) is committed to achieving the health promotion and disease prevention objectives of "Healthy People 2010," a PHS-led national activity for setting priority areas. This Request for Applications (RFA), SCOR: Molecular Medicine and Atherosclerosis, 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 for-profit and non-profit domestic institutions, public and private, such as universities, colleges, hospitals, laboratories, units of state or local governments, and eligible agencies of the Federal government. This RFA is intended to support SCOR grants for basic and clinical investigations; therefore, applications that include only basic or only clinical research will not be responsive to this announcement. In addition, clinical research projects focused on large epidemiologic studies or large clinical trials will be considered unresponsive to this RFA. 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. Racial/ethnic minority individuals, women, and persons with disabilities are encouraged to apply as principal investigators. The Principal Investigator should be an established research scientist with the ability to ensure high quality research and the experience to administer effectively and integrate all components of the program. A minimum time commitment of 25 percent is required 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. EXCLUSIONS 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 announcement. In addition, clinical research projects focused on large epidemiological studies or large clinical trials will be considered unresponsive to this RFA. Applicants should be aware that applications for administrative supplemental funds will be accepted only under unusual and well defined circumstances. The Institute staff should be consulted prior to submission of an application. Supplemental grants will not be awarded for the first 18 months or the last 12 months of a total project period. MECHANISM OF SUPPORT This RFA will use the Specialized Centers of Research (SCOR, P50) grant award mechanism. Responsibility for the planning, direction, and execution of the proposed project will be solely that of the applicant. All current policies and requirements that govern the research grant programs of the NIH will apply to grants awarded under this RFA. The anticipated award date is April 1, 2002. 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. 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 patients/subjects, which is defined as research conducted with human patients/subjects or on material of human origin such as tissue or other specimens for which an investigator directly interacts with human patients/subjects. Support may be provided for human biomedical and behavioral studies of etiology, pathogenesis, prevention and prevention strategies, diagnostic approaches, and treatment of diseases, disorders or conditions. Small population-based epidemiologic 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. Applicants from institutions that have a General Clinical Research Center (GCRC) funded by the 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. Length of SCOR Programs Each NHLBI SCOR program is limited to 10 years of support. The current SCOR program on Molecular Medicine and Atherosclerosis was funded in 1997 and, therefore, this RFA covers the second five-year funding period. Under this policy, SCOR grants funded in response to this RFA will only be for five years without the possibility of renewal. 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. The NHLBI comprehensive evaluation of the Molecular Medicine and Atherosclerosis SCOR program will be conducted during the second project period according to the following timetable: Program Announced July/August, 2000 Project Period (Second Competition) April 1, 2002 to March 31, 2007 Letter to SCOR Directors Regarding SCOR Evaluation Plans October, 2003 SCOR Evaluation Meeting January, 2004 Notification of SCOR Directors of NHLBI Decision October, 2004 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. FUNDS AVAILABLE The NHLBI intends to commit approximately $ 8.5 million in FY 2002 to fund five new and/or competitive continuation SCOR grants in response to this RFA. Applicants may request a project period of up to five years. New applications may request a first year budget for direct cost of up to $1,350,000. Applicants applying for competitive renewal may request a first year budget not to exceed 10% over the final year budget of the last funding period. The facilities and administrative costs for collaborating institutions are excluded from this ceiling and a maximum increase of no more than three percent is allowed in each additional year requested in the application. Although the financial plans of the NHLBI provide support for this program, awards pursuant to this RFA are contingent upon the availability of funds and the receipt of sufficient number of meritorious applications. Equipment is included in the budget limitation. However, requests for major equipment that cause an application to exceed this limit may be permitted on a case-by-case basis following staff consultation. Such equipment requires in- depth justification. Final decisions will depend on the nature of the justification and the Institute's fiscal situation. Consortium Arrangements When a grant application includes research activities that involve institutions other than the grantee institution, it 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. Applicants of SCOR grants 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 of the group at the parent institution. Facilities and administrative costs paid as part of a consortium agreement are excluded from the limit on the amount of direct costs that can be requested. 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 Kevin Keating, Grants Operations Branch, NHLBI, 301-435-0177. 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 inter-disciplinary approach integrating basic sciences with the clinical aspects of the disease is required to study this disorder, and the NHLBI adopted the SCOR mechanism 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. Despite the significant progress achieved, however, there remain many unresolved questions in atherosclerosis research, which are well suited for the comprehensive and multidisciplinary nature of the SCOR mechanism. The past accomplishments of the SCOR 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. 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 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 SCOR program, an emphasis needs to be placed on the processes that result 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 and state-of- the-art methodologies and approaches of molecular medicine such as gene regulation, gene transfer and therapy, three-dimensional structural biology, vascular imaging techniques, gene mapping and identification, and genetically modified animal models would be required, as well as the more standard research approaches. Because of the interdisciplinary nature of the research, collaboration among investigators of varied expertise is strongly encouraged. Specifically, "Networking" (i.e., shared biologic and information resources, reagents, patients, genetically altered animals, and the like), are needed 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. The list is not to be regarded as complete or exclusive and other research proposed by applicants that meets the objectives of this program will be considered by the NHLBI. Mechanisms Involved in Lesion Susceptibility and Initiation Hemodynamic factors influence the localization of the atherosclerotic lesion. The role of shear 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 which 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 progression 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 or erosion 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. Valvular and aortic stenosis and arterial calcification are prominent features of CVD and coronary atherosclerosis and correlate 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. Further research into the molecular mechanisms of arterial calcification may yield new insights into the aging of the vasculature and the stability of the atherosclerotic plaques, and may 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, can be utilized to shed light on the alterations in cellular and molecular regulatory mechanisms of atherogenesis. 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 humans influence these pathophysiological mechanisms. 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. An important 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 atherosclerosis prone animals. 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). New fundamental knowledge in immunobiology has added new insight to our understanding of the cellular and humoral immune responses, and our ability to manipulate elements of these basic mechanisms. The advances have encompassed structural biology (molecular details of MHC/antigen complexes in antigen recognition and presentation), delineation of co-stimulatory molecules, development of new concepts of helper T cell subtypes (TH1, TH2), characterization of numerous cytokines, their receptors, and signaling pathways, and the precise molecules involved in immune-mediated cytolysis and cell death. Such advances have begun to yield dividends in new approaches to infectious diseases and malignancies, but the opportunities they afford to atherogenesis remain less well explored. Significant knowledge would doubtless accrue from application and extension of these recent advances to studying the initiation, progression and complication of the atherosclerotic lesions. 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 Several recent advances in technology and analytical methods, together with the rapid construction of genetic and physical maps in animals and humans, have substantially improved the likelihood of detecting some genetic contributors to atherogenesis and for studying the molecular and physiological consequences of gene variation. For example, large-scale surveys of human genomic variation are now possible with efficient high-throughput methods using hybridization to high-density DNA probe arrays. Furthermore, polymorphism screening can serve to identify single-nucleotide polymorphisms in the identification of complex disease genes. 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 Biennial Research Meetings Upon initiation of the program, the NHLBI will sponsor periodic meetings to encourage exchange of information among investigators who participate in this program and to stimulate collaboration. Applicants should request additional travel funds for a two-day meeting every other year, most likely to be held in Bethesda, Maryland. Applicants should also include a statement in their applications indicating their willingness to participate in these meetings. STUDY POPULATIONS 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) . 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 first published in the Federal Register of March 28, 1994 (FR 14508-14513) and in the NIH Guide for Grants an 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 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. LETTER OF INTENT Prospective applicants are asked to submit, by March 16, 2001, 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 allows NHLBI staff to estimate the potential review workload and plan the review. The letter of intent is to be mailed to Chief, Review Branch at the address listed under inquiries. APPLICATION PROCEDURES 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. Instructions for the preparation of grant applications for SCORs are the same as those used for the preparation of Program Project Applications and are available at: http://www.nhlbi.nih.gov/funding/policies/ppg.htm 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 page of the application form and the YES box must be marked. The sample RFA label available at: http://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 the Chief, Review Branch at the address listed under INQUIRIES. It is important to send these two copies at the same time as the original and three copies are sent to the Center for Scientific Review (CSR), otherwise the NHLBI cannot guarantee that the application will be reviewed in competition for this RFA. Applications must be received by June 15, 2001. 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 announcement that is essentially the same as one currently pending initial review, unless the applicant withdraws the pending application. 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. REVIEW CONSIDERATIONS Upon receipt, applications will be reviewed for completeness by the CSR and responsiveness by the NHLBI. 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 National Heart, Lung, and Blood Advisory Council (NHLBAC). 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)? Does the Program Director have the appropriate scientific statue and proven leadership to serve in such capacity? (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? (6) Collaboration Does the submitted proposal represent collaborative research among investigators from basic and clinical research with necessary disciplines? What are the likelihood of effective collaboration among the investigators, and the likelihood of success of the research objectives proposed? 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 Applicants should be aware that, in addition to scientific merit, program priorities and program balance, the total costs of the proposed project and the availability of funds will be considered by NHLBI staff as well as NHLBAC in making funding recommendations. In circumstances in which applications have similar scientific merit, but vary in cost competitiveness, NHLBI is likely to select the more cost competitive application for funding. SCHEDULE Letter of Intent Receipt Date: March 16, 2001 Application Receipt Date: June 15, 2001 Peer Review Date: October, 2001 Review by NHLB Advisory Council: February, 2002 Anticipated Award Date: April 1, 2002 INQUIRIES Inquiries concerning this RFA are encouraged. The opportunity to clarify any issues or questions from potential applicants is welcome. Direct inquiries regarding scientific issues to: Momtaz Wassef, Ph.D. Division of Heart and Vascular Diseases National Heart, Lung and Blood Institute 6701 Rockledge Drive, MSC 7956 Bethesda, MD 20892 Telephone: (301) 435-0550 FAX: (301) 480-2858 E-mail: Wassefm@nih.gov Direct inquiries regarding review matters to: C. James Scheirer, Ph.D. Chief, Review Branch Division of Extramural Affairs National Heart, Lung, and Blood Institute 6701 Rockledge Drive, Room 7216, MSC 7924 Bethesda, MD 20892-7924 Telephone: (301) 435-0266 FAX: (301) 480-3541 Email: js110j@nih.gov. Direct inquiries regarding fiscal and administrative matters to: Mr. Kevin Keating Grants Operations Branch National Heart, Lung and Blood Institute 6701 Rockledge Drive, MSC 7926 Bethesda, MD 20892 Telephone: (301) 435-0177 FAX: (301) 480-3310 E-mail: KeatingK@nih.gov AUTHORITY AND REGULATIONS This program is described in the Catalog of Federal Domestic Assistance No. 93.837. 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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