PROTEASE INHIBITOR RELATED ATHEROSCLEROSIS IN HIV INFECTION Release Date: October 5, 1999 RFA: HL-00-007 National Heart, Lung and Blood Institute National Institute of Diabetes and Digestive and Kidney Diseases Letter of Intent Receipt Date: December 15, 1999 Application Receipt Date: January 12, 2000 THIS RFA USES THE "MODULAR GRANT" AND "JUST-IN-TIME" CONCEPTS. IT INCLUDES DETAILED MODIFICATIONS TO STANDARD APPLICATION INSTRUCTIONS THAT MUST BE USED WHEN PREPARING APPLICATIONS IN RESPONSE TO THIS RFA. PURPOSE The objective of this initiative is to support research on the effects of HIV protease inhibitors on lipid metabolism leading to hyperlipidemia and altered body fat distribution, the onset of insulin resistance, and the development of accelerated atherosclerosis. Solicited programs should address the possible basic mechanism(s) underlying the metabolic and hormonal alterations leading to dyslipidemias and lipodystrophy as well as insulin resistance observed in HIV- positive patients undergoing protease inhibitor treatment and the relationship between the development of these abnormal metabolic processes and the accelerated progression of atherosclerosis. The program requiresinvestigators to engage in interdisciplinary and collaborative research focused on clinical as well as basic studies. In addition, this program will foster collaborations among scientists with different expertise, abilities, and talents to solve problems that require a multifaceted approach, diverse skills, and special resources not typically located within a single department or at a given institution. Among the disciplines and expertise that may be appropriate for this research program are endocrinology, lipid metabolism, vascular medicine, clinical science, treatment of HIV-AIDS, physiology, biochemistry, vascular biology, pathology, molecular and cell biology, genetics, biostatistics, and imaging. The collaborations should focus on a common hypothesis with all component projects contributing scientifically to the central theme. The collaborative projects may include shared resources as long as the interdependence and multi disciplinary nature of the individual components is demonstrated. HEALTHY PEOPLE 2000 The Public Health Service (PHS) is committed to achieving the health promotion and disease prevention objectives of "Healthy People 2000," a PHS-led national activity for setting priority areas. This Request for Applications (RFA), "Protease Inhibitor Related Atherosclerosis in HIV Infection", is related to one or more of the priority areas. Potential applicants may obtain a copy of "Healthy People 2000" at http://odphp.osophs.dhhs.gov/pubs/hp2000. 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 very unusual merit, need, and promise, and in accordance with PHS policy governing such awards. MECHANISM OF SUPPORT This RFA will use the National Institutes of Health (NIH) research project grant (R01) award mechanism to support collaborative research projects. Responsibility for the planning, direction, and execution of each of the proposed projects will be solely that of the respective applicant. The total project period for an application submitted in response to this RFA may not exceed 5 years. This RFA is 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. The anticipated award date is July 1, 2000. Applicants must propose a multi disciplinary program, comprising basic and clinical science studies. Investigators are encouraged to establish collaborations to meet the objectives of this RFA. Collaborative groups may consist of either two or three research R01 projects consisting of basic science and clinical studies, and have a common theme. Interactions between basic and clinical scientists are expected to strengthen the research, enhance transfer of fundamental research findings to the clinical setting, and identify new research directions. Plans for transfer of findings from basic to clinical studies should be described. Applications not proposing both basic and clinical research studies will not be responsive to this solicitation and will be returned to the applicant without review. Collaborative R01 projects may be from a single institution or several institutions, may include shared resources, and should demonstrate synergism among the individual components. If core support is requested, it should be organized as a separate R01 application and submitted as part of the collaboration, but its funding will be part of one of the research R01s. The funding decision will be influenced by the scientific merit of the individual applications, the degree of collaboration between the investigators, the approaches taken to meet the objectives of the RFA, and the programmatic balance and needs of National Heart, Lung and Blood Institute ( NHLBI ) and the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK). Although applicants are required to submit collaborative applications, the NHLBI and the NIDDK may choose to fund individual R01s outside the collaborative arrangement owing to their special scientific merit and programmatic needs and balance. Specific application instructions have been modified to reflect "MODULAR GRANT" and "JUST-IN-TIME" streamlining efforts being examined by the NIH. Complete and detailed instructions and information on Modular Grant applications can be found at https://grants.nih.gov/grants/funding/modular/modular.htm For this RFA, funds must be requested in $25,000 direct cost modules. A feature of the modular grant concept is that no escalation is provided for future years, 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 at submission and any budget adjustments made by the Initial Review Group will be in modules of $25,000. A group of collaborative R01 applications may request up to a total of 26 modules ($650,000 direct cost), per year for all component R01s, including cores. Costs of individual R01 components may be substantially different from each other within a collaborative group. Equipment is included in the budget limitation. However, requests for expensive special equipment that cause an application to exceed this limit may be permitted on a case-by-case basis following staff consultation. Such equipment requires justification. Final decisions will depend on the nature of the justification and the availability of funds. Administrative adjustments in project period and/or amount may be required at the time of the award. Instructions for completing the Biographical Sketch have also been modified. In addition, Other Support information is not required as part of the initial application. If there is a possibility for an award, necessary budget and Other Support information will be requested by institute program 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 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. FUNDS AVAILABLE The NHLBI and the NIDDK intend to commit approximately $6,000,000 in total costs in FY 2000 to fund up to 14 new and/or competitive continuation grants in response to this RFA either as part of collaborative projects or as individual R01s. Applicants may request a project period of up to 5 years and a budget for direct costs of up to $650,000 per year for a group of collaborative R01 applications, excluding indirect costs on consortium arrangements. Because the nature and scope of the research proposed may vary, it is anticipated that the size of each award R01 in the group will also vary. Although the financial plans of the NHLBI and NIDDK provide support for this program, awards pursuant to this RFA are contingent upon the availability of funds, the receipt of a sufficient number of applications of outstanding scientific and technical merit, and the scope of applications received. Direct costs will be awarded in modules of $25,000, less any overlap or other necessary administrative adjustments. Facilities and Administrative costs (Indirect costs) will be awarded based on the negotiated rates. RESEARCH OBJECTIVES Background HIV-AIDS is a devastating disease and was responsible for about 35,000 deaths of relatively young people in the United States in 1996. It is expected to affect millions of patients with substantial health care costs. Until recently, the main treatments utilized nucleoside and non-nucleoside analogs, which are reverse transcriptase inhibitors, but had limited effect on the control or treatment of the disease. However, the discovery and use of HIV specific protease inhibitors in treatment beginning in late1995 has initiated a new era in the therapeutic management of the disease. Use of the protease inhibitors, alone and in combination therapy, are credited with substantially decreasing the number of American deaths from AIDS. The mechanism of action of the protease inhibitors is believed to be through their binding to the active site of HIV protease thus inhibiting the activity of the enzyme. By preventing the cleavage of the viral polyproteins, only immature non-infectious viral particles are formed resulting in a decrease in viral RNA. Four protease inhibitors are currently in use: saquinavir mesylate, ritonavir, indinavir sulfate and nelfinavir. Combinations of various protease inhibitors with nucleoside and non-nucleoside reverse transcriptase inhibitors usually have synergistic effects and are used effectively in clinical practice. The successful use of protease inhibitors to lower plasma virus to undetectable levels has led to the aggressive treatment of early HIV infection, before patients have experienced major clinical manifestations of the disease. Initial evidence demonstrated that the effects of therapy were dramatic and resulted in undetectable levels of virus in two to four months. Recent evidence, however, indicates that although the virus is not detectable in a patient's blood some of the virus continues to exist in latent reservoirs. Even after protease inhibitor treatment for up to two years, virus particles can still be detected in some cells. These findings have led to the present recommendations that protease inhibitor treatment be continued to suppress viral infection. In order to deplete latent stores of HIV, the protease inhibitor treatment may need to be maintained for up to 10 years and possibly longer. With extended treatment, HIV-positive patients have been experiencing a high prevalence of unexpected side effects. The most serious of the side effects include increases in cholesterol and triglyceride to levels where treatment to decrease the risk of premature atherosclerosis and cardiovascular diseases would be recommended. The magnitude of the problem is alarming. Prior to treatment, 59% of HIV-positive patients who had never received a protease inhibitor had cholesterol and triglyceride values considered in the normal, healthy range. After treatment, only 7% of these patients had normal lipid values. There also have been reported cases of heart attack and angina in patients receiving highly active antiviral therapy (HAART) treatment suggesting that premature atherosclerosis may be occurring. Atherosclerosis underlies most coronary heart disease, a major cause of death (500,000 per year) and disability, as well as much peripheral vascular disease, many cases of stroke, and several other diseases. Additional side effects that HIV-positive patients have experienced during protease inhibitor treatment include loss of peripheral fat tissue (lipodystrophy), and/or accumulation of fat intra-abdominally, in breast tissue of women, and over the cervical vertebrae. Also, insulin resistance has been reported. The observed protease inhibitor side effects (dyslipidemias, hyperglycemia, central adiposity, and lipodystrophy) suggest that protease inhibitors cause major metabolic perturbations. The mechanism(s) underlying these changes is not known. In normal individuals, there is a balance in the catabolism and synthesis of cholesterol, triglyceride, and the proteins associated with them so that their levels do not increase. Triglycerides are readily hydrolyzed by lipoprotein lipase resulting in fatty acids for energy or storage in adipose tissue. Lipoprotein lipase is known to be regulated by insulin. The remaining lipoprotein, enriched in cholesterol is removed primarily by receptors in the liver. Lipoprotein metabolism may be altered by a functional deficiency in the key apoproteins, tissue receptors or enzymes due to genetic mutations. A functional deficiency of lipoprotein lipase can result in very high plasma triglyceride levels and decreased high density lipoprotein (HDL) levels. Absence of functional receptors results in the accumulation of plasma cholesterol due to a lack of removal of the cholesterol-rich lipoproteins. It is not known whether the lipid changes observed with protease inhibitor therapy are due to altered synthesis or catabolism of the lipids directly, or reflect changes in lipoprotein receptor function or lipoprotein metabolizing enzymes. Furthermore, it is not clear whether those patients who respond most dramatically to the protease inhibitors have a genetic predisposition to altered lipid metabolism. It has been suggested that protease inhibitors may be interfering with the activity and levels of the gene expression of some of the known lipoprotein receptors. For example, it has been observed that the 12 amino acids spanning the catalytic site of HIV-1 protease have a 70% homology with the low density lipoprotein receptor-related protein, a hepatic scavenger of circulating lipids. This homology might mean that the protease inhibitors could bind to and interfere with the proper functioning of the receptor leading to increased plasma lipid levels. Alternatively, there are systems in the body that depend on protease enzymes to function and perhaps the protease inhibitors impair these enzymes. There has been little or no work done to determine the interaction between protease inhibitors and proteins that regulate lipid metabolism such as the lipases, cholesterol ester transfer protein, and the receptors. The various fat depots differ metabolically, and healthy individuals with upper-body (central) obesity are prone to metabolic and cardiovascular complications. In non-HIV positive subjects, insulin resistance correlates closely with abdominal obesity and hypertriglyceridemia and underlies the development of type 2 (non-insulin dependent) diabetes mellitus. These are fundamentally important differences that are thought to be related to the visceral adipose tissue being drained by the portal venous system with a direct connection with the liver. Thus, patients with upper-body obesity commonly develop dyslipidemia, hyperglycemia, and hyperinsulinemia. HIV-positive patients treated with protease inhibitors have reported substantial decreases in total body fat with peripheral lipodystrophy (fat wasting of the face and limbs) and relative conservation or enhancement of central adiposity in contrast to HIV-infected patients that have not been treated with these inhibitors. Often the HIV- positive patients with lipodystrophy due to protease inhibitor therapy also have significantly higher triglyceride, cholesterol, insulin and C-peptide levels and are more insulin-resistant than protease inhibitor recipients without lipodystrophy. The increases in triglyceride levels can appear concomitantly with the peripheral lipodystrophy, but independently of elevated cholesterol levels. In some cases both triglyceride levels and abnormal fat deposition may be reversed by switching therapy to a different protease inhibitor. These observations have led to the hypothesis that use of the protease inhibitors may be associated with the development of a new syndrome consisting of peripheral lipodystrophy, hyperlipidemia and insulin resistance. This hypothesis needs to be carefully examined especially since none of the mechanisms involved in or responsible for these side effects has been studied in any detail. There have been no studies to determine if the elevated plasma triglyceride levels reflect the active remodeling of particular adipose tissue stores. The mechanism(s) by which the protease inhibitors could selectively target adipose tissue depots is not known. Diabetes and hyperglycemia were reported in varying degrees with use of all four protease inhibitors. In some patients with dyslipidemia and lipodystrophy, there is evidence of insulin resistance. In a recent study, some protease inhibitor recipients had worsening or new diabetes mellitus. For the long- standing, type 1 (insulin-dependent) diabetic patient, daily insulin requirements increased by 70%. In the new diabetics, insulin was required for symptomatic hyperglycemia after 4 weeks of indinavir. Other patients had asymptomatic hyperglycemia 4 weeks after switching from indinavir to ritonavir-saquinavir. Thus, it seems that protease inhibitors can be associated with a non-ketosis-prone hyperglycemia that occurs 1-7 months after starting treatment. The mechanism of protease inhibitor-associated hyperglycemia is unknown, and its role in accelerated atherosclerosis and coronary heart disease needs to be systematically examined. If these secondary problems associated with protease inhibitors cannot be resolved, the potential impact on the management of HIV-positive patients is far reaching. In the general population, the first approach to lower plasma cholesterol levels involves lifestyle changes such as lowering fat and cholesterol content of the diet, decreasing body weight if obese, and increasing exercise. To lower fasting triglyceride levels and increase HDL levels the first approach includes weight loss if overweight, lowering excessive alcohol intake, lowering fat content of the diet, lowering the simple sugar content of the diet, and increasing exercise. The next approach for patients with low HDL and high triglyceride levels is to use gemfibozil or nicotinic acid. The normal approaches to lipid management may not be as successful in patients receiving protease inhibitors. Research is needed to determine which drugs are most appropriate. Statins are the most potent of cholesterol lowering drugs, and act directly by inhibiting cholesterol synthesis. However, statins may not be as effective in patients on protease inhibitors and greater caution needs to be exerted with their use since protease inhibitors may interfere with the metabolic pathway for statins in the liver. In fact these agents may act synergistically so that a potential side effect of the statins, rhabdomyolysis, may be more common in HIV-positive patients receiving protease inhibitor therapy. It is not clear if this is due to drug resistance. The difficulties in treating the hyperlipidemia associated with protease inhibitors create challenging problems for managing these patients which will need a systematic approach and careful study. High levels of glucose and insulin in the blood, and high levels of triglycerides and other lipids, are considered risk factors for atherosclerosis associated with the use of protease inhibitors. HDL levels are decreased in patients receiving protease inhibitors and the mechanism responsible is not known. The relationships and the biological mechanisms by which these protease inhibitors might influence insulin regulation, body fat redistribution, serum lipid elevation and metabolism are not known. This observation needs to be further investigated. Distal and proximal vascular lesions of the coronary arteries were observed in autopsied HIV-seropositive patients. These lesions were marked by major eccentric atherosclerosis (with 80-90% obstruction of the arterial lumen) or by fibrosis two-fold or six-fold the thickness of the tunica media. Coronary angiography documented severe premature atherosclerosis in young AIDS patients on protease inhibitors. Although there are reports of a few cases of coronary atherosclerosis in AIDS adults, whose life span is expected to increase in response to protease inhibitor treatment, the cardiovascular risk factors, the severity of atherosclerosis and associated fibrosis suggest that the AIDS virus plays an important role in the onset of the lesions. Other infectious agents have also been suggested to contribute to atherosclerosis. With HIV- seropositive patients, this may be augmented by the unfavorable lipid profile and onset of diabetes due to treatment with protease inhibitors. The cellular and molecular events that are responsible for these effects and the related changes in the vasculature need to be explored in more detail. Thus, the increased life expectancy provided HIV-positive patients by the use of protease inhibitors may be jeopardized or at least complicated by their being at greater risk for developing cardiovascular diseases. It is not clear how or why protease inhibitors may lead to unfavorable changes in lipid and carbohydrate metabolism, but these side effects alter the impact of protease inhibitors in the treatment of HIV-positive patients and the successful management of AIDS. The side effects are a critical issue because HIV-positive patients who have discontinued protease inhibitor treatment due to concerns about the increased risk for coronary heart disease, diabetes, or altered fat distribution have experienced an increase in viral load and the clinical manifestations of the disease. Patients that continue therapy with the protease inhibitors face more complicated treatment schedules to manage the lipid and carbohydrate side effects. The basic mechanism(s) involved in the altered metabolism needs to be determined to facilitate the management of HIV-positive patients and help in the rational development of therapies for the treatment and prevention of premature atherosclerosis and other cardiovascular diseases in protease inhibitor treated patients. Objectives It is proposed to support up to 14 R01s either as part of collaborative projects or as individual R01 projects for research into the pathogenesis of atherosclerosis in HIV-positive patients treated with protease inhibitors, especially research that relates to the basic mechanisms underlying the altered lipid metabolism and body fat distribution and the development of atherosclerosis. Applications must be multi disciplinary. Furthermore, to achieve its objectives and to accelerate the transition from bench to bed-side, this RFA requires applicants to propose basic as well as clinical studies during the grant cycle. Applicants are strongly encouraged to establish collaborations to augment their basic or clinical proposals to meet the objectives of the RFA. The funding decision will be influenced by the scientific merit of the individual applications, the degree of collaboration between the investigators, the approaches taken to meet the objectives of the RFA, and the programmatic balance and needs of NHLBI and NIDDK. Proposed Research The known information on the dyslipidemias and lipodystrophy associated with protease inhibitor therapy for HIV-positive patients is derived from clinical observations. Little is known about the basic science or mechanisms causing these syndromes or side effects. It is desired that the proposed research have a broad base of interdisciplinary studies to address these problems. It is expected that the various side effects of protease inhibitors will encourage investigators with expertise in a variety of disciplines to focus on lipid metabolism and possible alterations due to protease inhibitors, and to integrate these studies with approaches involving vascular cell biology, tissue-specific pathology, clinical investigations, and molecular biology (gene expression and regulation). Physicians specializing in cardiology, lipid metabolism, diabetes, treatment of HIV-AIDS, and vascular medicine as well as basic scientists focusing on corresponding areas would be the most appropriate to collaborate in this research. A more detailed analysis of factors influencing the lipid metabolic pathway, especially new approaches for clinical management, is also likely to generate new testable hypotheses. The cause of dyslipidemia and type 2 diabetes mellitus in patients treated with protease inhibitors needs careful and systematic investigation. Appropriate topics for investigation would include, but are not limited to, the following: o Altered lipid metabolism resulting in dyslipidemia in HIV-positive patients in response to protease inhibitor therapy. Proposals may include metabolic and enzymatic studies to determine the cause of the elevated total cholesterol due to increased low density lipoprotein cholesterol with decreased HDL cholesterol levels associated with protease inhibitor therapy. Studies of the effects of protease inhibitors on lipoprotein receptors and other regulatory molecules involved in lipid metabolism. o Elevated triglyceride levels in HIV-positive patients in response to protease inhibitor therapy. Studies will need to control for potential lipid alterations due to secondary infections and distinguish this from potential minor changes from the presence of HIV. Studies may include metabolic approaches and enzymatic studies to determine if altered synthesis or degradation is involved. Studies relating the elevated triglyceride levels to changes in adipose tissue metabolism and insulin resistance are also relevant. o Changes in adipose tissue in HIV-positive patients in response to protease inhibitor therapy resulting in loss of peripheral and increases in intra-abdominal adipose tissue masses. Studies may include the effects of protease inhibitors on the enzymes, receptors, and hormones important in regulation of specific adipose tissue depots. o The effect of protease inhibitors on vascular wall cells and atherogenesis. Basic studies may include effects on the autocrine and paracrine systems including endothelial cell activation and other reactions involved in atherogenesis. Studies of vascular cell biology are appropriate. o Basic studies to determine the underlying mechanisms involved in the observed responses in lipid and carbohydrate metabolic to protease inhibitors. Studies to examine the role of receptors, signal transduction, and other cell regulatory mechanisms are appropriate. The use of suitable animal models, cell studies and in vitro systems are encouraged. o Clinical studies to determine the effect of protease inhibitors on premature atherosclerosis and coronary heart disease in HIV positive patients. Studies will need to control for the potential contribution of secondary infections to the development of atherosclerosis. Approaches may include imaging to determine the progression, stability, regression of lesions using angiography and other non-invasive modalities. o Correlates of dyslipidemia and other risk factors of coronary heart disease. Adipose tissue abnormalities with protease inhibitors and dyslipidemia. Relationship of fat deposits over the cervical vertebrae (buffalo hump) with protease inhibitor therapy to sterol metabolism. o Dose dependence on the severity of the lipid response to the various protease inhibitors and how this correlates with their potency or uptake. Because of the interdisciplinary nature of the research, collaboration among investigators of varied expertise within the same or different institution is strongly encouraged. Specifically, "Networking" (i.e., shared biologic and information resources, reagents, patients, and the like), should be established to prevent duplication of efforts and to maximize benefits in the most cost-efficient manner possible. The applicants may request special modifications to their equipment or additional small equipment for the safe handling of HIV-positive samples if this is a new aspect of their research. EXCLUSIONS This RFA is intended to support multi disciplinary collaborative R01 research programs. Proposals including only basic or only clinical research will not be responsive to this announcement and will be returned without review. In addition, clinical research projects focused on large epidemiological studies or large clinical trials will be considered unresponsive to this initiative. SPECIAL REQUIREMENTS Each collaborative R01 program grant application and award must include research involving human studies. Support may be provided for human biomedical studies of etiology, pathogenesis, prevention and prevention strategies, diagnostic approaches, and treatment of diseases, disorders or conditions. Small population-based studies, where the research can be completed within five years, may also be proposed. Upon initiation of the program, annual meetings will be held to encourage exchange of information among investigators who participate in this program. A major goal of these meetings is to facilitate progress by providing a forum that will lead to sharing ideas, technology, data, skills, and biological materials. Applicants must budget for travel funds that will allow principal investigators and other key research scientists to participate in these meetings. INCLUSION OF WOMEN AND MINORITIES IN RESEARCH INVOLVING HUMAN SUBJECTS It is the policy of the NIH that women and members of minority groups and their subpopulations must be included in all NIH supported biomedical and behavioral research projects involving human subjects, unless a clear and compelling rationale and justification is provided that inclusion is inappropriate with respect to the health of the subjects or the purpose of the research. This policy results from the NIH Revitalization Act of 1993 (Section 492B of Public Law 103-43. All investigators proposing research involving human subjects should read the "NIH Guidelines for Inclusion of Women and Minorities as Subjects in Clinical Research," which was 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, available on the web at: https://grants.nih.gov/grants/guide/notice-files/not94-100.html. 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: https://grants.nih.gov/grants/guide/notice-files/not98-024.html Investigators also may obtain copies of these policies 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 a letter of intent by December 15, 1999, 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 mailed, or faxed, by the letter of intent receipt date listed in the heading of this RFA 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: js110j@nih.gov. APPLICATION PROCEDURES The research grant application form PHS 398 (rev. 4/98) is to be used in applying for these grants. These forms are available at most institutional offices of sponsored research and from the Division of Extramural Outreach and Information Resources, National Institutes of Health, 6701 Rockledge Drive, MSC 7910, Bethesda, MD 20892-7910, telephone 301/710-0267, email: GrantsInfo@nih.gov. The modular grant concept establishes specific modules in which direct costs may be requested as well as a maximum level for requested budgets. Only limited budgetary information is required under this approach. The just-in-time concept allows applicants to submit certain information only when there is a possibility for an award. It is anticipated that these changes will reduce the administrative burden for the applicants, reviewers and Institute staff. The research grant application form PHS 398 (rev. 4/98) is to be used in applying for these grants, with the modifications noted below. The RFA label available in the PHS 398 (rev. 4/98) application form must be affixed to the bottom of the face page of the application. Failure to use this label could result in delayed processing of the application such that it may not reach the review committee in time for review. In addition, the RFA title (PROTEASE INHIBITOR RELATED ATHEROSCLEROSIS IN HIV INFECTION) and number (HL-00-007) must be typed on line 2 of the face page of the application form and the YES box must be marked. The sample RFA label available at: https://grants.nih.gov/grants/funding/phs398/label-bk.pdf has been modified to allow for this change. Please note this is in pdf format. State on the face page, Title Line (line 1), of each application that the submission is part of a "Collaborative R01". The individual components and cores must be submitted as one package accompanied by a cover letter that lists the principal investigators of each R01. Include this letter with each of the individual R01s, and in each R01 list the collaborating projects and principal investigators on page 2, under "Performance Sites". In addition, the description section for each R01 within a collaborative R01 should be the same and the applicants should define how and why the individual participants propose to collaborate. Applicants should elaborate on the significance and nature of the collaboration in an Introduction section of the "Research Plan" of each component R01. Sample budgets and justification page will be provided upon request from Ms. Jane Davis at the address listed under INQUIRIES. Submit a signed, typewritten original of the application, including the Checklist, and three signed, photocopies, in one package to: CENTER FOR SCIENTIFIC REVIEW NATIONAL INSTITUTES OF HEALTH 6701 ROCKLEDGE DRIVE, ROOM 1040, MSC 7710 BETHESDA, MD 20892-7710 BETHESDA, MD 20817 (for express/courier service) At the time of submission, two additional copies of the application must be sent to Dr. C. James Scheirer, at the address listed under LETTER OF INTENT. Applications must be received by the application receipt date listed in the heading of this RFA. If an application is received after that date, it will be returned to the applicant without review. 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. BUDGET INSTRUCTIONS Modular Grant applications will request direct costs in $25,000 modules, up to a total direct cost request of $650,000 per year for all component R01s, including cores. 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. PHS 398 o FACE PAGE: Items 7a and 7b should be completed, indicating Direct Costs (in $25,000 increments) and Total Costs [Modular Total Direct plus Facilities and Administrative (F&A) costs] for the initial budget period. Items 8a and 8b should be completed indicating the Direct and Total Costs for the entire proposed period of support. o DETAILED BUDGET FOR THE INITIAL BUDGET PERIOD - Do not complete Form Page 4 of the PHS 398. It is not required and will not be accepted with the application. o BUDGET FOR THE ENTIRE PROPOSED PERIOD OF SUPPORT - Do not complete the categorical budget table on Form Page 5 of the PHS 398. It is not required and will not be accepted with the application. 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 26 modules ($650,000 direct costs) for the entire collaborative package, including cores, per year may be requested. Applicants may request up to 5 years of support for this RFA. Direct cost budgets typically 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 NARRATIVE BUDGET JUSTIFICATION - Prepare a Modular Grant Budget Narrative page. (See https://grants.nih.gov/grants/funding/modular/modular.htm for sample pages.) At the top of the page, enter the total direct costs requested for each year. This is not a Form page. o Under Personnel, list key project personnel, including their names, percent of effort, and roles on the project. Provide a narrative justification for each person (including consultants) based on his/her role on the project. No individual salary information should be provided. However, the applicant should use the NIH appropriation language, salary cap, and the NIH policy for graduate student compensation in developing the budget request. 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. For Consortium/Contractual costs, provide an estimate of total costs (direct plus facilities and administrative) for each year, each rounded to the nearest $1,000. List the individuals/organizations with whom consortium or contractual arrangements have been made, the percent effort of key personnel, and the role on the project. Indicate whether the collaborating institution is foreign or domestic. The total cost for a consortium/contractual arrangement is included in the overall requested modular direct cost amount. Include the Letter of Intent to establish a consortium. 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. Provide an additional narrative budget justification for any variation in the number of modules requested. o BIOGRAPHICAL SKETCH - The Biographical Sketch provides information used by reviewers in the assessment of each individual's qualifications for a specific role in the proposed project, as well as to evaluate the overall qualifications of the research team. A biographical sketch is required for all key personnel, following the instructions below. No more than three pages may be used for each person. A sample biographical sketch may be viewed at: https://grants.nih.gov/grants/funding/modular/modular.htm - Complete the educational block at the top of the form page. - List position(s) and any honors. - Provide information, including overall goals and responsibilities, on research projects ongoing or completed during the last three years. - List selected peer-reviewed publications, with full citations. o CHECKLIST - This page should be completed and submitted with the application. If the F&A rate agreement has been established, indicate the type of agreement and the date. All appropriate exclusions must be applied in the calculation of the F&A costs for the initial budget period and all future budget years. 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. REVIEW CONSIDERATIONS Upon receipt, applications will be reviewed for completeness by the CSR and responsiveness by the NHLBI and NIDDK. Incomplete and/or non- responsive 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 the review criteria stated below. The roster of reviewers for the RFA will be available on the NHLBI home page approximately four weeks prior to the scheduled review date. The initial review group will evaluate all applications as individual investigator-initiated grant applications. Additionally, the initial review group will consider in their evaluation the overall strength and likelihood of effective collaboration of each collaborative program. As part of the initial merit review, a process will be used by the initial review group in which applications 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 the 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. Review Criteria The goals of NIH-supported research are to advance our understanding of biological systems, improve the control of disease, and enhance health. In the written comments reviewers will be asked to discuss the following aspects of the application in order to judge the likelihood that the proposed research will have a substantial impact on the pursuit of these goals. Each of these criteria will be addressed and considered in assigning the overall score, weighting them as appropriate for each application. Note that the application does not need to be strong in all categories to be judged likely to have major scientific impact and thus deserve a high priority score. For example, an investigator may propose to carry out important work that by its nature is not innovative but is essential to move a field forward. (1) Significance: Does this study address an important problem? If the aims of the application are achieved, how will scientific knowledge be advanced? What will be the effect of these studies on the concepts or methods that drive this field? (2) Approach: Are the conceptual framework, design, methods, and analyses adequately developed, well-integrated, and appropriate to the aims of the project? Does the applicant acknowledge potential problem areas and consider alternative tactics? (3) Innovation: Does the project employ novel concepts, approaches or method? Are the aims original and innovative? Does the project challenge existing paradigms or develop new methodologies or technologies? (4) Investigator: Is the investigator appropriately trained and well suited to carry out this work? Is the work proposed appropriate to the experience level of the principal investigator and other researchers (if 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? (6) Collaboration: Do the submitted R01 projects represent collaborative research among investigators from different disciplines? What are the likelihood of effective collaboration among the investigators, and the likelihood of success of the research objectives proposed? The personnel category will be reviewed for appropriate staffing based on the requested percent effort. The direct costs budget request will be reviewed for consistency with the proposed methods and specific aims. Any budgetary adjustments recommended by the reviewers will be in $25,000 modules. The duration of support will be reviewed to determine if it is appropriate to ensure successful completion of the requested scope of the project In addition to the above criteria, in accordance with NIH policy, all applications will also be reviewed with respect to the following: o The adequacy of plans to include both genders, minorities and their subgroups, and children as appropriate for the scientific goals of the research. Plans for the recruitment and retention of subjects will also be evaluated. o The reasonableness of the proposed budget and duration in relation to the proposed research. o The adequacy of the proposed protection for humans, animals or the environment, to the extent they may be adversely affected by the project proposed in the application. Schedule Letter of Intent Receipt Date: December 15, 1999 Application Receipt Date: January 12, 2000 Peer Review Date: February/March, 2000 Council Review: May 18-19, 2000 Earliest Anticipated Start Date: July 1, 2000 AWARD CRITERIA Award criteria that will be used to make award decisions include: o scientific merit (as determined by peer review) o availability of funds o programmatic priorities. Applicants should be aware that, in addition to scientific merit, program priorities and program balance, the total costs of the proposed project and the availability of funds will be considered by the awarding Institutes in making funding recommendations. The Institutes may fund individual applications based on a number of considerations, the most important of which are based on their scientific merit and their importance in meeting the objectives of the RFA. In addition, NHLBI appreciates the value of complementary funding from other public and private sources including foundations and industrial concerns. In circumstances in which applications have similar scientific merit, but vary in cost competitiveness, NHLBI and NIDDK are likely to select the more cost competitive application for funding. INQUIRIES Inquiries concerning this RFA are encouraged. Potential applicants should request a copy of the full RFA, which will include sample budget pages. The opportunity to clarify any issues or questions from potential applicants is welcome. Direct inquiries regarding programmatic issues to: Deborah Applebaum-Bowden, Ph.D. Division of Heart and Vascular Diseases National Heart, Lung, and Blood Institute 6701 Rockledge Drive, Suite 10184, MSC 7956 Bethesda, MD 20892-7956 Telephone: (301)435-0550 FAX: 301/480-2858 Email: da40q@nih.gov Philip F. Smith, Ph.D. Division of Diabetes, Endocrinology, and Metabolic Diseases National Institute of Diabetes and Digestive and Kidney Diseases Natcher Building, Room 5AN-12C 45 Center Dr MSC 6600 Bethesda MD 20892-6600 Telephone: (301)594-8816 smithp@extra.niddk.nih.gov Direct inquiries regarding fiscal matters to: Ms. Jane Davis Division Extramural Affairs National Heart, Lung, and Blood Institute 6701 Rockledge Drive, MSC 7926 Bethesda, MD 20892-7926 Telephone: (301) 435-0166 FAX: (301) 480-3310 Email: jane_davis@nih.gov Mr. Kieran Kelley Division of Extramural Activities National Institute of Diabetes and Digestive and Kidney Diseases 45 Center Drive, MSC 6600 Bethesda, MD 20892-6600 Telephone: (301) 594-0417 FAX: (301) 480-3504 Email: kk27g@nih.gov AUTHORITY AND REGULATIONS This program is described in the Catalog of Federal Domestic Assistance No. 93.837 and No. 93.847. 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 NIH grants policies and Federal Regulations 42 CFR 52 and 45 CFR Parts 74 and 92. 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 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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