Full Text HL-94-013 SPECIALIZED CENTERS OF RESEARCH IN HEMOSTATIC AND THROMBOTIC DISEASE NIH GUIDE, Volume 23, Number 13, April 1, 1994 RFA: HL-94-013 National Heart, Lung, and Blood Institute P.T. Keywords: Letter of Intent Receipt Date: May 31, 1994 Application Receipt Date: September 15, 1994 PURPOSE The objectives of the Specialized Centers of Research (SCOR) program in Hemostatic and Thrombotic Diseases are to improve the basic understanding of the processes involved in hemostasis and thrombosis and to encourage application of this fundamental knowledge to clinical situations. This initiative emphasizes the use of new and innovative technology to provide better insight and develop treatment for thrombosis and related cardiovascular disorders, which are the leading cause of death in the United States. 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 Request for Applications (RFA), Specialized Centers of Research in Hemostatic and Thrombotic Diseases, is related to the priority area of blood diseases and resources. Potential applicants may obtain a copy of "Healthy People 2000" (Full Report: Stock No. 017-001-00474 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, and laboratories. 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 RFA. 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 part of that project. Women and minority investigators are encouraged to apply. MECHANISM OF SUPPORT This RFA will use the National Heart, Lung, and Blood Institute (NHLBI) SCOR (P50) grant to support this research program. 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. Basic and Clinical Research The overall concept of a SCOR program focuses on scientific issues related to diseases and therapies 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. 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 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. 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. Each project leader must agree to commit at least 20 percent effort to each project for which he/she is responsible. Applications from institutions that have a General Clinical Research Center (GCRC) funded by the National Center for Research Resources, NIH may wish to identify the GCRC as a resource for conducting the proposed research. If so, a letter of agreement from the GCRC program director/principal investigator could be included with the application. Length of SCOR Programs Each NHLBI SCOR program is limited to 10 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. Thus, under this policy, a given SCOR grant is awarded for a five-year project period following an open competition. If the one five-year competing renewal that is permitted is awarded, a total of no more than 10 years of support is possible, unless the SCOR program is recommended for extension. The NHLBI comprehensive evaluation of the Hemostatic and Thrombotic Diseases SCOR will be conducted during the second project period according to the following timetable: Program Announced FY 1994 Project Period (First Competition) FY 1996 to FY 2000 Program Reannounced FY 1999 Project Period (Second Competition) FY 2001 to FY 2005 Letter to SCOR Directors Regarding FY 2002 SCOR Evaluation (midway in year 02 of 2nd project period) SCOR Evaluation Meeting FY 2003 (late in year 02 of 2nd project period) Notification of SCOR Directors FY 2003 Regarding NHLBI Decision (midway in year 03 of 2nd project period) Number of Applications 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 listed under INQUIRIES. FUNDS AVAILABLE Up to $1,125,000 in 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 additional year may be requested in each application. Award of grants pursuant to this RFA is contingent upon receipt of funds for this purpose. It is anticipated that at least two new SCOR grants will be funded. NHLBI's FY 1996 plans for this initiative include a maximum of $4.4 million. The specific amount to be funded will, however, depend on the merit and scope of the applications received and on the availability of funds. 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 in-depth justification. Final decisions will depend on the nature of the justification and the fiscal situation of the NHLBI. Consortium Arrangements If a grant application includes research activities that involve institutions other than the proposed 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 Ms. Jane Davis, Grants Operations Branch, NHLBI, 301-594-7436. 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. Indirect costs paid as part of a consortium agreement are excluded from the limit on the amount of direct costs that can be requested. RESEARCH OBJECTIVES Background Nearly 50 percent of mortality in the United States is related to cardiovascular diseases and amounts to about one million deaths per year. Thrombotic events precipitate myocardial infarction, deep vein thrombosis and pulmonary embolism, and stroke. Unconstrained thrombosis is the scourge of the present time. The cost in lives lost, morbidity, and lost productivity is enormous. The economic cost of cardiovascular diseases was an estimated $151 billion in 1989. In spite of these alarming figures, it is important to note that there have been significant improvements in the ability to combat thrombotic disorders and cardiovascular diseases. The death rates for coronary heart disease and stroke have declined 50 and 58 percent respectively during the 20-year period from 1970 to 1990. Because of the rapid decline in mortality from heart attack since its peak in 1963, there were 491,000 fewer deaths from this cause in 1990. This remarkable improvement would not have been possible without major and consistent progress in research on thrombosis. However, the present risk of thrombosis, heart attack, and stroke remains high and is not acceptable. The rapid progress in genetics, molecular biology, and protein chemistry has opened up frontiers and led to the development of new tools that provide new opportunities to combat thrombosis and cardiovascular diseases. Also, the major research advances made by investigators in thrombosis have significantly contributed to basic understandings and clinical developments in other disease areas. Proposed Research Although significant progress has been made, there are many opportunities in hemostasis and thrombosis research and the application of the results to clinical situations. The following are intended to serve only as examples and to emphasize the need for employing a multidisciplinary research approach to important clinical problems. o Risk factors for thrombosis The pathogenesis of thrombosis is complex and its etiology is likely to be multi-factorial. Both hereditary and acquired conditions are involved; inherited predispositions are more clinically disturbing because they affect patients at an younger age. There are a number of genes - antithrombin, protein C, protein S, fibrinogen - in which a mutation may be prothrombotic. However, heterozygosity for a particular mutant allele can be clinically silent in some individuals but devastating in others. These differences could be due to intergene interactions, i.e., variant alleles of other genes may exacerbate or reduce the effect of the primary genetic trait. Since the gene structure of many candidate proteins involved in hemostasis and thrombosis are known, it may be possible with improved technologies to perform multigene analysis and provide a genetic basis of thrombotic disorders. Recent reports of resistance to prolongation in clotting time induced by activated protein C in majority of thrombophillic patients offer hope of identification of additional risk factors for thrombosis. Research on the natural inhibitors of coagulation/fibrinolysis including the development of animal models may allow genetic manipulations leading to the delineation of the role of these proteins in hemostasis and thrombosis. These studies may allow determination of the causative factors, provide an objective definition of thrombosis proneness and application of preventive approaches. o Influence of nutritional elements and environmental factors on thrombotic disease There is an emerging consensus that many human diseases are related to behavior, nutrition and environmental factors. Increasing emphasis is being placed on prevention by alterations in lifestyle. Recent data indicate that certain nutritional elements, such as vitamin E, wine, garlic, fish oil, may be beneficial in the prevention of thrombosis. Once the candidate genes that lead to proneness to thrombosis have been identified, then the effect of external factors may be studied. This area related to prevention requires further research. o Diagnosis, assays, and treatment for venous thrombosis Two million Americans a year develop deep vein thrombosis and approximately 50,000 will die. Venous thromboembolism usually occurs as a complication of a major illness or major surgical procedure in hospitalized patients. There are important issues involving diagnosis, optimal anticoagulation therapy, laboratory assays, and efficacy of thrombolytic therapy that need further studies. The advent of newer agents, such as low molecular weight heparin and analogues of hirudin, is likely to require systematic and controlled studies on their efficacy and standardization. There is a need for optimal therapy to prevent extensions of thrombosis at early stages and restore involved vessels to as normal a state as possible. o Regulation of adhesive proteins and processes A number of processes important in hemostasis and thrombosis are regulated by adhesive protein ligands and their receptors. The adhesion of platelets and other cells to the endothelium, and the aggregation of platelets to each other are thought to be mediated by this process. The role of platelet and endothelial (glyco)proteins including the selectins and integrins in inflammation, signal transduction and thrombosis need further study. A detailed understanding of the regulation of integrin structure-function, affinity modulation and the role of other environmental factors are important, not only to thrombosis/hemostasis, but also to other biological processes. It is necessary to develop markers of a dysfunctional endothelium that may be applicable to in vivo situations and better understand the leukocyte-endothelial interactions. The data generated may provide the foundation for the development of new antithrombotic and anti-inflammatory agents. o Genetic regulation of the synthesis, catabolism, and function of fibrinolytic proteins Widespread use of thrombolytic therapy has exposed gaps in the knowledge of the fibrinolytic system, role of platelets in thrombolysis, thromboselectivity of the lytic agents, and the mechanism of reocclusion. The success rate of thrombolytic therapy has stubbornly stuck around 70 percent. There is an opportunity here for collaborative basic research and clinical investigation. Structure-function relationships in coagulation and fibrinolytic proteins, studies of macromolecular assembly in the coagulation and fibrinolytic systems, the enzymology and kinetic analyses of these systems, although important and productive, are considered mature and may be supported by other NHLBI grant mechanisms. Similarly, qualitative studies on platelet function, for example by aggregometry, and classification of patient populations are not encouraged to form the main themes of SCOR applications. Quantitative studies that address important questions of platelet dysfunction in specific patient populations and may also contribute to the understanding of normal platelet biology may form a component of the application. There is a need for further education and research on the influence of behavior, gender, race, and age in hemostasis and thrombosis. 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) 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 9, 1994 (FR 59 11146-11151) 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. (NOTE: When the proposed study or studies in the RFA or PA involves a gender specific study or a single or limited number of minority population groups, this should also be stated to inform potential applicants and reviewers.) LETTER OF INTENT Prospective applicants are asked to submit, by May 31, 1994, 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. It allows NHLBI staff to estimate the potential review workload and to avoid conflict of interest in the review. The letter of intent is to be sent to: Chief, Review Branch Division of Extramural Affairs National Heart, Lung and Blood Institute Westwood Building, Room 557A Bethesda, MD 20892 APPLICATION PROCEDURES The research grant application form 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, telephone (301) 710-0267. 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 Centers of Research in Hemostatic and Thrombotic Diseases," and the RFA number HL-94-013 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** Send two additional copies of the application to the Chief, Review Branch 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 (DRG), otherwise the NHLBI cannot guarantee that the application will be reviewed in competition for this RFA. Applications must be received by September 15, 1994. If an application is received after that date, it will be returned to the applicant. DRG 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. DRG 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 by National Institutes of Health (NIH) staff for completeness and responsiveness. Incomplete applications or applications deemed not responsive to the RFA will be returned to the applicant without further consideration. Those applications that are complete and responsive will be evaluated for scientific and technical merit by an appropriate peer review group convened by the NHLBI. Crucial to the initial scientific review will be a triage process that will eliminate all applications that are deemed not scientifically competitive within the goals and criteria of the RFA from further review. The second level of review will be provided by the National Heart, Lung, Blood Advisory Council. 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. Factors to be considered in the evaluation of each application will be similar to those used in review of traditional research grant applications and, in addition, will include overall proposed interactions among basic and clinical research projects. Major factors to be considered in the evaluation of applications include: o Scientific merit of the proposed basic and clinical research projects including significance, importance, and appropriateness of the theme; innovation, originality, and feasibility of the approach; and adequacy of the experimental design. o Leadership, scientific stature, and commitment of the program director; competence of the investigators to accomplish the proposed research goals and their time commitment to the program; and the feasibility and strength of consortium arrangements. o Collaborative interaction among basic and clinical research components, the balance between them, and plans for transfer of potential findings from basic to clinical studies. o Adequacy of the environment for performance of the proposed research including clinical populations and/or specimens; laboratory facilities; proposed instrumentation; quality controls; administrative structure; institutional commitment; and, when needed, data management systems. o Appropriateness of the budget for the proposed program. INQUIRIES Written and telephone 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: Pankaj Ganguly, Ph.D. Division of Blood Diseases and Resources National Heart, Lung, and Blood Institute Federal Building, Room 5C14 Bethesda, MD 20892 Telephone: (301) 402-2237 FAX: (301) 496-9940 Direct inquiries regarding fiscal and administrative matters to: Ms. Jane Davis Division of Extramural Affairs National Heart, Lung and Blood Institute Westwood Building, Room 4A15C Bethesda, MD 20892 Telephone: (301) 594-7436 FAX: (301) 594-7492 AUTHORITY AND REGULATIONS This program is described in the Catalog of Federal Domestic Assistance No. 93.839. 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. All current policies and requirements that govern the research grant programs of the NIH will apply to grants awarded under this RFA. The Public Health Service (PHS) strongly encourages all grant recipients to provide a smoke-free workplace and promote the non-use of all tobacco products. This is consistent with the PHS mission to protect and advance the physical and mental health of the american people. .
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