HIV IN THE LUNGS, HEART and BLOOD: ROLE OF CHEMOKINES AND THEIR RECEPTORS Release Date: October 2, 1998 RFA: HL-99-002 P.T. National Heart, Lung, and Blood Institute Letter of Intent Receipt Date: December 1, 1998 Application Receipt Date: January 13, 1999 THIS RFA USES "MODULAR GRANT" AND "JUST-IN-TIME" CONCEPTS. THE FULL RFA INCLUDES DETAILED MODIFICATIONS TO STANDARD APPLICATION INSTRUCTIONS THAT MUST BE FOLLOWED WHEN PREPARING APPLICATIONS IN RESPONSE TO THIS RFA. PURPOSE This solicitation invites research grant applications focused on the role of chemokines and chemokine receptors in the lungs, cardiovascular system and bone marrow to elucidate virus-cell interactions in the pathogenesis of HIV in the pulmonary, cardiovascular and hematopoietic systems. An important aspect of this RFA is to determine if chemokines or their derivatives can effectively block infection of tissue macrophages and macrophage-lymphocyte transfer of virus. Another facet of the initiative is to determine if potential new antiviral agents, based on the molecular interactions between chemokines, their receptors and virus, block infection of cells in the lungs, cardiovasculature and bone marrow or alter the evolution of virus in the involved organs. Another crucial question pertinent to this Request for Applications (RFA) is the developmental timing of vulnerability to infection by cells, especially, in the bone marrow. Human studies, e.g., in subjects with various chemokine receptor phenotypes, or with varying stages of HIV infection as compared to healthy persons, and studies in animal models would be of interest. Among the disciplines and expertise that may be appropriate for this research program are immunology, molecular immunology, cell biology, molecular biology, virology, genetics, infectious diseases, pathology, pulmonology, cardiology, hematology, and mathematical modeling. 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, HIV in the Lungs, Heart, and Blood: Role of Chemokines and Their Receptors, is related to the priority areas of HIV infection and immunization and infectious diseases. 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 National Institutes of Health (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 PHS policy governing such awards. MECHANISM OF SUPPORT This RFA will use the NIH individual research project grant (R01) mechanism of support. Investigators without prior R29 or R01 support are encouraged to apply for this RFA and to identify their status on the front of the grant application. Specific R01 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 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, applicant institutions, reviewers, and Institute staff. Although multidisciplinary approaches are encouraged, it is not the intent of this RFA to solicit applications for large studies encompassing a variety of individual subprojects, i.e., program projects. If collaborative arrangements through subcontracts with other institutions are planned, consult the program staff listed under INQUIRIES. For this RFA, funds must be requested in $25,000 direct cost modules and a maximum of eight modules ($200,000 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 budgetary 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. Since a variety of approaches would represent valid responses to this RFA, it is anticipated that there will be a range of costs among individual grants awarded. Up to 5 years of support may be requested on R01 applications. 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 July 1999. Administrative adjustments in project period and/or amount may be required at the time of the award. Applicants from institutions that have a General Clinical Research Center (GCRC) funded by the NIH National Center for Research Resources may wish to identify the GCRC as a resource for conducting the proposed research. If so, a letter of agreement from either the GCRC program director or principal investigator should be included with the application. The National Institute of Allergy and Infectious Diseases (NIAID) has interest in understanding how chemokines and chemokine receptors affect the pathogenesis of HIV disease. Therefore, applications that are of mutual interest are likely to be given a secondary assignment to NIAID in accordance with the NIH referral guidelines. FUNDS AVAILABLE It is anticipated that for fiscal year 1999, approximately $4,000,000 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 15 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. Applicants may request up to 5 years of support. RESEARCH OBJECTIVES Background Two years ago a second receptor for HIV, CCR5, was discovered that helps explain why some individuals are apparently resistant to HIV infection despite continued exposure to the virus, and why some individuals with infection do not develop overt clinical symptoms. People unable to make normal CCR5 were found to be resistant to infection when exposed to HIV. These people carry a mutation of CCR5 (the CCR5 32 deletion) that makes the receptor non-functional, therefore not allowing certain strains of the HIV virus to enter their cells. Presumably, because the abnormal CCR5 chemokine receptor is unable to bind to HIV-1 gp120. Heterozygosity for the CCR5 mutation was observed to slow the progression of HIV disease in a study of infected infants. However, the risk of mother-to-infant transmission in these infants with one copy of the mutant CCR5 receptor did not appear to be reduced. Other studies have revealed that CCR5 is also the receptor for chemokines that blocks HIV infection. A derivative of RANTES (regulated on activation, normal T cell expressed and secreted), one of the chemokines that binds to CCR5, has been produced. Unlike the parent molecule, the derivative cannot attract and activate cells that participate in inflammatory reactions and immune defenses, but it can block binding of HIV to CCR5 and other similar receptors. Such an agent has the potential of acting as an anti-viral substance and opens up the possibility of developing new classes of anti-HIV drugs. It is also clear that CCR5 is not the only coreceptor, many others probably exist. Some HIV viruses have already been found that can use other chemokine receptor molecules in addition to CCR5. Thus far, at least thirteen of them, such as CXCR4, CCR2b and CCR3 have been identified and more receptors are likely to emerge. As yet, little is known concerning the identity of the cells carrying these receptors and in what tissues these other receptor molecules are expressed. It is likely that cells in different tissues express different receptors. Because HIV seems to evolve independently in specific organs, particularly in the lung and brain, it is important to learn more about their function. Although the lung is still the major organ affected by opportunistic infection, the role of chemokines in modulating the expression of HIV in the lung has received little attention. This program would support research on the chemokine receptors and cofactors expressed in cells in the lung from HIV infected persons as well as in animal models. Although a great deal of chemokine receptor work is being performed on tissue other than the lung, little work is currently being done on the tissue most often affected by opportunistic infection. Studies would require access to BAL specimens and possibly to animal models. It is likely that new animal models will soon be available, based on the discovery of the HIV coreceptors, such as transgenics expressing human CD4 along with cofactors. It may be possible to use such new models in the lung to address the pathogenesis of HIV at the end organ level to see how this affects the establishment of altered immunity in the lung, the development of tuberculosis, opportunistic infections and cellular infiltrates associated with HIV. The role of HIV infection in the development of cardiovascular complications has only recently been recognized. The mechanisms for HIV-1 related cardiovascular complications may derive from direct infection of the myocytes and endothelial cells, or may be due to indirect, secondary effects of viral infection mediated by monocytes and macrophages and other inflammatory mediators. At present little is known about the pathogenesis of cardiovascular disease associated with HIV-1 infection. Recently, results of mice lacking PBSF/SDF-1 (for pre-B-cell growth-stimulating factor/stroma-cell-derived factor), a CXC chemokine, indicate that PBSF/SDF-1 is essential for viability of the embryo, B lymphopoiesis, bone marrow myelopoiesis, and cardiac ventricular septum formation. CXCR4, a receptor for PBSF/SDF-1 and HIV, is expressed in cells of both the immune and the central nervous systems, and in developing vascular endothelial cells. Mice lacking CXCR4 exhibit hematopoietic and cardiac defects identical to those of PBSF/SDF-1-deficient mice, and they also have defective vascular development. Examples of chemokine receptors and chemokines expressed in the heart and lung include a human receptor-HCR, a rat chemoattractant-like receptor, a murine MIP-1 alpha receptor, MCP-4 and human MCP-2. Circulating levels of C-C chemokines (MCP-1, MIP-1 alpha, and RANTES) have been reported to be increased in congestive heart failure, with particularly high levels measured in patients with severe disease. Platelet factor 4 (PF-4), an archetype of the "chemokine" family, acts as a potent inhibitor of endothelial cell proliferation. Chemokines have also been implicated in the pathogenesis of atherosclerosis. RANTES mRNA and protein were detected in endothelial cells of arteries undergoing accelerated atherosclerosis, but not in normal coronary arteries. RANTES is proposed to be a pivotal mediator of the cellular infiltrate seen in graft atherosclerosis. Mice with the selective absence of CCR2, the receptor for MCP-1, have decreased lesion formation, markedly decreased in apoE-/- mice. These data suggest a role for chemokines, particularly MCP-1, in the development of early atherosclerotic lesions. While the expression and function of some chemokines and chemokine receptors have been implicated in the cardiovascular system in the absence of HIV infection, information is lacking on the role and the expression of chemokines and chemokine receptors in the cardiovasculature in the setting of HIV-1 infection. How these factors may relate to the prevention or enhancement of HIV infection in cardiovascular system and the progression of cardiovascular complications is unclear. More accurate assessment of the impact of immunity, chemokine and chemokine receptor expression, viral infection, and genetic mutations upon cardiovascular structure and function is required. The role of chemokines in HIV-associated hematopoietic suppression needs to be elucidated. This might include how the chemokines and their receptors function in mediating HIV-associated cell injury and death in the bone marrow. Chemokines may also alter cell ontogeny such that there are critical times of vulnerability for HIV access and integration into the cell. Objectives and Scope The objective of this program is to learn more about the role of chemokines and chemokine receptors in the pathogenesis of HIV in the lungs, the cardiovascular system, and bone marrow. Whether chemokines, chemokine derivatives or potential antiviral agents based on chemokine-chemokine receptor-viral interactions block the entry of HIV into tissue macrophages and alter the course of infection in these and other cells in the lungs, cardiovascular system, and bone marrow is of particular interest. Examples of areas of research (in HIV-infected, other immunodeficient or "normal" human subjects, suitable animal models, in vitro models, or non-linear mathematical models) that might be included under this RFA are as follows: In new animal models based on the discovery of the HIV coreceptors, address mechanisms relevant to the pathogenesis of HIV at the end organ level. This might include studying various aspects of immune dysfunction in the lungs, cardiovascular system, or bone marrow that are pertinent to HIV"s secondary consequences such as tuberculosis, opportunistic infections or pulmonary infiltrates, cardiomyopathy, endothelial dysfunction and suppression of hematopoiesis. Examine questions relating to the distribution of receptors and how they determine cell-specific permissiveness to HIV infection. The production, accumulation, and role of chemokines in regulating virus replication in the lungs, cardiovascular system, and bone marrow could also be addressed. Further identify and characterize chemokines which serve as hematopoietic suppressors in HIV infected patients with an emphasis on reversal of the suppression. Study the role of chemokines in hematopoietic and immune function in HIV infected patients. Study the ontogeny of stem cells to mature cells that delineate the chemokine receptor developmental process with emphasis on the timing of vulnerability to HIV infection. Elucidate signal transduction mechanisms involved in the interplay of chemokines and their receptors which may influence viral-associated cytopathicity or apoptotic responses in the marrow, lungs or cardiovascular system. Study the expression of chemokines and chemokine receptors in the heart during HIV-1 infection. Determine how these factors may relate to the progression of cardiovascular complications. Assess the impact of immunity, chemokine and chemokine receptor expression, viral infection, and genetic mutations upon lung, cardiovascular, and bone marrow structure and function. These are examples only. Investigators should not feel limited to the subjects mentioned above and are encouraged to submit other topics pertinent to the objectives of the RFA. Individual applications may address lung, cardiovascular system, or bone marrow research. It is not necessary for any one project to address issues related to all three. It is anticipated that human, animal, in vitro studies and studies that include non-linear mathematical models would be appropriate. Investigators are encouraged to apply findings from theoretical and in vitro work to in vivo studies when this is feasible. The initiative is relevant to black and Hispanic minority populations who are disproportionately affected by HIV in comparison to the total population. 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 of the grant application, travel funds for a one day meeting each year, most likely to be held in Bethesda, Maryland, should be included in the modules. Applicants should also include a statement in their applications indicating their willingness to participate in these meetings. Applications that focus exclusively on normal chemokine and chemokine receptor function in the lungs, cardiovascular system, and bone marrow are not acceptable. However, studies of normal chemokine and chemokine receptor function may be included, for comparison purposes, along with studies of HIV infection, appropriate models of HIV infection, HIV-associated abnormalities of function, HIV-associated opportunistic infections and complications. Applications that propose descriptive studies and do not contain hypothesis driven studies directed at understanding the mechanisms of chemokine, chemokine receptor and viral interactions, will not be acceptable. Applications that focus on molecular mechanisms are of particular interest. Although studies in human subjects are strongly encouraged, large clinical studies are not within the scope of this RFA. Applicants who propose to test hypotheses in animal, in vitro models or theoretical models must provide a strong rationale for relevance to the human host. This program will not support studies directed at development of animal models alone. Therefore, models must be applied to the study of role chemokines and/or chemokine receptors in the lungs, cardiovascular system, or bone marrow in HIV-infection or in other infections and immunodeficient states relevant to elucidating dysfunction in HIV-infection. 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 follow 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 for Grants and Contracts, Vol. 23, No. 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 RESEARCH INVOLVING HUMAN SUBJECTS It is the policy of NIH that children (i.e., individuals under the age of 21) must be included in all human subjects research, conducted or supported by the NIH, unless there are scientific and ethical reasons not to include them. This policy applies to all initial (Type 1) applications submitted for receipt dates after October 1, 1998. All investigators proposing research involving human subjects should read the "NIH Policy and Guidelines on the Inclusion of Children as Participants in Research Involving Human Subjects" that was published in the NIH Guide for Grants and Contracts, March 6, 1998, and is available at the following URL address: LETTER OF INTENT Prospective applicants are asked to submit, by December 1, 1998, 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. If the applicant is a new investigator (i.e., an investigator without prior R29 or R01 support), you may wish to take the opportunity to identify yourself as such in the letter of intent as well as on the cover page of the application. Although a letter of intent is not required, is not binding, and does not enter into the review of subsequent applications, the information that it contains allows NHLBI staff to estimate the potential review workload and to avoid conflict of interest in the review. The letter of intent is to be faxed or sent to Dr. C. James Scheirer, at the address listed under INQUIRIES. APPLICATION PROCEDURES The research grant application form PHS 398 (rev. 5/95) is to be used in applying for these grants. Application kits are available at most institutional offices of sponsored research and may be obtained from the Division of Extramural Outreach and Information Resources, National Institutes of Health, 6701 Rockledge Drive, MSC 7910, Bethesda, MD 20898-7910, telephone 301-710-0267, Email: 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. This RFA is restricted to R01 grants. All will be awarded as modular grants. The modular grant concept establishes specific modules (increments) in which direct costs may be requested and a maximum level for requested direct cost. Only limited budgetary information is required in the application, a detailed budget need not be provided. Sample budgets and justification page will be provided upon request, from Mr. Raymond Zimmerman at the address listed under INQUIRIES or following the submission of a letter of intent. 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: o FACE PAGE As a reminder, Item 7 should be completed to indicate Modular Direct Costs requested and Item 8 should reflect Total Costs (Modular Direct plus F&A costs). o DETAILED BUDGET FOR THE INITIAL BUDGET PERIOD Do not complete Form Page 4 of the PHS 398 (rev 5/95). It is not required nor will it be accepted at the time of application. o BUDGET FOR THE ENTIRE PROPOSED PERIOD OF SUPPORT Do not complete the categorical budget tables on Form page 5 of the PHS 398 (rev. 5/95). 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 EIGHT modules ($200,000 direct costs) per year may be requested and each applicant may request up to FIVE years of support for this RFA. Direct cost budgets will 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. o BUDGET JUSTIFICATION - Budget justifications should be provided under "Justifications" on Form Page 5 of the PHS 398. - 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. UNDER THE JUSTIFICATION FOR THE PRINCIPAL INVESTIGATOR, INDICATE IF YOU ARE A NEW INVESTIGATOR (I.E. AN INVESTIGATOR WITHOUT PRIOR R29 OR R01 SUPPORT). - Identify all consultants by name and organizational affiliation and describe the services to be performed. - 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. No specific costs for items or categories should be shown. o 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 indirect) 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 $175,000 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. o 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. - Complete the education block at the top of the form page, - List current position(s) and those previous positions directly relevant to the application, - List selected peer-reviewed publications directly relevant to the proposed project, with full citation, - 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. o 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 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 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 listed under INQUIRIES. Applications must be received by January 13, 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 Applications will be reviewed for completeness by the CSR and for responsiveness by NHLBI. Incomplete and/or unresponsive applications will be returned to the applicant without further consideration. Applications that are complete and responsive to the RFA will be evaluated for scientific and technical merit by an appropriate peer review group convened by the NHLBI, in accordance with NIH peer review procedures. As part of the initial merit review, all applications will receive a written critique and undergo a review in which only those applications deemed to have the highest scientific merit of the applications under review (usually two to three times the number of applications that the NHLBI anticipates being able to fund under the program) 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 justification provided. 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. 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 review, comments on the following aspects of the application will be made 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 the assignment of the overall score. (1) Significance Does this study address an important problem? If the aims of the application are achieved, how will scientific knowledge be advanced? What will be the effect of these studies on the concepts or methods that drive this field? (2) Approach Are the conceptual framework, design, methods, and analyses adequately developed, well-integrated, and appropriate to the aims of the project? Does the applicant acknowledge potential problem areas and consider alternative tactics? (3) Innovation Does the project employ novel concepts, approaches or method? Are the aims original and innovative? Does the project challenge existing paradigms or develop new methodologies or technologies? (4) Investigator Is the investigator appropriately trained and well suited to carry out this work? Is the work proposed appropriate to the experience level of the principal investigator and other researchers (if any)? (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? In addition, the adequacy of plans to include both genders and minorities and their subgroups as appropriate for the scientific goals of the research will be reviewed. 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, the safety of the research environment, and conformance with the NIH Guidelines for the Inclusion of Women and Minorities as Subjects in Clinical Research. The roster of the initial review group will be available, via the NHLBI homepage. 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. Applications from new investigators will be strongly considered. The anticipated date of award is July 1, 1999 INQUIRIES Inquiries concerning this RFA are encouraged. The opportunity to clarify any issues or questions from potential applicants is welcome. Direct inquiries regarding programmatic issues to: Hannah H. Peavy, M.D. Division of Lung Diseases National Heart, Lung, and Blood Institute 6701 Rockledge Drive, Suite 10018, MSC 7952 Bethesda, MD 20892-7952 Telephone: (301) 435-0222 FAX: (301) 480-3557 Email: Dr. Lan-Hsiang Wang Division of Heart and Vascular Disease National Heart, Lung, and Blood Institute 6701 Rockledge Drive, Suite 9044, MSC 7940 Bethesda, MD 20892-7940 Telephone: (301) 435-0510 FAX: (301) 480-1335 Email: Dr. Carol Letendre Division of Blood Diseases and Resources National Heart, Lung, and Blood Institute 6701 Rockledge Drive, Suite 10042, MSC 7950 Bethesda, MD 20892-7950 Telephone: (301) 435-0080 FAX: (301) 480-0867 Email: Direct inquiries regarding fiscal matters (e.g. sample budget pages) to: Raymond L. Zimmerman Grants Operations Branch Division of Extramural Affairs National Heart, Lung, and Blood Institute 6701 Rockledge Drive, Suite 7154, MSC 7926 Bethesda, MD 20892-7926 Telephone: (301) 435-0171 FAX: (301) 480-3310 Email: Inquires regarding review, letters of intent and two copies of the grant application should be directed to: C. James Scheirer, Ph.D. 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: AUTHORITY AND REGULATIONS This program is described in the Catalog of Federal Domestic Assistance, No. 93.838. Awards are made under authorization of the Public Health Service Act, Title IV, Part A (Public Law 78-410, amended by Public Law 99-158, 42 U.S.C. 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 a 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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