Full Text HL-96-004 ANGIOGENESIS AND VASCULAR REMODELING IN THE MICROVASCULATURE NIH GUIDE, Volume 24, Number 40, November 24, 1995 RFA: HL-96-004 P.T. 34 Keywords: Cardiovascular System Biology, Cellular Biology, Molecular 0705048 National Heart, Lung, and Blood Institute Letter of Intent Receipt Date: February 1, 1996 Application Receipt Date: April 11, 1996 THIS RFA USES "MODULAR GRANT" AND "JUST-IN-TIME" CONCEPTS. THIS RFA INCLUDES DETAILED MODIFICATIONS TO STANDARD APPLICATION INSTRUCTIONS THAT MUST BE USED TO PREPARE AN APPLICATION IN RESPONSE TO THIS RFA. PURPOSE The purpose of this solicitation is to encourage research on the molecular, cellular, and physiological mechanisms involved in determining the structure and arrangement of blood vessels during the processes of angiogenesis and vascular remodeling. The Request for Applications (RFA) focuses on changes that occur at the microcirculatory level, particularly as they relate to hypertension. HEALTHY PEOPLE 2000 The Public Health Service (PHS) is committed to achieving the health promotion and disease prevention objectives of "Healthy People 2000," a PHS-led national activity for setting priority areas. This RFA, Angiogenesis and Vascular Remodeling in the Microvasculature, is related to the priority areas of heart disease and stroke, and diabetes and chronic disabling conditions. 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 and 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 unusual merit, need, and promise, and in accordance with Public Health Service policy governing such awards. Among the disciplines and expertise that may be appropriate for this research program are cell biology, molecular biology, biochemistry, immunology, pharmacology, and microvascular physiology. MECHANISM OF SUPPORT This RFA will use the NIH individual research project grant (R01) mechanism of support. However, specific application instructions have been modified to reflect "MODULAR GRANT" and "JUST-IN-TIME" streamlining efforts being examined by the NIH. The modular grant concept establishes specific modules (increments) 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 NHLBI staff. For this RFA, funds must be requested in $25,000 direct cost modules and a maximum of nine modules ($225,000 direct costs) per year may be requested. A feature of the modular grant concept is that no escalation is provided for future years, and all anticipated expenses for all years of the project must be included within the number of modules being requested. Only limited budget information will be required and any budget adjustments made by the Initial Review Group will be in modules of $25,000. 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. Applicants are expected to furnish their own estimates of time required to achieve the objectives of the proposed research project. Up to four years of support may be requested. 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 September, 1996. 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 1996, approximately $1.2 million total costs will be available 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 approximately four new grants will be awarded under this program. 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. Indirect costs will be awarded based on the negotiated rates. RESEARCH OBJECTIVES Background A knowledge of the mechanisms that regulate angiogenesis is important for understanding normal processes, such as wound healing, that are characterized by rapid, but controlled, neovascularization. In addition, this knowledge will provide important insights for understanding abnormal angiogenic processes such as those involved in diabetes mellitus, the origin of new microcirculation in the atherosclerotic plaque, and the growth of neoplastic tumors. Furthermore, the potential for manipulating the process of neovascularization has important implications for the treatment of peripheral vascular disease, coronary heart disease, and cardiac hypertrophy, because promoting appropriate vessel growth could provide a means for restoring nutritive blood flow to ischemic tissues. Another area of emerging importance is the vascular adaptation and complications associated with hypertension. Hypertension is a serious public health problem that afflicts more than 50 million people in the U.S. It is essential to understand both the genetic and environmental factors that contribute to its development, and the phenomenon of vascular remodeling provides an appropriate focus for such research because it is a measurable incremental pathologic consequence of hypertension. In addition to the acute changes in tone, blood vessels are capable of structural alteration over time. The types of restructuring include an increase in vascular mass; vessel wall thickening, enlargement or dilation; and alteration in capillary density, as seen in rarefaction, a hallmark of diabetic vasculopathy and essential hypertension. The loss of microvascular density seen in chronic reduced renal mass hypertension is thought to be mediated by structural degeneration of vascular smooth muscle and endothelial cells. Vascular remodeling can be viewed as a physiological protective response, but it can also contribute to certain circulatory disorders, such as hypertensive vascular disease, atherosclerosis, restenosis, and aneurysm formation. These vascular changes are likely to enhance vasoconstriction and further reduce blood flow and reserve, which are major contributing factors to the clinical complications of hypertension, such as myocardial ischemia and stroke. Angiogenesis and vascular remodeling represent two aspects of a series of events that determines the structure and arrangement of vascular beds, and understanding the factors that regulate one of these processes should shed light on regulation of the other. Both are complex processes involving cell growth, cell migration, cell rearrangement, or programmed cell death, as well as production, degradation, and realignment of the extracellular matrix. There is evidence that both restructuring processes are initiated by humoral factors generated by mechanisms that sense a change of hemodynamic conditions. The angiogenic process gives rise to new vessels; the remodeling process finally leads to structural changes in the vessel wall or to the loss of microvasculature. The list of factors known to trigger or influence vascular growth has lengthened extensively over the past twenty years, and now includes acidic and basic fibroblast growth factors (aFGF, bFGF), transforming growth factors TGF-alpha and TGF-beta, epithelial growth factor (EGF), vascular endothelial growth factor (VEGF), hepatocyte growth factor, and interleukin-8 (IL-8). Other molecules are angiogenic in vivo, but are considered to act indirectly because they are not mitogenic in vitro. Heparin, an example of such an indirectly-acting angiogenic substance, produces its action by releasing bFGF from storage sites in the extracellular matrix. Conversely, it is also recognized that there exists a variety of other molecules, exemplified by the extracellular matrix protein thrombospondin, that inhibit endothelial mitogenesis. In addition, vascular growth and remodeling are also strongly dependent on the extracellular matrix (ECM) environment in which they occur. Currently, most research activities related to vascular remodeling and hypertrophy in hypertension focus on the endothelial-dependent growth control of vascular smooth muscle cells, and the effects of altered blood flow and pressure in larger vessels. However, changes in the pre-capillary arterioles are thought to be responsible for the increased peripheral resistance observed in patients with essential hypertension. These vessels are especially important in determining nutritive blood flow (e.g., coronary reserve) in physiological and pathophysiological states and are the vessels that determine local vascular resistance. How these forces act in the microvasculature is of considerable interest. Understanding the action of humoral agents and mechanical forces on vascular structure will require a knowledge of the specific gene activity that they provoke. The techniques being used to probe the molecular biology of other kinds of endothelial cell function could be applied to these processes to identify the promoters and cis- regulatory factors involved in triggering, modulating, and terminating endothelial and smooth muscle mitogenesis. Transgenic animal models could provide a means for examining the effects of specific genomic changes on angiogenesis and vascular remodeling in normal vessels. Additionally, the role of genetic predisposition in the process and how expression of that predisposition may be modulated by secondary responses resulting from hypertension require clarification. Objectives and Scope The objective of this program is to elucidate the regulation of molecular, cellular, and physiological mechanisms involved in determining the structure and arrangement of the microvasculature during the processes of angiogenesis and vascular remodeling, particularly, but not exclusively, in the setting of hypertension. Research could be directed toward genesis of new capillary structures, neovascularization, or remodeling of mature arterioles, venules, or capillary structures, and might include studies of the role of programmed cell death in rarefaction of the microvasculature. Whereas most research efforts have focused on the structural changes in larger arteries, the intention of this solicitation is to direct attention to the microvasculature. It is also the intent of this solicitation to foster studies in cell-culture and small animal models, rather than in human subjects or primates. Areas of interest under this program might include studies to identify the genes, promoters, cis-regulatory elements, and transcriptional events involved in endothelial or vascular smooth muscle cell replication. Also of interest would be exploration of the genomic basis for terminating the effect of an angiogenic stimulus. Transgenic animal models would provide a means for examining the effects of specific genomic changes on vascular structure. It is thought by some that the numerous angiogenic peptides constitute elements of a cascade, much like that responsible for blood coagulation. Others regard changes in vascular structure as involving an interplay between redundant, reinforcing mitogenic agents and growth factors, modulated by similarly redundant inhibitors. Much current research into the action of these peptides is highly descriptive, and a need exists for hypothesis-driven fundamental inquiries into the relationships among the wide array of such agents. In addition to humoral regulation, angiogenesis and remodeling are also strongly dependent on elements of the extracellular matrix (ECM), and the investigation of how they are affected by substances produced in the ECM, or by realignment of structural elements of the ECM, would also be important thrusts for research. The pericyte, the vascular wall stromal cell in contact with the abluminal surface of the capillary endothelium, appears to be another potential determinant of vascular growth and remodeling. Clinical observations indicate that the loss of these cells is associated with abnormal capillary growth, and experimental studies confirm that pericytes can inhibit endothelial growth. Understanding the role that pericytes play in modulating vascular growth could provide valuable information about remodeling. Existing in vivo models of angiogenesis have produced primarily a descriptive view of this process, and no suitable in vivo models currently address the vascular remodeling seen in hypertension. Therefore, the development of in vivo techniques to examine fundamental mechanisms of regulation involved in angiogenesis or remodeling at the microvasculature level would be considered an important research goal, as would the design of cell co-culture systems to investigate fundamental mechanisms that determine vascular structure. Applications addressing vascular remodeling in the setting of hypertension are of particular interest. Although understanding of the processes involved in vascular remodeling is far from complete, ultimately, the development of novel therapeutic approaches that target hypertensive remodeling would be highly desirable. The topics discussed above represent examples of research that would be responsive to this solicitation, but other types of studies may also be appropriate. However, applications that propose only descriptive studies and do not contain hypothesis-driven research directed at understanding the mechanisms underlying the regulation of angiogenesis or vascular remodeling will not be acceptable. Studies intended to specifically investigate inhibition of angiogenesis would not be considered responsive to this announcement. SPECIAL REQUIREMENTS Upon initiation of the program, the NHLBI will sponsor periodic meetings to encourage exchange of information among investigators who participate in this program. In the budget for the grant application, applicants should request travel funds for a one-day meeting each year, most likely to be held in Bethesda, Maryland. Applicants should also include a statement in their applications indicating their willingness to participate in these meetings. INCLUSION OF WOMEN AND MINORITIES IN RESEARCH INVOLVING HUMAN SUBJECTS It is the policy of the NIH that women and members of minority groups and their subpopulations must be included in all NIH supported biomedical and behavioral research projects involving human subjects, unless a clear and compelling rationale and justification is provided that inclusion is inappropriate with respect to the health of the subjects or the purpose of the research. This new policy results from the NIH Revitalization Act of 1993 (Section 492B of Public Law 103-43) and supersedes and strengthens the previous policies (Concerning the Inclusion of Women in Study Populations, and Concerning the Inclusion of Minorities in Study Populations), that have been in effect since 1990. The new policy contains some provisions that are substantially different from the 1990 policies. All investigators proposing research involving human subjects should read the ~NIH Guidelines for Inclusion of Women and Minorities as Subjects in Clinical Research~, which have been published in the Federal Register of March 28, 1994 (FR 59 14508-14513)and reprinted in the NIH Guide 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. LETTER OF INTENT Prospective applicants are asked to submit, by February 1, 1996, 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 sent 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. 5/95) 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; from the Office of Grants Information, Division of Research Grants, National Institutes of Health, 6701 Rockledge Drive, Room 3034, MSC 7762, Bethesda, MD 20898-7762, telephone 301-710-0267, email: girg@drgpo.drg.nih.gov; and from the program administrator listed under INQUIRIES. The RFA label found in the PHS 398 application form must be affixed to the bottom of the face page of the application. Failure to use this label could result in delayed processing of the application such that it may not reach the review committee in time for review. In addition, 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 following modifications are made to the standard PHS 398 application instructions: Applications not conforming to these guidelines will be considered unresponsive to this rfa and will be returned without further review. o INITIAL BUDGET PERIOD - Only the names of personnel and level of effort must be itemized in the Personnel section of the "Detailed Budget for the Initial Budget Period" (Form Page 4). In addition, consultants, equipment, supplies, travel, patient care activities, alterations and renovations and other needs, should be listed as appropriate. Costs are not to be indicated for these individual items or categories. If subcontracts are involved, state the name(s) of collaborating institutions in the "Consortium/Contractual Costs" section and provide individual budgets as detailed in the "SUBCONTRACTS" section below. The "Total Direct Costs" line at the bottom of the page 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 nine modules ($225,000 direct costs) per year may be requested. Any large one-time purchases, such as large equipment requests, must be accommodated within these limits. o FUTURE BUDGET PERIODS - It is anticipated that direct cost budgets will remain the same for each year of the period of award (i.e., the same number of modules requested for each and every budget period). All necessary costs must be considered when determining the number of modules to be requested. However, in the exceptional event that the number of modules requested must change in any future year, appropriate justification must be provided. The "Budget for Entire Proposed Project Period" (top section of Form Page 5) must include Total Direct Costs requested for each year and the Total Direct Costs for the Entire Proposed Project Period. The Justification section must be completed based on instructions provided on Form Page 5. o SUBCONTRACTS - 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 agreement from each collaborating institution must be submitted with the application. Initial and future year budgets for subcontracts must be prepared using the same guidelines as for the main grant except that total subcontract costs need not be in $25,000 modules. Requested amounts must be based on individual needs of the subcontract and must reflect both direct and indirect costs. The subcontract costs are included in the total budget request, which must conform with the number of $25,000 modules requested. o BIOGRAPHICAL SKETCH - In addition to the standard information requested on Form Page 6, the applicant has the option of providing the title and source of any sponsored support relevant to the proposed research. o OTHER SUPPORT - No other support information is required on "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 staff if there is a possibility for an award. o 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. o The applicant must 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. Submit a signed, typewritten original of the application and three signed, photocopies, in one package to: DIVISION OF RESEARCH GRANTS 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 same address given above in the section on LETTER OF INTENT. Applications must be received by April 11, 1996. If an application is received after that date, it will be returned to the applicant without review. The Division of Research Grants (DRG) will not accept any application in response to this RFA that is essentially the same as one currently pending initial review, unless the applicant withdraws the pending application. The DRG will not accept any application that is essentially the same as one already reviewed. This does not preclude the submission of substantial revisions of applications already reviewed, but such applications must include an introduction addressing the previous critique. REVIEW CONSIDERATIONS Applications that are complete and responsive to the RFA will be evaluated for scientific and technical merit by an appropriate peer review group convened in accordance with NIH peer review procedures. As part of the initial merit review, all applications will receive a written critique and undergo a process in which only those applications deemed to have the highest scientific merit, generally the top half of applications under review, will be discussed, assigned a priority score, and receive a second level review by the National Heart, Lung, and Blood Advisory Council. The personnel category will be reviewed for appropriate staffing based on the requested percent effort and any changes requested in future years. The total budget request will be reviewed for consistency with the proposed methods and specific aims. The duration of support will be reviewed to determine if it is appropriate to ensure successful completion of the recommended scope of the project. Other review criteria will include: o scientific, technical or medical significance and originality of proposed research o appropriateness and adequacy of the experimental approach and methodology proposed to carry out the research o qualifications and research experience of the Principal Investigator and staff, particularly, but not exclusively, in the area of the proposed research o availability of the resources necessary to perform the research o adequacy of plans to include both genders and minorities and their subgroups as appropriate for the scientific goals of the research. Plans for the recruitment and retention of subjects will also be evaluated. The initial review group will also examine the provisions for the protection of human and animal subjects and the safety of the research environment. AWARD CRITERIA The following will be considered in making funding decisions: quality of the proposed project as determined by peer review, availability of funds, and program priority. INQUIRIES Inquiries concerning this RFA are encouraged. The opportunity to clarify any issues or questions from potential applicants is welcome and sample budget pages are available. Direct inquiries regarding programmatic issues to: Alfred Small, Ph.D or Michael Lin, Ph.D. Division of Heart and Vascular Diseases National Heart, Lung, and Blood Institute Two Rockledge Center, Suite 10193 6701 Rockledge Drive Bethesda, MD 20892-7956 Telephone: (301) 435-0565 FAX: (301) 480-2849 Email: ALFRED_SMALL@NIH.GOV, MICHAEL_LIN@NIH.GOV Direct inquiries regarding fiscal matters to: Jane Davis Grants Operations Branch National Heart, Lung, and Blood Institute Two Rockledge Center, Suite 7128 6701 Rockledge Drive Bethesda, MD 20892-7128 Telephone: (301) 435-0166 FAX: (301) 480-3310 Email: JANE_DAVIS@NIH.GOV AUTHORITY AND REGULATIONS This program is described in the Catalog of Federal Domestic Assistance No. 93.837. Awards are made under authorization of 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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