SPECIALIZED CENTERS OF CLINICALLY ORIENTED RESEARCH (SCCOR) IN VASCULAR INJURY, REPAIR, AND REMODELING RELEASE DATE: August 17, 2004 RFA Number: RFA-HL-05-001 EXPIRATION DATE: May 12, 2005 Department of Health and Human Services (DHHS) PARTICIPATING ORGANIZATION: National Institutes of Health (NIH) (http://www.nih.gov) COMPONENT OF PARTICIPATING ORGANIZATION: National Heart, Lung, and Blood Institute (NHLBI) (http://www.nhlbi.nih.gov) CATALOG OF FEDERAL DOMESTIC ASSISTANCE NUMBER(S) 93.837 LETTER OF INTENT RECEIPT DATE: April 11, 2005 APPLICATION RECEIPT DATE: May 11, 2005 THIS RFA CONTAINS THE FOLLOWING INFORMATION o Purpose of this RFA o Research Objectives o Mechanism(s) of Support o Funds Available o Eligible Institutions o Individuals Eligible to Become Principal Investigators o Special Requirements o Where to Send Inquiries o Letter of Intent o Submitting an Application o Supplementary Instructions o Peer Review Process o Review Criteria o Receipt and Review Schedule o Award Criteria o Required Federal Citations PURPOSE OF THIS RFA The primary objective of the Specialized Centers of Clinically Oriented Research (SCCOR) programs is to foster multidisciplinary research on clinically relevant questions enabling basic science findings to be more rapidly applied to clinical problems. The clinical and basic research supported through this RFA must focus on vascular injury, repair, and remodeling. It is expected that the results from the SCCOR grants will have a positive impact on the prevention, diagnosis, and treatment of vascular diseases. This program has three major goals: (1) to stimulate interdependent clinical and multidisciplinary basic research projects that investigate molecular and cellular mechanisms of vascular injury, repair, and remodeling, (2) to promote patient-oriented research that will improve our ability to prevent, detect, characterize, manage, and treat vascular diseases, and (3) to develop the skills and research capabilities of new clinical investigators. RESEARCH OBJECTIVES The National Heart, Lung, and Blood Institute (NHLBI) revised the Specialized Centers of Research (SCOR) program, based primarily on recommendations from the National Heart, Lung, and Blood Advisory Council. The new program is called the Specialized Centers of Clinically Oriented Research (SCCOR) program http://www.nhlbi.nih.gov/funding/policies/sccor_desc.htm. The original SCOR program required both basic and clinical research, but the preponderance of funded projects was in the basic science arena. The new title and the revisions to the program reflect the Institute's desire to capitalize on basic research advances by encouraging their translation to the clinical arena. The guiding principle of the new SCCOR program is the central focus on clinically relevant research, and the key change to achieve this goal is the requirement that at least one-half of funded projects be clinical. The specific components of the new SCCOR program are detailed in this RFA. Special instructions for preparing a SCCOR application are available from the program contact listed under WHERE TO SEND INQUIRIES or at http://www.nhlbi.nih.gov/funding/policies/sccor_supp.htm. Vascular Injury, Repair, and Remodeling Vascular diseases are responsible for the major causes of morbidity and mortality in the United States. They comprise disorders of arteries, veins, microvessels, and lymphatics. These disorders include coronary, peripheral, visceral and cerebral vascular occlusive diseases, restenosis, aortic coarctation, aneurysms and dissection, vasospasm, vasculitis, arterial and venous thrombosis, venous insufficiency, and lymphedema. Although vascular disorders are heterogeneous in their causes and orientation, they share the common denominator of pathological vascular repair and remodeling in response to underlying injury due to dyslipidemia, hypertension, mechanical forces, diabetes, obesity, hypercoagulability, oxidative stress, inflammatory or immunological processes, advanced age, gender or genetics. Vascular injury, repair, and remodeling are regulated by a myriad of local events and stimuli. Repair and remodeling mechanisms are influenced by local availability and activity of mitogens, differentiation factors, cytokines/chemokines, adhesion molecules, proteases, matrix components, and vasoactive agents. All of these factors may represent potential targets for improved diagnosis, patient stratification, and therapeutic intervention. The vascular repair can be successful and complete, in which case the systemic reaction may resolve; but in many situations, the repair is incomplete and unsuccessful and leads to remodeling of the vascular wall. For some patients the remodeling of the vascular wall may be functional, while for others it may lead to enlarging or narrowing of the lumen or thromboembolic complications. For example, pathological remodeling can lead to aneurysm formation, stenosis, restenosis, or dissection. While circulating cytokines and growth factors can lead to accelerated inflammation of the injured vascular wall, such molecules can also promote the recruitment of bone marrow-derived progenitor vascular cells, endothelial progenitor cells in particular, with intrinsic capacity to repair the vascular wall. Such cells are produced by the marrow in response to signals derived from the injured vascular wall, released in the systemic circulation and anchored at the level of vascular lesions. They appear to contribute to the repair of the arterial wall, as their absence results in more vascular lesions, and their administration to animals deprived of vascular progenitor cells can retard the onset of vascular disorders. Understanding the production of cells involved in the repair of the vessel wall from a distance (bone marrow) is nascent, potentially important and a great opportunity for advancing the field of vascular disorders. Both the susceptibility of blood vessels to injury and their amenability to repair and/or remodel are profoundly affected by vascular cell heterogeneity. Vascular cell morphology can differ dramatically from one vascular bed to another, according to specific functional requirements. Endothelial cells destined to reside within the arterial or venous vascular beds, moreover, follow diverging differentiation pathways, and those assigned to these specific locations express characteristic molecular markers. Vessel size, anatomic location, and geometry, in addition, determine the quality and magnitude of hemodynamic forces to which vascular cells are exposed. Finally, vascular cells are subject to regional molecular cues and signals derived from specialized surrounding tissues. As a result, vascular cell gene expression profiles and functional responses vary significantly from one setting to another and profoundly influence the cell’s remodeling and repair capabilities. While normal tissues maintain equilibrium between vascular growth and cellular demands, the loss of such balance may lead to either excessive or insufficient angiogenesis and neovascularization. Although numerous pathways and molecular players that relate to vascular proliferation have been identified, their integrated function and co-regulation are poorly understood. Further studies in this area are expected to reveal a host of opportunities for defining the molecular basis and treatment of ischemic myocardium and limbs and to prevent the progression of atherosclerosis. A complication of vascular inflammation is thrombosis and thromboembolic complications. The occlusion of an arterial vessel by a thrombus can lead to the damage of end-organs, such as myocardial infarction and stroke. While hemostasis at the level of sectioned vessels can be lifesaving, the coagulation system was not designed to differentiate vascular wall disruption resulting from a traumatic injury versus the spontaneous fracture of an atherosclerotic plaque at the level of a coronary vessel. Hence, excess and misguided coagulation can be detrimental, whereas some degree of thrombosis may enhance the repair process. The dual role of platelets and coagulation in the process of vascular injury and repair represents another opportunity for investigations. This dual role is perhaps particularly true at the level of branching vessels, where atherosclerotic lesions occur earlier, and hemodynamic conditions are particularly stringent. Such hemodynamic strain might prevent the successful repair of vascular injuries. For example, it might be challenging for progenitor cells to anchor on the surface of damaged arteries. The presence of adhering platelets might facilitate the attachment of progenitor cells, and further participation into the repair process. Hypertension exerts a profound effect upon blood vessel structure and function. Vascular alterations that occur in this setting may include reconfiguration of vessel wall matrix components, dysregulation of cellular proliferation profiles, arterial stiffening, and microvessel rarefaction. A detailed appreciation of these mechanisms, particularly as they relate to individual genomic and proteomic profiles, will likely lead to new opportunities for diagnostic and therapeutic interventions. Measures of the functional and structural properties of blood vessels can be used to assess preclinical vascular disturbances such as endothelial dysfunction and increased vascular stiffness. Abnormalities of endothelial function have been identified in patients with dyslipidemia, hypertension, diabetes, metabolic disorders, obesity and atherosclerosis, and have been shown to predict future vascular events. Vascular compliance decreases with aging and is altered in patients with hypertension. Moreover, increased vascular stiffness contributes to systolic hypertension and adversely affects cardiac function. The relationship between vascular stiffness and arterial diseases is not well defined. Aortic aneurysms and dissections are examples of vascular diseases characterized by serious distortions in arterial architecture due to remodeling. Recent research on the pathophysiology of abdominal aortic aneurysms (AAAs) has highlighted the importance of chronic inflammation and immune responses, enzymatic destruction of aortic elastin and collagen, and depletion of vascular smooth muscle cells from the aortic media. Numerous therapeutic opportunities may exist to influence the biology and natural history of AAAs, as well as the development of non-surgical treatments for small AAAs. A variety of established and emerging imaging technologies will be important in providing qualitative and quantitative measures of vascular wall dysfunction that will be especially applicable to clinical studies. Applications of nanotechnology and molecular imaging are encouraged as a means to facilitate longitudinal studies in patients, both in detecting and stratifying vascular disease, assessing the functional characteristics of vascular lesions over time, and in assessing the results of various interventions. Translation of basic science findings into improvements in the diagnosis and treatment of vascular disease is important. It is apparent that there is significant human variability in the rate of vascular disease or its progression, for example, in the growth of aortic aneurysms or in atherosclerotic plaque burden. Furthermore, clinical heterogeneity exists in the response to treatment, whether pharmacological, endovascular or surgical. Improved methods for detecting those at increased risk for vascular disease progression will permit initiation of preventive and therapeutic measures at an earlier, sub-clinical stage. Better stratification of individuals into those likely to respond versus those likely to fail therapy will permit more effective therapy and tailored approach in the management of vascular disease in the individual patient. The need for clinical trials to investigate the efficacy, safety and durability of new treatment methods for vascular disease is critical. Examples include cell- and gene-based therapies, endovascular and novel pharmacological interventions, as well as development of durable bioprosthetic devices to treat vascular disorders such as coronary, peripheral, visceral, and cerebral vascular occlusive diseases. RESEARCH TOPICS The objective of the SCCOR in vascular injury, repair, and remodeling is to stimulate clinically relevant, multidisciplinary collaborations leading to clinical and basic science research efforts on important public health problems for individuals with vascular diseases. The translation of knowledge into clinical practice should be a goal of applications submitted in response to this initiative. Recent advances in understanding the genetic, molecular, and physiologic underpinnings of vascular function and pathophysiology of disease offer new directions to study normal and abnormal vascular function, to develop early diagnostic tools and markers, and to stratify patients based on genetic and molecular markers. The research encompassed by this program will (1) emphasize the development and translation of basic discoveries to understand the mechanisms of vascular disease; (2) improve the detection, characterization, staging, and management of vascular disease by using cutting-edge methodologies, such as nanotechnology, molecular imaging, genomics, proteomics, quantitative systems analysis; and (3) develop new methods to treat vascular diseases such as cell- and gene-based therapies for regenerative medicine. The SCCOR mechanism provides both the incentive and the structure to maintain critical collaborative cores or other resources necessary for translational research. For example, the SCCOR mechanism affords the ability to establish and maintain a large clinical/DNA sample database of patients with various types of vascular disease. The following examples of research topics are intended to provide a perspective on the scope of research that would meet the objectives of this program. It is not required that all or any of these topics be included. Applicants are encouraged to consider other topics that are relevant to the goals of the Vascular Injury, Repair, and Remodeling SCCOR program. A unified program of clinical and basic research is needed to address such topics as: o Define cellular and molecular factors and signals involved in vascular injury, repair, and remodeling including inflammatory, immune and humoral responses, high- blood-pressure and lipid effects, and biochemical and biomechanical interactions o Study mechanisms involved in the vascular injury, repair, and remodeling due to diabetes, the metabolic syndrome, and obesity o Identify the origin of cells and mechanisms that contribute to the repair and remodeling of vascular lesions, and examine the use of stem or progenitor cells to repair, regenerate, or replace defective or damaged vascular tissue o Determine how vascular cell heterogeneity contributes to the susceptibility of blood vessels to injury, repair, and remodeling o Investigate the role of blood components (e.g., platelets, leukocytes, red blood cells) in the process of vascular injury, repair, and remodeling o Determine biological mechanisms responsible for variation in human susceptibility and progression of vascular diseases, and response to therapy as it relates to vascular, injury, repair and remodeling o Apply emerging noninvasive or minimally invasive technologies (e.g., nanotechnology and molecular imaging) to study vascular injury, repair, and remodeling, and use that knowledge and technology to detect and stratify vascular diseases, to assess the functional characteristics of vascular lesions over time and the results of therapeutic interventions o Apply state-of-the-art global technologies such as proteomics and genomics to understand the mechanisms of vascular injury, repair, and remodeling, and how gene and protein variations influence therapeutic success. o Develop novel and improved markers of subclinical vascular disease, including genetic and proteomic determinants, that can enhance our ability to detect and diagnose vascular diseases early in the disease process. o Develop and test: (1) novel drugs to prevent, treat or manage vascular diseases; (2) novel therapeutic approaches to treat vascular diseases, including cell- and gene-based therapies; and (3) novel surgical interventions. THE FOLLOWING TOPICS ARE OUTSIDE THE SCOPE OF THIS SCCOR AND ITS INDIVIDUAL PROJECTS: o Studies that focus on basic or clinical science only o Phase III clinical trials o Epidemiological studies o Studies that are focused purely on stem cell characterization without consideration of vascular repair and remodeling o Studies in coronary artery disease that focus on the injury of the myocardium CLINICAL RESEARCH SKILLS DEVELOPMENT CORE The newly developed Specialized Centers of Clinically Oriented Research (SCCOR) program mechanism requires clinical and basic scientists with a broad range of skills to work together on a unified theme. It, therefore, presents a rich environment for young clinical investigators to be exposed to and develop additional research skills. The individual centers can be expected to include among their research staff clinical personnel who are newly trained and relatively inexperienced in research. To assist the SCCOR grants in enhancing the developmental environment for their new clinical investigators, the NHLBI will permit applicants for a SCCOR to request up to an additional $100,000 in direct costs per year for a Clinical Research Skills Development Core. The objective of the Core is to support activities to assist new clinical investigators in progressing to more senior status by enhancing their research skills. This support is in addition to the usual cap on the SCCOR mechanism that is updated annually. A Clinical Research Skills Development Core is not required, however, and its absence will not disadvantage an applicant. The quality of the Clinical Research Skills Development Core, if proposed, will be evaluated based on the specific components listed below. The priority score on the Core will have no effect on the overall score of an application. Developmental opportunities that provide experience with new technologies and skills are encouraged for inclusion in the Core. Innovative strategies should be proposed for cross-disciplinary career development to achieve the goal of exposing new clinical investigators to additional research techniques and opportunities. Examples include a program of seminars focusing on scientific topics that include an integration of basic and clinical studies or an "exchange" program, wherein clinical investigators spend time in basic science laboratories. In addition to developing the research skills of new clinical investigators, the Cores must ensure that the participating new clinical investigators receive the mentoring they need to foster their research careers. The Clinical Research Skills Development Core is intended for staff investigators with limited clinical research experience, including fellows and junior faculty members. Investigators who have had a previous K series award are not eligible to participate as new investigators under this program. Individuals with an active K grant can participate until the end of the award period for the K grant, but may not receive salary on the Skills Development Core. The Core should also address other skills necessary for a successful research career, such as grant writing, ethical conduct of research, and clinical trial design. Additional information about the Clinical Research Skills Development Core can be found at http://www.nhlbi.nih.gov/funding/policies/sccor_skill.htm If a Clinical Research Skills Development Core is proposed, it must be directed by an investigator with strong educational and mentoring credentials who will devote a minimum of 5 percent effort as its Leader. To facilitate mentoring and multidisciplinary developmental activities, active involvement by the principal investigator and other senior investigators within the SCCOR is strongly encouraged. An application for a Clinical Research Skills Development Core will be evaluated in terms of its potential effectiveness in developing the skills and research capabilities of new clinical investigators as reflected in the following required elements of the application: o A summary of the types of skills that would be developed and a description of proposed project-specific activities. o A detailed discussion of how mentoring and the professional development of the new clinical investigators will be achieved, including their progression to more independent status. o The credentials and track records of the Clinical Research Skills Development Core Leader, the Principal Investigator, and other participating senior staff in developing new investigators. o A plan for coordinating the activities of participating senior investigators. o A plan for monitoring the progress of the new clinical investigators. o A description of existing opportunities within the applicant's institution for supporting investigator development and steps taken to avoid overlap with or duplication of these efforts. o A detailed development plan for each proposed new investigator (or a representative plan and proposals for tailoring it to needs of multiple new investigators) including required course work and scientific enrichment activities such as special lectures, visiting scientist symposia, seminars, and workshops. Costs allowable for inclusion within the $100,000 direct costs per year limit for the Clinical Research Skills Development Core include salary support for the Core Leader and other participating senior investigators and staff, travel costs for new investigators, supplies and equipment to be used in support of developmental activities, and costs for courses, seminars, workshops, and other activities directly related to the development plan. All costs requested in this Core must be justified with respect to developmental activities and may not be used to supplement the costs of research proposed in the rest of the SCCOR. Since the Core is intended to serve new clinical investigators who occupy positions and receive salary support from the SCCOR grant, salary support for the new investigators is neither needed nor allowable as a Core cost. All new clinical investigators supported by the SCCOR grant should be eligible to participate in Core-sponsored activities so long as they have not attained independent status. However, attaining independent status should be an objective of the Core activities. So, participating new investigators should be encouraged to apply for either a Career Development Award, a patient-oriented regular research grant, or any other source of independent research or career development support. Although the participating new investigators will be expected to devote essentially full- time effort to research during this period, they may devote an appropriate percentage of their time to maintaining clinical skills. An application for a Clinical Research Skills Development Core will be evaluated in terms of its potential effectiveness in developing the skills and research capabilities of new clinical investigators as reflected in the required application components identified above. MECHANISM OF SUPPORT This RFA will use the NIH P50 award mechanism. All applications received in response to the Vascular Injury, Repair, and Remodeling SCCOR program will be considered as new applications and must meet the requirements for the new SCCOR program (please see http://www.nhlbi.nih.gov/funding/policies/sccor_desc.htm). As an applicant, you will be solely responsible for planning, directing, and executing the proposed project. The anticipated award date is April 1, 2006. Applicants should request a 5-year project period when responding to this announcement. Each NHLBI SCCOR 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 SCCOR program. Under this policy, a given SCCOR grant is awarded for a 5-year project period following an open competition. Only one 5-year competing renewal is permitted, for a total of 10 years of support, unless the SCCOR program is recommended for extension. The NHLBI comprehensive evaluation of the Vascular Injury, Repair, and Remodeling SCCOR program will be conducted during the second project period according to the following timetable: Program Announced: FY 2004 Project Period (First Competition): FY 2006 through FY 2010 Program Re-announced: FY 2008 Project Period (Second Competition): FY 2011 through FY 2015 Letter to Principal Investigators Regarding SCCOR Evaluation Plans: FY 2012 (mid-way through year 02 of 2nd project period) SCCOR Evaluation Meeting: FY 2012 (late in year 02 of 2nd project period) The NHLBI does not limit the number of applications for a given SCCOR program from one institution. However, each SCCOR application from the institution must have a different Principal Investigator and must be self-contained and independent of other SCCOR applications from the same institution. Institutions envisioning more than one application are encouraged to discuss their plans with the program contact listed under WHERE TO SEND INQUIRIES. This RFA uses just-in-time concepts and only non-modular budgeting formats. Follow the instructions for the non-modular budget research grant applications at http://grants.nih.gov/grants/funding/phs398/phs398.html. This program does not require cost sharing as defined in the current NIH Grants Policy Statement at http://grants.nih.gov/grants/policy/nihgps_2001/part_i_1.htm. FUNDS AVAILABLE The NHLBI intends to commit approximately $20.0 million in FY 2006 to fund 5 to 7 new grants in response to this RFA. An applicant may request a project period of 5 years and a budget for direct costs of up to $2.5 million per year not including Facilities and Administrative (F&A) costs for collaborating institutions in the first year (http://grants.nih.gov/grants/guide/notice-files/NOT-OD-04-040.html). In addition, applicants for a SCCOR may request up to $100,000 in direct costs per year above the usual cap ($2.5 million direct costs) for a Clinical Research Skills Development Core. All applications will be considered as new applications. An increase of no more than 3 percent may be requested in each additional year. Because the nature and scope of the proposed research will vary from application to application, it is anticipated that the size and duration of each award will also vary. 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 a sufficient number of meritorious applications. Consortium Arrangements If a grant application includes research activities that involve institutions other than the grantee institution, the application will be considered a consortium effort. Such applications are permitted, but it is imperative that the application be prepared so that programmatic, fiscal, and administrative considerations are explained fully. At least 50 percent of projects (including at least one clinical project) and 50 percent of the cores must be located at the applicant institution. The NIH published policy governing consortia is available in the business offices of institutions that are eligible to receive federal grants-in-aid and should be consulted before developing the application. For clarification of the policy, contact Mr. Dave Reiter, Grants Operation Branch, NHLBI (301) 435-0177. Applicants for SCCOR grants should exercise great care in preserving the interactions of the participants and the integration of the consortium project(s) with those of parent institution, because synergism and cohesiveness can be diminished when projects are located outside the group at the parent institution. Indirect costs paid as part of a consortium agreement are excluded from the limit on the amount of direct costs that can be requested. ELIGIBLE INSTITUTIONS You may submit (an) application(s) if your institution has any of the following characteristics: o For-profit or non-profit organizations o Public or private institutions, such as universities, colleges, hospitals, and laboratories o Units of state and local governments o Eligible agencies of the federal government o Domestic institutions/organizations o Foreign institutions are not eligible to apply. o Faith-based or community-based organizations INDIVIDUALS ELIGIBLE TO BECOME PRINCIPAL INVESTIGATORS Any individual with the skills, knowledge, and resources necessary to carry out the proposed research is invited to work with their institution to develop an application for support. Individuals from under-represented racial and ethnic groups as well as individuals with disabilities are always encouraged to apply for NIH programs. SPECIAL REQUIREMENTS 1. The overall concept of a SCCOR program focuses on clinical and basic scientific issues related to diseases and disorders relevant to the mission of the NHLBI. To be considered responsive to this announcement, all applications must include both clinical and basic research. In addition, interactions between clinical and basic scientists are expected to strengthen the research, enhance the translation of fundamental research findings to the clinical setting, and identify new research directions. Translation of findings from basic to clinical studies is an important focus of the SCCOR program. 2. The number of clinical research projects in each NHLBI SCCOR must be equal to or greater than the number of basic science projects, at the time of submission, award, and throughout the 5-year project period. For example, if an application has a total of three projects, two of the projects must be clinical research projects. Neither a clinical component in a basic science project nor a clinical core fulfills the requirement for a clinical project. However, a single project can integrate basic and clinical research. If the majority of the research within a project is clinical, it will be considered a clinical project; if the majority of the research within a project is basic, it will be considered a basic project. Because a SCCOR grant is a 5-year program, an applicant should submit a 5-year plan for all the projects. 3. In order for a project to be considered clinical research for the purposes of responsiveness to this RFA, the research must be patient-oriented research. Patient-oriented research is research in which an investigator (or colleague) directly interacts with patients having a disease or condition of interest. Normal healthy subjects may be included, but only in combination with studies involving patients. In studies involving the use of human specimens, the investigators must have direct interaction with the patient from whom the specimen is obtained and relate the research results to the patient status or outcome for this to be considered a clinical project. It is intended that the requirement for investigator interaction with the study participants will eliminate research involving archived tissue. Applicants are encouraged to pursue patient-oriented research on topics related to health disparities and the translation of this research to clinical practice for affected minority populations. At a minimum, clinical research projects must include women and minorities in the study population in representative numbers, unless such inclusion can be demonstrated to be inappropriate. Clinical studies involving interventions or treatments must give consideration to including sufficient numbers of women and minorities to conduct valid analyses of subgroup effects. Epidemiologic studies or Phase III clinical trials will be considered unresponsive to this RFA. 4. Each awarded SCCOR must consist of three or more projects, all of which are directly related to the overall clinical focus of the SCCOR. At least 50 percent of the projects and 50 percent of the cores must be located at the applicant institution, and at least one of the clinical projects must be at the applicant institution. Component projects not located at the applicant institution may be at a foreign institution, but must conform to NIH policy regarding the protection of human subjects. Each component project, whether clinical or basic, requires a well- described, clinically relevant hypothesis, preliminary data, and a time-table for conducting the proposed investigations. 5. The relationship of each core to each component project should be described. A core must provide services to two or more projects. 6. Each SCCOR must have a well-delineated organizational structure and administrative mechanism that foster interactions between investigators, accelerate the pace of research, enable translation of basic research findings to clinical applications, and ensure a productive research effort. 7. Applicants should provide a detailed data and safety monitoring plan for the clinical research proposed; the monitoring plan will be considered as part of peer review of the application. This plan should address informed consent, recruitment, reporting of adverse events, patient safety, oversight of clinical issues in the protocols, storage and analysis of confidential data, and dissemination of any research results. After a decision has been made regarding SCCOR awards, the Institute will determine whether to convene a Data and Safety Monitoring Board (DSMB) to oversee one or more clinical projects in a SCCOR program. It is NHLBI policy to appoint DSMBs for Institute-funded intervention studies when an independent group is needed to evaluate the data on an ongoing basis to ensure participant safety and/or study integrity. The decision to establish each board is made by the relevant Division Director with the concurrence of the NHLBI Director. In those cases where such interventional studies are proposed, applicants are encouraged to include funds in the budget for 5 DSMB members for 2 meetings a year to be held in Bethesda, Maryland. 8. The principal investigator (SCCOR Director) should be an established research scientist with the ability to ensure quality control and the experience to administer both clinical and basic research effectively and integrate all components of the program. A minimum time commitment of 25 percent is required for this individual. The Principal Investigator must be the Project Leader of one of the component research projects. If this project is not recommended by peer review, the overall SCCOR application will not be considered further. If this project is judged by peer review to be of low scientific merit, this will markedly reduce the overall scientific merit ranking assigned to the entire application. 9. Project Leaders should have significant research experience and must agree to commit at least 20 percent effort to each project for which they are responsible. Leaders of clinical projects should have experience in clinical research as defined in Item 2, above. Investigators with minimal research experience, but promising credentials, may participate; however, it is expected that most of the project leaders will be investigators with significant research experience. 10. Applicants are encouraged to establish links and utilize existing resources, including the NHLBI Program in Genomic Applications (http://www.nhlbi.nih.gov/resources/pga/); NHLBI Proteomics Centers (http://www.nhlbi.nih.gov/resources/medres/proteomics/index.htm); Programs of Excellence in Gene Therapy for Heart, Lung, and Blood Diseases with National Service Cores for Pre-Clinical Grade Vector Production, Cell Morphology, Hematopoietic Cell Processing, and Non-Human Primate Hematopoietic Transplantation (http://www.med.cornell.edu/pegt/); NHLBI clinical research networks; and General Clinical Research Centers, as feasible and appropriate. If applicants propose to utilize such resources, a letter of agreement from the Program Director or Principal Investigator of the resource should be included with the application. 11. The applicant should plan and budget for the SCCOR Director and the Project Leaders of the SCCOR to attend one annual grantee meeting per year in Bethesda, Maryland. 12. NIH recently reaffirmed support for the concept of timely sharing and distribution of model organisms for biomedical research. Applicants are expected to include in the application/proposal a description of a specific plan for sharing and distributing unique model organism research resources generated using NIH funding so that other researchers can benefit from these resources. More information can be found at http://grants.nih.gov/grants/guide/notice-files/NOT-OD-04-042.html. Applicants are encouraged to include funds in the budget for this purpose. WHERE TO SEND INQUIRIES We encourage inquiries concerning this RFA and welcome the opportunity to answer questions from potential applicants. Inquiries may fall into three areas: scientific/research, peer review, and financial or grants management issues: o Direct your questions about scientific/research issues to: H. Eser Tolunay, Ph.D. Director, Vascular Biology Research Program Division of Heart and Vascular Diseases National Heart, Lung, and Blood Institute Rockledge Centre ll 6701 Rockledge Drive, Room 10190 Bethesda, MD 20892-7956 Telephone: (301) 435-0545 FAX: (301) 480-2858 Email: TolunayE@nhlbi.nih.gov o Direct your questions about peer review issues to: Valerie Prenger, Ph.D. Chief, Review Branch Division of Extramural Affairs National Heart, Lung, and Blood Institute Rockledge Centre ll 6701 Rockledge Drive, Room 7214 Bethesda, MD 20892-7924 Telephone: (301) 435-0270 Fax: (301) 480-3541 Email: prengerv@nhlbi.nih.gov o Direct your questions about financial or grants management matters to: David Reiter Grants Operations Branch National Heart, Lung, and Blood Institute Rockledge Centre ll 6701 Rockledge Drive, Room 7172 Bethesda, MD 20892-7926 Telephone: (301) 435-0177 FAX: 301-480-3310 Email: reiterd@nhlbi.nih.gov LETTER OF INTENT Prospective applicants are asked to submit a letter of intent that includes the following information: o Descriptive title of the proposed research program o Name, address, and telephone number of the Principal Investigator o Names of other key personnel o Participating institutions o Number and title of this RFA Although a letter of intent is not required, is not binding, and does not enter into the review of a subsequent application, the information that it contains allows NHLBI staff to estimate the potential review workload and plan the review. The letter of intent is to be sent by the date listed at the beginning of this document. The letter of intent should be sent by mail or email to Dr. Valerie Prenger at the address listed under WHERE TO SEND INQUIRIES. SUBMITTING AN APPLICATION Applications must be prepared using the PHS 398 research grant application instructions and forms (rev. 5/2001). Applications must have a DUN and Bradstreet (D&B) Data Universal Numbering System (DUNS) number as the Universal Identifier when applying for federal grants or cooperative agreements. The D&B number can be obtained by calling (866) 705-5711 or through the web site at http://www.dunandbradstreet.com/. The D&B number should be entered on line 11 of the face page of the PHS 398 form. The PHS 398 document is available at http://grants.nih.gov/grants/funding/phs398/phs398.html in an interactive format. For further assistance contact GrantsInfo, Telephone (301) 710-0267, Email: GrantsInfo@nih.gov. SUPPLEMENTARY INSTRUCTIONS: Because of the size and complexity of a SCCOR, prospective applicants are urged to consult with the staff of the Division of Heart and Vascular Diseases early in the preparation of the application (see INQUIRIES Section). Special instructions are needed for preparing a SCCOR application and are available from the program contact listed under WHERE TO SEND INQUIRIES or at http://www.nhlbi.nih.gov/funding/policies/sccor_supp.htm. To provide opportunity for such interactions, the time frame for implementation of this program includes an ample interval between the release of this RFA and the receipt date for applications. USING THE RFA LABEL: The RFA label available in the PHS 398 (rev. 5/2001) 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 RFA label is also available at: http://grants.nih.gov/grants/funding/phs398/labels.pdf. SENDING AN APPLICATION TO THE NIH: 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 and all copies of the appendix material must be sent to: Valerie Prenger, Ph.D. Chief, Review Branch Division of Extramural Affairs National Heart, Lung, and Blood Institute Rockledge Centre 11, Room 7214 Bethesda, MD 20817 (express mail) Telephone: (301) 435-0270 Fax: (301) 480-3541 Email: prengerv@nhlbi.nih.gov APPLICATION PROCESSING: Applications must be received on or before the application receipt date listed in the heading of this RFA. If an application is received after that date, it will be returned to the applicant without review. Although there is no immediate acknowledgement of the receipt of an application, applicants are generally notified of the review and funding assignment within 8 weeks. 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. However, when a previously unfunded application, originally submitted as an investigator-initiated application, is to be submitted in response to an RFA, it is to be prepared as a NEW application. That is, the application for the RFA must not include an Introduction describing the changes and improvements made, and the text must not be marked to indicate the changes from the previous unfunded version of the application. Principal Investigators should not send supplementary material without first contacting the Scientific Review Administrator (SRA). The SRA will be identified in the letter sent to you indicating that your application has been received. If you have not received such a letter within three weeks after submitting the application, contact Dr. Valerie Prenger at the address listed under WHERE TO SEND INQUIRIES. PEER REVIEW PROCESS Upon receipt, applications will be reviewed for completeness by the CSR and responsiveness by the NHLBI. Incomplete or unresponsive applications will not be reviewed. 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: o 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 and assigned a priority score. o Receive a written critique. o Receive a second level review by the NHLBI National Advisory Council or Board. REVIEW CRITERIA The goals of NIH-supported research are to advance our understanding of biological systems, improve the control of disease, and enhance health. Factors to be considered in the evaluation of each application will be similar to those used in the review of traditional clinical and basic research grant applications and, in addition, will include overall proposed interactions between clinical and basic research projects. The review panel will include a majority of clinical researchers who will receive special instructions to place emphasis on strong clinical components. Major factors to be considered in the evaluation of applications include: o Scientific merit of the proposed clinical and basic research projects including significance, importance, clinical relevance and appropriateness of the theme; innovation, originality, and feasibility of the approach; and adequacy of the experimental design. o Leadership, scientific expertise, experience, and commitment of the principal investigator; competence of the investigators to accomplish the proposed research goals and their time commitment to the program; clinical research experience among the investigators; and the feasibility and strength of consortium arrangements. o Collaborative interaction between clinical and basic research components, 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; quality of the support cores; proposed instrumentation; quality controls; administrative structure; institutional commitment; and, when needed, data management systems. o Adequacy of the data and safety monitoring plan for the clinical research proposed. Each project will receive a priority score. Each core (except the Clinical Research Skills Development Core) will be Recommended or Not Recommended based on whether the core is essential for the proposed research and has the capability to fulfill the proposed function. Reviewers will evaluate the number of projects serviced by the core; strengths and weaknesses of the proposed approaches, resources, and interactions; whether the investigators are qualified for their role(s) in the core; and whether the proposed budget for the core is appropriate. Each application will receive an overall priority score based on the review criteria listed above. The Clinical Research Skills Development Core will receive a priority score based on the review criteria below, but the priority score will not enter into the overall priority score. Review Criteria for Clinical Research Skills Development Core: The Clinical Research Skills Development Core will be evaluated for its effectiveness in developing the skills and clinical research capabilities of new investigators. This will include an evaluation of: o Credentials and track record of the Principal Investigator, Clinical Research Skills Development Core Project Leader, and other participating senior investigators. o Methods by which new investigators are to be recruited and selected including plans to recruit women and minority individuals. o Plans for developing the skills of new investigators; the types of skill and technologic development proposed. o Means by which the new investigators' professional development will be achieved. ADDITIONAL REVIEW CRITERIA: In addition to the above criteria, the following items will be considered in the determination of scientific merit and the priority score: PROTECTION OF HUMAN SUBJECTS FROM RESEARCH RISK: The involvement of human subjects and protections from research risk relating to their participation in the proposed research will be assessed. (See criteria included in the section on Federal Citations, below.) INCLUSION OF WOMEN, MINORITIES AND CHILDREN IN RESEARCH: The adequacy of plans to include subjects from both genders, all racial and ethnic groups (and subgroups), and children as appropriate for the scientific goals of the research. Plans for the recruitment and retention of subjects will also be evaluated. (See Inclusion Criteria in the sections on Federal Citations, below.) CARE AND USE OF VERTEBRATE ANIMALS IN RESEARCH: If vertebrate animals are to be used in the project, the five items described under Section f of the PHS 398 research grant application instructions (rev. 5/2001) will be assessed. RECEIPT AND REVIEW SCHEDULE Letter of Intent Receipt Date: April 11, 2005 Application Receipt Date: May 11, 2005 Peer Review Date: Sept/Oct 2005 Council Review: February 2006 Earliest Anticipated Start Date: April 1, 2006 AWARD CRITERIA Award criteria that will be used to make award decisions include: o Scientific merit (as determined by peer review) o Availability of funds o Programmatic priorities REQUIRED FEDERAL CITATIONS ANIMAL WELFARE PROTECTION: Recipients of PHS support for activities involving live, vertebrate animals must comply with PHS Policy on Humane Care and Use of Laboratory Animals (http://grants.nih.gov/grants/olaw/references/PHSPolicyLabAnimals.pdf), as mandated by the Health Research Extension Act of 1985 (http://grants.nih.gov/grants/olaw/references/hrea1985.htm), and the USDA Animal Welfare Regulations (http://www.nal.usda.gov/awic/legislat/usdaleg1.htm), as applicable. HUMAN SUBJECTS PROTECTION: Federal regulations (45CFR46) require that applications and proposals involving human subjects must be evaluated with reference to the risks to the subjects, the adequacy of protection against these risks, the potential benefits of the research to the subjects and others, and the importance of the knowledge gained or to be gained. http://www.hhs.gov/ohrp/humansubjects/guidance/45cfr46.htm DATA AND SAFETY MONITORING PLAN: Data and safety monitoring is required for all types of clinical trials, including physiologic, toxicity, and dose-finding studies (phase I); efficacy studies (phase II); efficacy, effectiveness and comparative trials (phase III). The establishment of data and safety monitoring boards (DSMBs) is required for multi-site clinical trials involving interventions that entail potential risk to the participants. (NIH Policy for Data and Safety Monitoring, NIH Guide for Grants and Contracts, June 12, 1998: http://grants.nih.gov/grants/guide/notice-files/not98-084.html). SHARING RESEARCH DATA: Investigators submitting an NIH application seeking $500,000 or more in direct costs in any single year are expected to include a plan for data sharing or state why this is not possible. http://grants.nih.gov/grants/policy/data_sharing Investigators should seek guidance from their institutions on issues related to institutional policies, local IRB rules, as well as local, state and federal laws and regulations, including the Privacy Rule. Reviewers will consider the data sharing plan but will not factor the plan into the determination of the scientific merit or the priority score. INCLUSION OF WOMEN AND MINORITIES IN CLINICAL RESEARCH: It is the policy of the NIH that women and members of minority groups and their sub-populations must be included in all NIH-supported clinical research projects unless a clear and compelling justification is provided indicating 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 clinical research should read the "NIH Guidelines for Inclusion of Women and Minorities as Subjects in Clinical Research - Amended, October, 2001," published in the NIH Guide for Grants and Contracts on October 9, 2001 (http://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-001.html); a complete copy of the updated Guidelines are available at http://grants.nih.gov/grants/funding/women_min/guidelines_amended_10_2001.htm. The amended policy incorporates: the use of an NIH definition of clinical research, updated racial and ethnic categories in compliance with the new OMB standards, clarification of language governing NIH-defined Phase III clinical trials consistent with the new PHS Form 398, and updated roles and responsibilities of NIH staff and the extramural community. The policy continues to require for all NIH- defined Phase III clinical trials that: (1) all applications or proposals and/or protocols must provide a description of plans to conduct analyses, as appropriate, to address differences by sex/gender and/or racial/ethnic groups, including subgroups if applicable; and (2) investigators must report annual accrual and progress in conducting analyses, as appropriate, by sex/gender and/or racial/ethnic group differences. INCLUSION OF CHILDREN AS PARTICIPANTS IN RESEARCH INVOLVING HUMAN SUBJECTS: The NIH maintains a policy 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. 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 is available at http://grants.nih.gov/grants/funding/children/children.htm. REQUIRED EDUCATION ON THE PROTECTION OF HUMAN SUBJECT PARTICIPANTS: NIH policy requires education on the protection of human subject participants for all investigators submitting NIH proposals for research involving human subjects. You will find this policy announcement in the NIH Guide for Grants and Contracts Announcement, dated June 5, 2000, at http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-039.html. HUMAN EMBRYONIC STEM CELLS (hESC): Criteria for federal funding of research on hESCs can be found at http://stemcells.nih.gov/index.asp and at http://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-005.html. Only research using hESC lines that are registered in the NIH Human Embryonic Stem Cell Registry will be eligible for federal funding (see http://escr.nih.gov). It is the responsibility of the applicant to provide, in the project description and elsewhere in the application as appropriate, the official NIH identifier(s) for the hESC line(s) to be used in the proposed research. Applications that do not provide this information will be returned without review. PUBLIC ACCESS TO RESEARCH DATA THROUGH THE FREEDOM OF INFORMATION ACT: The Office of Management and Budget (OMB) Circular A-110 has been revised to provide public access to research data through the Freedom of Information Act (FOIA) under some circumstances. Data that are (1) first produced in a project that is supported in whole or in part with federal funds and (2) cited publicly and officially by a federal agency in support of an action that has the force and effect of law (i.e., a regulation) may be accessed through FOIA. It is important for applicants to understand the basic scope of this amendment. NIH has provided guidance at http://grants.nih.gov/grants/policy/a110/a110_guidance_dec1999.htm. Applicants may wish to place data collected under this RFA in a public archive, which can provide protections for the data and manage the distribution for an indefinite period of time. If so, the application should include a description of the archiving plan in the study design and include information about this in the budget justification section of the application. In addition, applicants should think about how to structure informed consent statements and other human subjects procedures given the potential for wider use of data collected under this award. STANDARDS FOR PRIVACY OF INDIVIDUALLY IDENTIFIABLE HEALTH INFORMATION: The Department of Health and Human Services (DHHS) issued final modification to the Standards for Privacy of Individually Identifiable Health Information, the Privacy Rule, on August 14, 2002. The Privacy Rule is a federal regulation under the Health Insurance Portability and Accountability Act (HIPAA) of 1996 that governs the protection of individually identifiable health information and is administered and enforced by the DHHS Office for Civil Rights (OCR). Decisions about applicability and implementation of the Privacy Rule reside with the researcher and his/her institution. The OCR website (http://www.hhs.gov/ocr/) provides information on the Privacy Rule, including a complete Regulation Text and a set of decision tools on Am I a covered entity? Information on the impact of the HIPAA Privacy Rule on NIH processes involving the review, funding, and progress monitoring of grants, cooperative agreements, and research contracts can be found at http://grants.nih.gov/grants/guide/notice-files/NOT-OD-03-025.html. 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. Furthermore, we caution reviewers that their anonymity may be compromised when they directly access an Internet site. 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 RFA is related to one or more of the priority areas. Potential applicants may obtain a copy of "Healthy People 2010" at http://www.healthypeople.gov/. AUTHORITY AND REGULATIONS: This program is described in the Catalog of Federal Domestic Assistance at http://www.cfda.gov/ and is not subject to the intergovernmental review requirements of Executive Order 12372 or Health Systems Agency review. Awards are made under the authorization of Sections 301 and 405 of the Public Health Service Act as amended (42 USC 241 and 284) and under Federal Regulations 42 CFR 52 and 45 CFR Parts 74 and 92. All awards are subject to the terms and conditions, cost principles, and other considerations described in the NIH Grants Policy Statement. The NIH Grants Policy Statement can be found at http://grants.nih.gov/grants/policy/policy.htm. The PHS strongly encourages all grant recipients to provide a smoke-free workplace and discourage the 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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