Full Text HL-96-017 ETIOLOGY OF CARDIOVASCULAR COMPLICATIONS IN HIV INFECTION NIH GUIDE, Volume 25, Number 27, August 9, 1996 RFA: HL-96-017 P.T. 34 Keywords: Cardiovascular Diseases AIDS Etiology National Heart, Lung and Blood Institute Letter of Intent Receipt Date: February 1, 1997 Application Receipt Date: April 24, 1997 THIS RFA USES "MODULAR GRANT" AND "JUST-IN-TIME" CONCEPTS. THE FULL RFA INCLUDES DETAILED MODIFICATIONS TO STANDARD APPLICATION INSTRUCTIONS AND MUST BE USED WHEN PREPARING APPLICATIONS IN RESPONSE TO THIS RFA. PURPOSE This solicitation is intended to foster fundamental research into the mechanisms responsible for the cardiovascular dysfunction and disease that has been seen in HIV+ patients. Investigations may be conducted on cells, tissues or whole animals, including those that have been genetically altered. The purpose is to develop understanding of the role of virus, viral proteins, immune cells, cytokine production, growth factor expression and co-infection with other pathogens in the altered function and disease manifestations of the cardiovascular system. HEALTHY PEOPLE 2000 The Public Health Service (PHS) is committed to achieving the health promotion and disease prevention objectives of "Healthy People 2000,"a PHS-led national activity for setting priority areas. This Request for Applications (RFA), Etiology of Cardiovascular Complications in HIV Infection, is related to the priority area of HIV Infection. 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 the RFA. Awards under this RFA to foreign institutions will be made only for research of very unusual merit, need, and promise, and in accordance with Public Health Service policy governing such awards. Among the disciplines and expertise that may be appropriate for this research program are cell biology, molecular biology, biochemistry, genetics, immunology, pathology, virology and 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 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. For this RFA, funds must be requested in $25,000 direct cost modules and a maximum of ten modules ($250,000 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 aspart 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 the RFA provides specific details of modifications to the standard PHS 398 application kit instructions. Responsibility for the planning, direction, and execution of the proposed project will be solely that of the applicant. FUNDS AVAILABLE It is anticipated that for fiscal year 1997, approximately $1.5 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 to six new grants will be awarded under this program. Applicants may request up to five years of support. 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 The incidence of HIV-infected patients suffering cardiac complications is unknown. Estimates vary considerably, depending upon geographical location, patient population and diagnostic procedures. Conservatively, it is estimated that about six percent to seven percent of HIV-infected adult patients have clinically significant heart disease, and a larger proportion, possibly as high as 18 percent, have clinically silent abnormalities. The two most common forms of HIV-related symptomatic cardiac disease are cardiomyopathy and pericardial effusion associated with cardiac tamponade. Left ventricular dysfunction occurs in all age groups including children and appears to increase when circulating CD4 cell counts are severely depressed. Left ventricular diastolic dysfunction has been reported in asymptomatic and symptomatic patients infected with HIV. HIV-infected intravenous drug users may develop severe cardiomyopathy and congestive heart failure with less CD4 cell depression than HIV patients who do not use drugs. Autopsy studies reveal a high prevalence of lymphocytic infiltrates in the hearts of AIDS patients, even though death may have been due to causes unrelated to cardiac disease, and some of these patients were not noted to have had symptomatic cardiac disease. In a meta-analysis of 402 cases, 46 percent were found to have histological evidence of myocarditis, yet a pathogenic viral, bacterial, or fungal agent was confirmed in only one out of five cases. There has been one report of significant coronary artery lesions in eight young HIV-infected patients who were found dead in unexplained circumstances. None of these patients had a family history of hypercholesterolemia, hypertension, or diabetes. The percentages of cardiac abnormalities are much higher in children infected with HIV. In one study of 81 patients, 64 percent were noted to have resting sinus tachycardia, and 11 percent sinus bradycardia. Dysrhythmias occurred in 35 percent, cardiorespiratory arrest occurred in 9 percent and 10 percent had chronic heart failure. In 12 percent, death was associated with marked cardiac dysfunction. Taking the Public Health Service estimate of 350,000 U.S. AIDS cases by the year 2000 and assuming a 6 percent rate of development of symptomatic heart disease in adults, a total of 21,000 HIV+ patients will require specialized cardiac care. The number will be very much larger worldwide. The susceptibility of cells within the heart to infection from HIV is undefined, as are possible mechanisms of indirect effects of HIV on the cardiovascular system. Research focused on the etiology and pathophysiology of cardiac disease in these patients could lead to improved treatment strategies and prevention of the onset of cardiovascular disease. Investigations of the etiology of cardiac complications in HIV-infected patients are confounded by a variety of factors, including drug use, the large number of self-prescribed medications, problems of nutrition, intercurrent illnesses, and of course, medications prescribed by the physician. For children with vertically transmitted HIV, the aforementioned factors may have affected the in utero environment. In addition, questions remain regarding: the effects of in utero infection; the possibility of increased susceptibility of immature and growing cells of the fetus and infant to HIV infection; and abnormal expression of growth factors and cytokines. For these reasons, it is proposed to study the effects of HIV on the cardiovascular system in animal models, in terms of a direct role and of an indirect role via expression of viral proteins, dysregulation of the immune system, cytokine expression and the pathogenicity of other infectious agents. In general, the role of viruses in the etiology of cardiac disease is poorly understood. Theories include injury as a result of viral infection of cardiac cells, apoptosis, myocytolysis as a consequence of a T-cell response to virus infected myocytes, autoimmune responses which target normal and infected myocytes, and cytokine and growth factor mediated dysfunction and injury. Susceptibility to inflammation may involve a genetic component. Similar speculations have been advanced for the occurrence of cardiac disease in HIV-infected patients. Thus, study of the role of HIV in cardiac complications might well lead to an overall advance in understanding the immunopathological mechanisms of cardiac injury resulting from infection by cardiotropic viruses and provide the basis for rational therapeutic strategies. One approach to understanding some of the mechanisms of dysfunction and disease of various organs and tissues seen in AIDS patients is to examine the role of various gene products by constructing transgenic mice, possibly with cardiotropic promoters. Several attempts have been made in organs and tissues other than heart, using various strains of mice, including SCID mice. This latter model may be useful in studying the role of immunodeficiency in the development of cardiac dysfunction and as an approach to cardiac disease in pediatric patients with HIV infection. Transgenic mice containing the complete HIV coding sequences fused to the mouse mammary tumor virus long terminal repeat have been generated. These mice produce gag and env HIV proteins in organs such as mammary gland, spleen and liver. In some transgenic lines, low levels of HIV proteins could also be detected in serum. The report states that animals sacrificed at 17 months of age were indistinguishable from non-transgenic mice on macroscopic and histologic examination. Thus, it would appear that cells from various tissues in the mouse are capable of replicating retroviruses and producing HIV proteins without causing disease. However, the heart was not among the tissues examined. Transgenic mice expressing the entire HIV genome under the control of the promoter for the human neurofilament NF-L gene exhibited neuropathological changes 7 to 12 months after birth. HIV was expressed in the neurons of these mice in contrast to the findings in humans where neurons are only rarely found to be infected with HIV. However, there were parallels between the hypoactivity of these mice and the psychomotor slowing and apathy seen in the early stages of AIDS dementia. These experiments suggest that disease may be caused not by the replication of the virus but by other related factors. Of more specific relevance is the transgenic mouse constructed to investigate the pathogenesis of HIV-associated nephropathy which occurs in about 10 percent of HIV-infected patients. The mice were made transgenic for a subgenomic proviral HIV construct, pNL4-3:d1443, which lacks the gag and pol genes and is therefore non-infectious. Abnormal renal histology was noted beginning at about 35 to 45 days of age. About 20 percent of these animals developed cardiac lesions at the base of the aortic valve, an adventitial process with macrophage and neutrophil infiltrates. Vasculitis involving the coronary arteries was also observed. The interesting aspect of this proviral construct was that its expression in heart tissue could not be detected by Northern analysis, although low level expression would only be detected by more sensitive methods. However, there was increased expression of atrial natriuretic factor, a molecular marker of myocyte hypertrophy, in the ventricles of these mice. One line of these transgenic mice carrying a subgenomic HIV proviral construct lacking the gag and pol genes was found to develop proliferative epidermal lesions with some similarities to those seen in HIV-infected patients. Dermal lesions similar to Kaposi's sarcoma were not seen in this model, in contrast to those seen in an HIV LTR-tat transgenic mouse. Thus, the proteins expressed by the genes appear to play an important role in pathogenesis of skin disorders in HIV-infected patients. There have been a few reports of the detection of HIV transcripts in endomyocardial biopsies of HIV-infected patients, but the significance of these findings is unclear since the transcripts have been detected in cardiac tissues of patients with and without known cardiac dysfunction. This leads to the speculation that viral proteins, immune mechanisms and cytokine and growth factor dysregulation might be implicated in the pathogenesis of cardiac dysfunction. It is possible that host genetic susceptibility may also play a role since it has been shown that, in mice infected with CVB3, macrophage inflammatory protein (MIP-l-alpha) is an absolute requirement for development of myocarditis. It is also possible that the constant, repeated cycles of viral replications lead to mutations with differential pathogenic effects which result in neurologic, kidney, or heart disease, or cancer. While some studies may be performed on cells, organs or whole animals, many will require the development and exploitation of transgenic animal models which could contribute to knowledge of the pathogenesis of cardiac complications in patients with HIV infection. However, because the presence of virus or viral proteins in a tissue does not necessarily induce dysfunction or disease and because cardiac dysfunction can occur in the absence of gross abnormalities it is important to evaluate these animals in terms of physiologic function and pathology of the cardiac disorders. Although not yet applied to the study of HIV-associated cardiac disorders, it has been demonstrated recently that microsurgical techniques can be used to study systolic and diastolic abnormalities that occur in transgenic mice. The use of such techniques has provided valuable mechanistic information regarding adrenergic signaling and calcium handling mechanisms that regulate ventricular function in vivo. These experiments suggest that similar approaches could be used to study relevant issues of ventricular dysfunction associated with HIV infection. Research Objectives and Scope The following items are provided as examples only. Applicants are urged to consider other projects within the scope of this solicitation based on their knowledge of the field and their expertise. Development of animal models is encouraged but preliminary data must be provided to indicate that the model will have relevance to the research requested. o Interaction of viral proteins with cardiovascular cells and the effects on cardiac function in HIV infection o Examination of circulating antibodies for cross-reactivity with cardiac tissue in HIV infection o Elucidation of the role of endothelium in the cardiovascular complications of HIV infection o Role of the immune system and cytokine production in the etiology of cardiac dysfunction in HIV infection o Evaluation of ventricular function and myocyte contractility in transgenic mice that exhibit neuropathologic changes in HIV-related studies o Investigations in cell culture and whole heart of the mechanisms whereby HIV infection perturbs the contractile function of the myocardium o Identification of the mechanisms whereby HIV mediates disorders of impulse generation, conduction and EC coupling o Investigations of the alterations of gene expression of cardiac contractile proteins, calcium regulatory proteins, and markers of ventricular hypertrophy such as ANF in HIV-related complications o The role of coinfection with other pathogens, such as cytomegalovirus, which have been implicated in HIV cardiomyopathy. 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. 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. INCLUSION OF WOMEN AND MINORITIES IN RESEARCH INVOLVING HUMAN SUBJECTS It is the policy of the NIH that women and members of minority groups and their subpopulations must be included in all NIH supported biomedical and behavioral research projects involving human subjects, unless a clear and compelling rationale and justification is provided that inclusion is inappropriate with respect to the health of the subjects or the purpose of the research. This new policy results from the NIH Revitalization Act of 1993 (Section 492B of Public Law 103-43) and supersedes and strengthens the previous policies (Concerning the Inclusion of Women in Study Populations, and Concerning the Inclusion of Minorities in Study Populations), which have been in effect since 1990. The new policy contains some provisions that are substantially different from the 1990 policies. All investigators proposing research involving human subjects should read the "NIH Guidelines For Inclusion of Women and Minorities as Subjects in Clinical Research," which have been published in the Federal Register of March 20, 1994 (FR 59 14508-14513) and reprinted in the NIH Guide for Grants and Contracts, Volume 23, Number 11, March 18, 1994. Investigators also may obtain copies of the policy from the program staff listed under INQUIRIES. Program staff may also provide additional relevant information concerning the policy. LETTER OF INTENT Prospective applicants are asked to submit, by February 1, 1997, 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 NHLBI staff to estimate the potential review workload and 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 ujsed in applying for these grants. Applications kits are available at most institutional offices of sponsored research and may be obtained from the Grants Information Office, Office of Extramural Outreach and Information Resources, National Institutes of Health, 6701 Rockledge Drive, MSC 7910, Bethesda, MD 20892-7910, telephone 301/710-0267, email: ASKNIH@odrockm1.od.nih.gov. The RFA label available in the application kit 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. 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. Sample budgets and justification page will be provided upon request 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 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 ten modules ($250,000 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. 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. 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 educational 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. Applications must be received by April 24, 1997. 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 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 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. 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. 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. 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 Applications will compete for available funds with all other approved applications. 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. Direct inquiries regarding programmatic issues to: Dr. Constance Weinstein Division of Heart and Vascular Diseases 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: WEINSTEC@GWGATE.NHLBI.NIH.GOV Direct inquiries regarding fiscal matters to: Mr. William Darby Grants Operations Branch National Heart, Lung, and Blood Institute 6701 Rockledge Drive, Suite 7128, MSC 7926 Bethesda, MD 20892-7926 Telephone: (301) 435-0177 FAX: (301) 480-3310 Email: DARBYW@GWGATE.NHLBI.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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