THROMBOSIS OF THE ARTERIAL AND CEREBRAL VASCULATURE: NEW MOLECULAR GENETIC CONCEPTS FOR PREVENTION AND TREATMENT Release Date: April 15, 1999 RFA: HL-99-015 P.T. National Heart, Lung, and Blood Institute National Institute of Neurological Disorders and Stroke Letter of Intent Receipt Date: August 16, 1999 Application Receipt Date: September 15, 1999 THIS RFA USES "MODULAR GRANT" AND "JUST-IN-TIME" CONCEPTS. THIS RFA INCLUDES DETAILED MODIFICATIONS TO STANDARD APPLICATION INSTRUCTIONS THAT MUST BE USED WHEN PREPARING AN APPLICATION IN RESPONSE TO THIS RFA. PURPOSE The objective of this initiative is to establish collaborative teams of closely interacting investigators with diverse, complementary areas of expertise to elucidate the molecular genetic mechanisms of thrombosis in the arterial and cerebral vasculature. The overall goal is to stimulate innovative multidisciplinary research to expedite progress in understanding the pathogenesis of thrombosis in both the arterial and cerebral vasculature and to facilitate the application of new findings for better detection, prevention, and treatment. This initiative will support research to map and identify genes that confer susceptibility to or protection from arterial thrombosis, to perform mechanistic studies that will clarify the role of specific genetic alterations that lead to or help prevent organ specific arterial thrombosis, and to apply and further refine sophisticated molecular genetic methods and technologies, such as DNA arrays, gene knock-outs, gene knock-ins, and gene alterations directed to specific tissues at specific times in development. In addition, this program will foster collaborations among scientists with different expertise, abilities, and talents to solve problems that require a multifaceted approach, diverse skills, and special resources (populations, equipment, etc.) not typically located within a single department or at a given institution. The collaborations should focus on a common hypothesis with all component projects contributing scientifically to the central theme. The collaborative projects may include shared resources as long as the interdependence and multidisciplinary nature of the individual components is demonstrated. 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 is related to the priority area, 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 202-512-1800). ELIGIBILITY REQUIREMENTS Applications may be submitted by domestic and foreign, for-profit and non-profit organizations, public and private, such as universities, colleges, hospitals, laboratories, units of State or local governments, and eligible agencies of the Federal government. Racial/ethnic minority individuals, women, and persons with disabilities are encouraged to apply as Principal Investigators. All current policies and requirements that govern the research grant programs of the NIH will apply to grants awarded under this RFA. Awards under this RFA to foreign institutions will be made only for research of very unusual merit, need, and promise, and in accordance with Public Health Service policy governing such awards. Cell biology, molecular biology, biochemistry, physiology, pathology, and genetics are among the disciplines and expertise that may be appropriate for this research program. MECHANISM OF SUPPORT The mechanism of support for applications in response to this RFA is the collaborative Research Project (R01) grant. Applicants should propose a program comprising basic and/or clinical science studies. Investigators are encouraged to establish collaborations to complement their projects to meet the objectives of this RFA. Collaborative groups may consist of two or more research R01 projects consisting of basic science and/or clinical studies. Collaborative groups must have a common theme. Collaborative R01 projects may be from a single institution or several institutions, may include shared resources, and should demonstrate synergism among the individual components. If core support is requested, it should be organized as a separate R01 application and submitted as part of the collaboration, but its funding will be part of one of the research R01s. The funding decision will be influenced by the scientific merit of the individual applications, the degree of collaboration among the investigators, the approaches taken to meet the objectives of the RFA, and the programmatic balance and needs of NHLBI and NINDS. Although applicants are required to submit collaborative applications, the Institute may choose to fund individual R01s outside the collaborative arrangement owing to their special scientific merit and programmatic needs and balance. Specific application instructions have been modified to reflect "MODULAR GRANT" and "JUST-IN-TIME" streamlining efforts being introduced by the NIH. The modular grant concept establishes specific modules in which direct costs may be requested as well as a maximum level for requested budgets. Only limited budgetary information is required under this approach. The just-in-time concept allows applicants to submit certain information only when there is a possibility for an award. It is anticipated that these changes will reduce the administrative burden for the applicants, reviewers and Institute staff. For this RFA, funds must be requested in $25,000 direct cost modules. A feature of the modular grant concept is that no escalation is provided for future years. All anticipated expenses for all years of the project must be included within the number of modules being requested. If substantially increased costs are anticipated in one or more of the future years, a full and complete justification must be submitted with the application. Only limited budget information will be required and any budget adjustments made by the Initial Review Group will be in modules of $25,000. A group of collaborative R01 applications may request up to a total of 32 modules ($800,000 direct cost), per year for all component R01s, including cores. Costs of individual R01 components may be substantially different from each other within a collaborative group. Instructions for completing the Biographical Sketch have also been modified. In addition, Other Support information and the application Checklist page are not required as part of the initial application. If there is a possibility for an award, necessary budget, Other Support and Checklist information will be requested by NHLBI staff following the initial review. The APPLICATION PROCEDURES section of this RFA provides specific details of modifications to standard PHS 398 application kit instructions. This RFA is a one-time solicitation. Future unsolicited competing continuation applications will compete with all investigator-initiated applications and be reviewed according to the customary peer review procedures. It is anticipated that support for this program will begin in August 2000. Administrative adjustments in project period and/or amount may be required at the time of the award. FUNDS AVAILABLE It is anticipated that for fiscal year 1999, approximately $10 million total costs will be available from the NHLBI and $2.3 million from NINDS for the first year of support for this initiative. Award of grants pursuant to this RFA is contingent upon receipt of such funds for this purpose. It is anticipated that eight to ten collaborative groups will be funded. The specific number to be funded will, however, depend on the merit and scope of the applications received and on the availability of funds. Direct costs will be awarded in modules of $25,000, less any overlap or other necessary administrative adjustments. Facilities and Administrative costs (Indirect costs) will be awarded based on the negotiated rates. Applicants may request up to five years of funding. A small number of programs with well-justified needs for a research period of longer than five years may be funded. A maximum of seven years can be requested in the case of studies in which identification and study of individuals and families at risk for arterial thrombosis are involved to allow sufficient time for development and testing of protocols, ascertainment and recruitment, and data clean-up and analysis. Other types of studies should be completed in five years or less. It is expected that all components of a collaborative group will request the same length of funding. RESEARCH OBJECTIVES A. Background Arterial thrombosis is the underlying mechanism responsible for myocardial infarction, peripheral vascular occlusion, and most cases of non-hemorrhagic cerebrovascular stroke as well as an important contributor to many other human disorders central to the mission of the NHLBI and the NINDS. Indeed, this pathologic process represents the leading cause of mortality and morbidity in the Western world. Significant advances in the biochemistry and molecular biology of the hemostatic system and the blood vessel wall as well as the pathophysiology of arterial thrombotic disorders provide the underpinnings for rapid progress in understanding the genetic abnormalities responsible for arterial thrombosis. Moreover, these advances have led directly to improved therapy for thrombosis. The goal of this initiative is to speed the development of new treatment for arterial thrombosis through promoting identification and characterization of genes involved in the process. The concept of a "hypercoagulable state" in which the hemostatic system is in a state of enhanced but sub-thrombotic activity is supported by a number of large epidemiologic studies. The relationship between hemostatic abnormalities and arterial thrombosis in coronary heart disease as well as cerebrovascular stroke has been established. For example, individuals with high levels of fibrinogen, von Willebrand Factor VIIIc, and tissue plasminogen activator/tissue plasminogen activator inhibitor-1 exhibit an increased risk of arterial thrombosis. Polymorphisms of certain hemostatic factor genes may be correlated with increased levels of these components, as well as with the arterial thrombotic phenotype as evidenced by the recent reported link between polymorphisms in the coagulation factor VII gene to the risk of myocardial infarction. Until now, it has been believed that genetic mutations important for the prediction of venous thrombosis such as factor V Leiden and antithrombin III are not relevant in arterial thrombosis. However, a newly described mutation in the prothrombin gene is reported to be a risk factor for both venous and arterial thrombosis. Measurements of coagulation system activation fragments and enzyme-inhibitor complexes are also correlated with the arterial thrombotic phenotype. It remains unclear whether the relatively small alterations in the levels/activities of hemostatic components contribute to more extensive arterial thrombosis or whether these abnormalities merely reflect underlying blood vessel wall dysfunction that is responsible for the increased risk of this disorder. Furthermore, it has not yet been demonstrated that these small alterations are predictive of arterial thrombotic disease in any specific individual. We now understand fluid phase blood coagulation in considerable detail. These advances in understanding have led directly to new anti-coagulants of considerable potential value in the treatment of venous thrombosis. However, further advances beyond anticoagulation are required to provide effective prophylaxis and therapy of arterial thrombosis. This may be because cellular components such as platelets and leukocytes play a more central role in the process. Fundamental research, supported by the NHLBI, has led to a new generation of anti-arterial thrombotics based on inhibition of platelet glycoprotein IIb-IIIa. These agents along with other anti-platelet agents are of proven value in this process. Our understanding of platelet adhesive events are somewhat less advanced than blood coagulation, primarily because the key components have only recently been identified. Furthermore, the adhesive events are under the control of complex intracellular signaling pathways. In contrast to blood coagulation, many of the components of these pathways have yet to be identified. In addition, polymorphisms in platelet adhesion receptors may be directly linked to the risk of arterial thrombosis. For example, the PLA2 polymorphisms in GP IIb-IIIa have been implicated in myocardial infarction. Further, there is wide individual variation in the expression of a collagen receptor, integrin 2 1, on platelets. This hereditary variation may also correlate with the risk for myocardial infarction. Since there are many unidentified gene products involved in regulating platelet adhesive interactions, the identification of such gene products should provide candidate genes for risk factors in arterial thrombosis. Arterial thrombosis almost invariably occurs at sites of abnormalities in the vessel wall. Consistent progress is being made in identifying vascular factors involved in regulating coagulant and adhesive activities of blood elements. Yet, the identification of the critical gene products in the vessel wall has only begun. An important clue is the occurrence of arterial thrombosis at particular sites in the vasculature. This suggests that the hemodynamics also play an important role in influencing gene expression in the vessel and, consequently, the predilection for arterial thrombosis. Thus, the interplay between hemodynamics and gene expression is another critical area for an understanding of the predisposition towards arterial thrombosis. Molecular genetic studies using the mouse are proving to be extremely valuable in identifying candidates for genetic studies in humans. In this regard, gene knockout mouse models appear to represent an important breakthrough. For example, gene knockouts of a number of different natural anticoagulant mechanisms, such as thrombomodulin, nitric oxide, tissue plasminogen activator, and urokinase have demonstrated that significant amounts of fibrin are deposited in arterial segments in an organ-specific fashion. In the case of thrombomodulin, fibrin deposition in arterial segments of the mouse heart results in stress-induced myocardial infarction. Furthermore, there are striking similarities between phenotypes observed in the mouse knockout studies and occurrence of arterial thrombotic phenotypes observed in humans. For example, the knockout of the endothelial nitric oxide synthase gene in the mouse resulted in fibrin deposition within the blood vessels of the heart. Interestingly, human mutations in this enzyme are associated with ischemic heart disease in several different ethnic populations. Hence, these studies have provided a significant number of candidate genes that appear to be involved in the initiation of arterial thrombosis. It is anticipated that additional studies with mice will provide many more candidate genes as strategies are designed to develop genetic defects in both time and location and to delete, mutate, or over express gene products. The Mouse Genome and the Rat Genome Projects are also generating tools to identify the genetic bases of complex phenotypes that will provide additional candidate genes. There now exist exciting new opportunities for employing the knowledge gained from the investigations and strategies described above to pinpoint the genetic abnormalities in humans that lead to arterial thrombosis. Given the available biochemical assays of hypercoagulability, candidate genes, appropriate families, the reagents, methods, and informational resources that are being generated by the Human Genome Project, new analytical strategies, and more powerful study designs, there is a strong rationale for supporting a significant effort to map and identify the genes responsible for arterial thrombosis in humans and to elucidate the complex interplay of genetic and environmental factors. To this end, it may be possible to use existing cell and DNA samples from already completed American and European epidemiological and intervention trials concerned with myocardial infarction, stroke, and peripheral vascular disease. It would also be of great interest to carry out similar studies in relatively young individuals (below the age of 45) who exhibit arterial thrombosis with minimal atherosclerotic disease. Research using animal models also offer significant opportunities. Animals can be used to map and identify genetic variants responsible for arterial thrombosis. This information can be used for comparative mapping efforts in humans. Furthermore, animal models can be used to assess the biological mechanisms of genetic variation that confers susceptibility to or protection from arterial thrombosis. An understanding of the basis for genetic susceptibility to the hypercoagulable state and resultant arterial thrombosis would help identify individuals at risk for developing disease before the manifestation of clinical symptoms. Furthermore, molecular genetic studies will help investigators develop measures to characterize the prevalence of genetic variants associated with arterial thrombosis at the population level. Pinpointing the key genes and how they interact with each other and the environment to produce arterial thrombosis would have a significant impact on public health in a number of ways. Such information will aid in identifying individuals at greatest risk for developing arterial thrombosis and tailoring prevention strategies, as well as providing information vital for the development of safer and more effective prophylactic and therapeutic drugs. Current data suggest that arterial thrombosis may represent a local imbalance between procoagulant pathways, regulated by specific cellular circuits within a particular organ, and natural anticoagulant mechanisms present on the blood vessel wall. If such is the case, down-regulation of the pro-coagulant circuits or up-regulation of the anticoagulant mechanisms would result in a local antithrombotic effect. This would represent a new paradigm for prophylactic therapy of arterial thrombosis, with a potentially dramatic reduction of bleeding side effects which frequently occur with systemic anticoagulant therapy. Studies are encouraged to develop approaches for identifying molecules that would help in regulating these processes and elucidating their mechanisms of action. Molecular genetic studies could ultimately have a substantial impact on the prevention of arterial thrombotic disease. A major challenge of the future will be the development and implementation of effective preventive measures. A better understanding of disease mechanisms, which may result from molecular genetic studies, should strengthen efforts at prevention by targeting those individuals who are most likely to benefit from environmental and lifestyle modification and by identifying individuals whose disease may not be improved through such measures. B. Mechanism of Support The mechanism available for support of applications in response to this initiative is the collaborative R01. In the case of collaborative R01 projects, a group of investigators may submit simultaneously at least two research project grants (R01s) with a common theme. Collaborative R01 projects may be from a single institution or several institutions, may include shared resources, and must demonstrate the interdependence of the individual components. Applicants for collaborative R01s may request funds to facilitate the logistics of collaboration. Such requests may include shared equipment or resources, communication strategies, quality control activities, shared consultations or seminars with experts complementing the project, or other mechanisms to cement and enhance the relationships between investigators. The justification for such equipment or activities needs to be clearly made that they are designed to promote collaborations and do not replicate ongoing activities or research. Core support for collaborative R01s is permissible and needs to be justified on the basis of providing cohesion to collaborations or providing essential resources. Upon initiation of the program, annual meetings will be held to encourage exchange of information among investigators who participate in this program. A major goal of these meetings is to facilitate progress by providing a forum that will lead to sharing ideas, technology, data, skills, and biological materials. Applicants must include travel funds that will allow principal investigators and other key research scientists to participate in these meetings. C. Proposed Research The goal of this initiative is to provide scientific underpinnings for rapid advances in development of new therapeutic options in arterial thrombosis. Three critical areas are identified for emphasis: 1. Identification of genes involved in thrombosis in the arterial tree: A key approach to identification of genes is genetic study of human populations and pedigrees. However, a common limiting factor in such studies is the identification of candidate genes and the characterization of intermediate phenotypes that are more easily tracked in positional cloning efforts. Innovative studies in animal models, or in vitro cell-based genetic approaches are anticipated to be useful in pinpointing candidate genes. Examination of abundance of mRNA transcripts using array or related technologies are also anticipated to provide rapid identification of candidate genes. 2. Validation of identified genes as molecular targets for arterial thrombosis: Such studies are anticipated to make use of experimental alteration of the genome of animal models such as mice. In addition, other innovative approaches to test the functionality of identified candidate genes in arterial thrombosis are encouraged. 3. Identification of local genes contributing to arterial thrombosis within the brain: The Blood-Brain-Barrier is an integral part of the pathology of ischemic stroke. Investigating the molecular and cellular interactions at the blood-brain interface is critical to increase our understanding of the pathobiological processes of stroke. Elucidating the involvement of brain-selective gene expression on local arterial thrombosis can lead to stroke prevention and neuroprotective strategies. The identification of genes involved in thrombosis in the arterial vasculature and a mechanistic analysis of how these genes contribute to hemostasis and to the pathophysiology of arterial thrombosis in a vascular-bed and organ-specific fashion will require the collaboration of investigators with expertise in many fields, such as, genetics, biostatistics, clinical science, molecular biology, biochemistry, physiology, bioinformatics, genomics, genotyping, and statistics. In addition, key aspects of infrastructure may also be supported, and might include immortalization of cell lines to act as perpetual sources of DNA, the banking of DNA, the development and maintenance of appropriate databases, specialized equipment, and animal colonies. It is important to emphasize that there are a variety of approaches to gene mapping and identification and to the mechanistic analyses of the consequences of genetic variation. Therefore, a given strategy must be rigorously justified and must demonstrate that all key personnel are involved in the formulation of the rationale and approach. For human genetic studies, as one example, the applicants must carefully justify the study design, the phenotype, the human population chosen for study, methodologies and technologies, statistical analytical tools, and describe the limitations of the approaches. Molecular genetics is a rapidly evolving field. Hence, applications must include a discussion of how its investigators will be poised to take advantage of technical and methodological advances. Although a key factor in the funding will be the scientific and technical merit as judged through the peer review system, willingness and ability to participate actively in a collaborative program will also be a key factor in selecting applications for award. Molecular genetic studies to map and identify genes responsible for arterial thrombosis can involve human and/or animal studies. Either approach will require convincing justification of a phenotype reflective of the consequences of genetic alteration on one or more factors involved in the etiology of arterial thrombosis. Genetic studies in humans may propose the use of existing tissue and DNA samples from already completed epidemiologic and intervention trials or the identification and study of new cohorts. Animal studies to understand the biological consequences of genetic variation might involve the development and use of techniques to introduce and express new genetic information; development and use of approaches to abolish or modify the expression of endogenous genes; utilization of genetic ablation techniques to unravel the complex interactions of systems comprised of multiple cell types; and so forth. D. Sharing Data and Biological Materials in Human Genetic Research Timely sharing of information and materials will speed scientific discovery by permitting researchers access to sufficiently large and well-characterized resources as quickly as possible. This sharing of materials and data, including those that have not yet or may never be published, is essential to rapid progress and will help to avoid unnecessary duplication of large data collections. In order to ensure the timely sharing of information and materials, applicants will be requested to describe how, when, and in what manner data and materials will be made available to the scientific community, with adequate safeguards to the rights and interests of the participants for genetic research. The initial review group will comment on the proposed plan for sharing and data release. The adequacy of the plan and associated human subject protections will also be considered by NIH staff as part of the criteria for award. The proposed sharing plan, after negotiation with the applicant when necessary, will be made a condition of the award. It is recognized that time may be required to verify the accuracy of data, to perform initial analyses, and to protect intellectual property rights to ensure that inventions, including therapeutic agents, are pursued and developed rapidly for the benefit of the public. Thus, a protected period - from the time data and materials are collected to the time they are made available to other qualified investigators - may be appropriate. The onset and duration of the period will vary, depending upon the nature of the research project. Applicants must justify the length of the protected period. Where appropriate, grantees may work with the private sector to make unique resources available to the larger biomedical research community at a reasonable cost. Applicants may request funds to defray the costs of sharing materials or submitting data, with adequate justification. EXCLUSIONS This RFA is intended to support collaborative R01 research programs studying the molecular genetic mechanisms of arterial thrombosis by mapping and identifying genes that confer susceptibility, performing mechanistic studies to clarify the role of specific genetic alterations, and to apply and further refine molecular genetic methods and technologies directed to specific tissues at specific times in development. Genetic studies in humans may propose the use of existing tissue and DNA samples from already completed epidemiologic and intervention trials or the identification and study of new cohorts. Large clinical trials will be considered unresponsive to this initiative. SPECIAL REQUIREMENTS Upon initiation of the program, the NHLBI and NINDS will sponsor periodic meetings to encourage exchange of information among investigators who participate in this program. Applicants should include travel funds for a one day meeting each year, most likely to be held in Bethesda, Maryland to the requested modules. Applicants should include a statement in their applications indicating their willingness to participate in these meetings. INCLUSION OF WOMEN AND MINORITIES IN RESEARCH INVOLVING HUMAN SUBJECTS It is the policy of the NIH that women and members of minority groups and their subpopulations must be included in all NIH supported biomedical and behavioral research projects involving human subjects, unless a clear and compelling rationale and justification is provided that inclusion is inappropriate with respect to the health of the subjects or the purpose of the research. This policy results from the NIH Revitalization Act of 1993 (Section 492B of Public Law 103-43). All investigators proposing research involving human subjects should read the "NIH Guidelines for Inclusion of Women and Minorities as Subjects in Clinical Research," which have been published in the Federal Register of March 28, 1994 (FR 59 14508-14513) and in the NIH Guide to 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. INCLUSION OF CHILDREN AS PARTICIPANTS IN THE RESEARCH INVOLVING HUMAN SUBJECTS It is the policy of the 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 LETTER OF INTENT Prospective applicants are asked to submit, by July 23, 1999, a letter of intent that includes a descriptive title of the proposed research, the name, address, and telephone number of the Principal Investigator, the identities of other key personnel and participating institutions, and the number and title of the RFA in response to which the application may be submitted. Although a letter of intent is not required, is not binding, and does not enter into the review of a subsequent application, the information that it contains allows staff to estimate the potential review workload and to avoid conflict of interest in the review. The letter of intent is to be mailed, or faxed, to: Dr. C. James Scheirer Division of Extramural Affairs National Heart, Lung, and Blood Institute 6701 Rockledge Drive, Room 7220, MSC 7924 Bethesda, MD 20892-7924 Telephone: (301)435-0266 FAX: (301)480-3541 Email: James_Scheirer@NIH.GOV APPLICATION PROCEDURES The research grant application form PHS 398 (rev. 4/98) is to be used in applying for these grants, with the modifications noted below. These forms are available at most institutional offices of sponsored research, and from the Division of Extramural Outreach and Information Resources, National Institutes of Health, 6701 Rockledge Drive, MSC 7910, Bethesda, MD 20892-7910, telephone 301/710-0267, email: GrantsInfo@nih.gov. The RFA label found in the PHS 398 (rev. 4/98) 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, the RFA title (Arterial Thrombosis) and number (HL 99-015) must be typed on line 2 of the face page of the application form and the YES box must be marked. State on the face page, Title Line (line 1), of each application that the submission is part of a "Collaborative R01." The individual components and cores must be submitted as one package accompanied by a cover letter that lists the principal investigators of each R01. Include this letter with each of the individual R01s, and in each R01 list the collaborating projects and principal investigators on page 2, under "Performance Sites". In addition, the description section for each R01 within a collaborative R01 should be the same and the applicants should define how and why the individual participants propose to collaborate. Applicants should elaborate on the significance and nature of the collaboration in an Introduction section of the "Research Plan" of each component R01. Sample budgets and justification page will be provided upon request or following the submission of a letter of intent from Ms. Marie Willet at the address listed below. BUDGET INSTRUCTIONS The total direct costs must be requested in accordance with the program guidelines and the modifications made to the standard PHS 398 application instructions described below: DETAILED BUDGET FOR THE INITIAL BUDGET PERIOD Do not complete Form Page 4 of the PHS 398 (rev 4/98). It is not required nor will it be accepted at the time of application. BUDGET FOR THE ENTIRE PROPOSED PERIOD OF SUPPORT Do not complete the categorical budget tables on page 5 of the PHS 398 (rev. 4/98) Form. Only the requested total direct costs line for each year must be completed based on the number of $25,000 modules being requested. Applicants may not request a change in the amount of each module. A maximum of 32 modules ($800,000 direct costs) for the entire collaborative package, including cores, per year may be requested . Applicants may request up to five years of support for this RFA. Genetic studies in humans which propose the identification and study of new cohorts may request up to seven years of support. Detailed justification and time line for these studies should be included. Direct cost budgets will normally remain constant throughout the life of the project (i.e., the same number of modules requested for all budget periods). Any necessary escalation should be considered when determining the number of modules to be requested. However, in the event that the number of modules requested must change in any future year due to the nature of the research proposed, appropriate justification must be provided. Total Direct Costs for the Entire Proposed Project Period should be shown in the box provided. BUDGET JUSTIFICATION o Budget justifications should be provided under "Justifications" on Form Page 5 of the PHS 398. o List the names, role on the project and proposed percent effort for all project personnel (salaried or unsalaried)and provide a narrative justification for each person based on his/her role on the project. o Identify all consultants by name and organizational affiliation and describe the services to be performed. o Provide a general narrative justification for individual categories (equipment, supplies, etc.) required to complete the work proposed. More detailed justifications should be provided for high cost items. Any large one- time purchases, such as large equipment requests, must be accommodated within these limits. CONSORTIUM/CONTRACTUAL COSTS If collaborations or subcontracts are involved that require transfer of funds from the grantee to other institutions, it is necessary to establish formal subcontract agreements with each collaborating institution. A letter of intent from each collaborating institution should be submitted with the application. Only the percentage of the consortium/contractual TOTAL COSTS (direct and F&A) relative to the total DIRECT COSTS of the overall project needs to be stated at this time. The following example should be used to indicate the percentage cost of the consortium, "The consortium agreement represents 27% of overall direct costs requested in the first year." A budget justification for the consortium should be provided as described in the "Budget Justification" section above (no Form Page 5 required for the consortium). Please indicate whether the consortium will be in place for the entire project period and identify any future year changes in the percentage relative to the parent grant. If there is a possibility for an award, the applicant will be requested to identify actual direct and indirect costs for all years of the consortium. Please note that total subcontract costs need not be calculated in $25,000 modules. However, when subcontract funds are added to the parent grant budget, the total direct cost amount must be included in the number of $25,000 modules requested. BIOGRAPHICAL SKETCH A biographical sketch is required for all key personnel, following the modified instructions below. Do not exceed the two-page limit for each person. o Complete the educational block at the top of the form page; o List current position(s) and those previous positions directly relevant to the application; o List selected peer-reviewed publications directly relevant to the proposed project, with full citation; o The applicant has the option to provide information on research projects completed and/or research grants participated in during the last five years that are relevant to the proposed project. OTHER SUPPORT - Do not complete the "Other Support" pages (Form Page 7). Selected other support information relevant to the proposed research may be included in the Biographical Sketch as indicated above. Complete Other Support information will be requested by NHLBI or NINDS staff if there is a possibility for an award. CHECKLIST No "Checklist" page is required as part of the initial application. A completed Checklist will be requested by NHLBI staff if there is a possibility for an award. The applicant should provide the name and phone number of the individual to contact concerning fiscal and administrative issues if additional information is necessary following the initial review. Applications not conforming to these guidelines will be considered unresponsive to this RFA and will be returned without further review. Submit a signed typewritten original of the application and three signed, photocopies, in one package to: CENTER FOR SCIENTIFIC REVIEW NATIONAL INSTITUTES OF HEALTH 6701 ROCKLEDGE DRIVE, ROOM 1040 - MSC 7710 BETHESDA, MD 20892-7710 BETHESDA, MD 20817 (for express/courier service) At the time of submission, two additional copies of the application must be sent to Dr. C. James Scheirer, at the address listed under LETTER OF INTENT. Applications must be received by September 15, 1999 If an application is received after that date, it will be returned to the applicant without review. The Center for Scientific Review (CSR) will not accept any application in response to this RFA that is essentially the same as one currently pending initial review, unless the applicant withdraws the pending application. The CSR will not accept any application that is essentially the same as one already reviewed. This does not preclude the submission of substantial revisions of applications already reviewed, but such applications must include an introduction addressing the previous critique. REVIEW CONSIDERATIONS Upon receipt, applications will be reviewed for completeness by the CSR, and responsiveness by NHLBI and NINDS. Incomplete and/or non-responsive applications will be returned to the applicant without further consideration. Remaining applications may be subjected to a streamlined review process by a Special Emphasis Panel convened by NHLBI Scientific Review Office to determine their scientific merit relative to other applications received in response to the RFA. The roster of reviewers for the RFA will be available on the NHLBI home page approximately four weeks prior to the scheduled review date. Applications determined to be meritorious will be evaluated for scientific and technical merit by the review committee, be discussed and receive a priority score. All other applications will not be discussed or scored. The initial review group will evaluate all applications as individual investigator-initiated grant applications. Additionally, the IRG will consider in their evaluation the overall strength and likelihood of effective collaboration of each collaborative program. Each R01 will receive a priority score. Secondary review of the applications will be conducted by the National Heart, Lung, and Blood Advisory Council (NHLBAC) and the National Advisory Neurological Disorders and Stroke Council (NANDS). 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 an)? 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 What are the likelihood of effective collaboration among the investigators, and the likelihood of success of the research objectives proposed? The personnel category will be reviewed for appropriate staffing based on the requested percent effort. The direct costs budget request will be reviewed for consistency with the proposed methods and specific aims. Any budgetary adjustments recommended by the reviewers will be in $25,000 modules. The duration of support will be reviewed to determine if it is appropriate to ensure successful completion of the requested scope of the project. AWARD CRITERIA Applications will receive a secondary level of review by National Heart, Lung, and Blood Advisory Council (NHLBAC) and by the National Institute of Neurological Disorders and Stroke Advisory council (NANDS) in May 2000. The earliest anticipated date of award is July 2000. 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 and by NINDS staff as well as NHLBAC and the NANDS in making funding recommendations. The Institute may fund individual applications based on a number of considerations, the most important of which are based on their scientific merit and their importance in meeting the objectives of the RFA. In addition, both Institutes appreciate the value of complementary funding from other public and private sources including foundations and industrial concerns. SCHEDULE Letter of Intent Receipt Date: August 16, 1999 Application Receipt Date: September 15, 1999 Review by NHLBI and NINDS Advisory Councils: May 2000 Anticipated Award Date: August 2000 INQUIRIES Inquiries concerning this RFA are encouraged. Potential applicants should request a copy of the full RFA, which will include sample budget pages. The opportunity to clarify any issues or questions from potential applicants is welcome. Direct inquiries regarding programmatic issues to: Carol H. Letendre, Ph.D. Division of Blood Diseases and Resources National Heart, Lung, and Blood Institute 6701 Rockledge Drive, Suite 10142 Bethesda, MD 20892-7950 Telephone: (301) 435-0080, FAX: (301) 480-0867 Email: letendrc@gwgate.nhlbi.nih.gov Sonia Skarlatos, Ph.D. Division of Heart and Vascular Diseases National Heart, Lung, and Blood Institute 6701 Rockledge Drive, Suite 10186 Bethesda, MD 20892-7956 Telephone: (301) 435-0550, FAX: (301) 480-2848 Email: skarlats@gwgate.nhlbi.nih.gov Thomas P. Jacobs, Ph.D. Division of Stroke, Trauma, and Neurodegenerative Diseases National Institute of Neurological Disorders and Stroke 6001 Executive Blvd., suite 2209 Bethesda, MD 20892 Telephone: (301) 496-4226, FAX: (301) 480-1080 Email: tj12g@nih.gov Direct inquiries regarding fiscal matters to: Ms. Marie Willet Grants Operations Branch National Heart, Lung, and Blood Institute 6701 Rockledge Drive, Suite 7156 Bethesda, MD 20892-7926 Telephone: (301)435-0144; FAX: (301)480-3310 Email: willetm@gwgate.nhlbi.nih.gov Ms. Kathleen Howe Grants Management Branch National Institute of Neurological Disorders and Stroke Neuro-Science Center 6001 Executive Boulevard Bethesda, MD 20892-9537 Telephone: (301) 496-7392; FAX: (301) 402-0219 Email: kh52x@nih.gov AUTHORITY AND REGULATIONS This program is described in the Catalog of Federal Domestic Assistance No. 93.839 and 93.854. Awards are made under authorization of the Public Health Service Act, Title IV, Part A (Public Law 78-410, as amended by Public Law 99-158, 42 USC 241 and 285) and administered under PHS grants' policies and Federal Regulations 42 CFR 52 and 45 CFR Part 74. 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 and contract recipients to provide a smoke-free workplace and promote the non-use of all tobacco products. In addition, Public Law 103-227, the Pro-Children Act of 1994, prohibits smoking in certain facilities (or in some cases, any portion of a facility) in which regular or routine education, library, day care, health care or early childhood development services are provided to children. This is consistent with the PHS mission to protect and advance the physical and mental health of the American people.


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