NONHUMAN PRIMATE MODELS OF HIV-ASSOCIATED PULMONARY, CARDIOVASCULAR, AND HEMATOLOGICAL DISORDERS RELEASE DATE: December 4, 2002 RFA: HL-03-005 National Heart, Lung, and Blood Institute (NHLBI) ( LETTER OF INTENT RECEIPT DATE: February 20, 2003 APPLICATION RECEIPT DATE: March 20, 2003 THIS RFA CONTAINS THE FOLLOWING INFORMATION o Purpose of this RFA o Research Objectives o Mechanism(s) of Support o Funds Available o Eligible Institutions o Individuals Eligible to Become Principal Investigators o Special Requirements o Where to Send Inquiries o Letter of Intent o Submitting an Application o Peer Review Process o Review Criteria o Receipt and Review Schedule o Award Criteria o Required Federal Citations: PURPOSE OF THIS RFA The National Heart, Lung, and Blood Institute (NHLBI) invites applications on the use of nonhuman primate models for the study of Human Immunodeficiency Virus (HIV)-associated pulmonary, cardiovascular, and hematologic disorders. These primate models (e.g., Simian Immunodeficiency Virus [SIV]- and Simian-Human Immunodeficiency Virus [SHIV]-infected monkeys) should be designed to facilitate the study of the biological and clinical characteristics of disorders of lung, heart, blood, and bone marrow, associated with HIV infections and co-infections as well as to evaluate novel methods for prevention and treatment of these conditions. RESEARCH OBJECTIVES Background HIV infection results in progressive damage of the immune system of infected individuals and makes them susceptible to a wide variety of opportunistic (bacterial, viral, fungal, and protozoan) infections. Lung infections that occur in patients during the course of HIV infection and AIDS (prominently among them, tuberculosis) represent a major cause of morbidity and mortality for HIV-infected individuals around the world. Dual infection and synergism between HIV and Mycobacterium tuberculosis (Mtb) represent a worldwide health crisis affecting millions of people, especially in developing nations in Africa and Asia. Each year an estimated 8 million people develop clinical tuberculosis and the annual death toll from this disease is estimated at 2 to 3 million people. The majority of tuberculosis cases occur in the same populations in which there are also millions of cases of HIV infection. Individuals infected with HIV are far more susceptible to Mtb infection than those without HIV infection. Therefore, dual HIV-Mtb infections in humans are extremely common and their clinical course is more severe and more rapidly fatal. Likewise, infection with Mtb increases HIV production in patients with dual HIV- Mtb infections and hastens the progression of AIDS and other HIV- related diseases. The concurrent presence of infections other than tuberculosis in the lungs of humans, such as Pneumocystis carinii pneumonia and pneumococcal pneumonia, can also increase the replication of HIV and accelerate the course of AIDS. HIV-associated immune dysfunction increases the likelihood and severity of these lung infections and also appears to alter the pathogenesis and clinical course of these respiratory infections in ways that are different from other immunodeficient conditions. By altering local immunity in the lung, HIV infection can also result in harmful inflammatory responses and infiltrates that may cause acute or chronic lung injury (e.g., HIV- associated emphysema and pulmonary hypertension). In the era prior to availability of highly active antiretroviral therapy, cardiac involvement in HIV disease was estimated to be approximately 6-7%. Autopsy series and retrospective analyses suggest that cardiac lesions are present in 25-75% of patients with AIDS. HIV- related cardiovascular diseases include pericardial effusion, myocarditis, dilated cardiomyopathy, endocarditis, atherosclerosis, hypertension, malignant neoplasms and drug-related cardiotoxicity. Contributory roles of the HIV virus itself, the extent of immunodeficiency, and the existence of co-infection in the pathogenesis of HIV-associated cardiovascular disorders are not well defined. Furthermore, other factors such as inflammation, nutritional deficiencies, autoimmune responses, and pharmacologic effects of anti- retroviral agents warrant exploration in the context of HIV-related cardiovascular disorders. SIV- and SHIV-infected non human primates provide an opportunity for in-depth, controlled study of these matters. Blood- and marrow-related disorders have been observed in SIV-infected monkeys, and parallel findings have been found in humans infected with HIV. Therefore, the nonhuman primate model system is useful for furthering our understanding of the mechanism(s) associated with these disorders and for exploring strategies for prevention and treatment. Hematopoietic abnormalities associated with HIV infection include: decreased proliferation of hematopoietic stem and progenitor cells, increased destruction of mature cells, and alterations in the supportive marrow stromal environment and in the production of regulatory cytokines. The pathophysiologic mechanisms of these abnormalities are poorly understood and require study. Also, it is known that thrombocytopenia is one of the earliest manifestations of HIV infection in human and primates. HIV infection of humans is likely to bring about changes in the functions of cytokines and matrix proteins, in the migration of megakaryocytes, and in the production and destruction of platelets (which can lead to development of thrombocytopenia). Many opportunistic infections involve pathogenic agents that encode and express proteins that, in turn, modulate host immune responses. The synergism of these molecules during co-infection may profoundly alter lymphoid cell trafficking, signaling, and function. These effects may have profound implications on homeostatic regulation of the heart, lung, and bone marrow. The roles that dendritic cells play in the initial systemic infection by virus, in the induction of humoral and cell-mediated immunities, and in the development of local immunity need to be actively investigated. Objective and Scope Since the discovery of the SIV in 1984, the disease that occurs in experimentally infected nonhuman primates (i.e., simian AIDS) has been extensively investigated and is considered a useful model for the study of human AIDS. This model has been utilized to assess HIV pathogenesis, to validate therapies, and to develop and test AIDS vaccines. Through this initiative, we wish to stimulate collaborations among scientists devoted to studies of SIV/SHIV disease in primates as a model for human AIDS, and investigators with expertise and experience in the following fields of relevant research: studies of tuberculosis, Pneumocysis carinii pneumonia, pneumococcal pneumonia, and other pulmonary and cardiovascular infections/disorders and studies of the roles of blood cellular components in the genesis and progression of AIDS. Such collaborations should take advantage of the large wealth of knowledge and resources (e.g., biological and immunologic reagents) that have been generated during the past 15 years. Some examples of research topics that will be considered responsive to this RFA include, but are not limited to: o Analysis of local immunological status, and heart or lung pathology, in the course of acute and chronic SIV/SHIV infection and simian AIDS o Research to elucidate the mechanism(s) of cardiac ventricular dysfunction associated with HIV infection o The study of SIV/SHIV-Mtb co-infections aimed at the understanding of their molecular and biological interactions and their synergistic effect(s) on the lung immune system o Research to determine the mechanism by which Tumor Necrosis Factor- alpha (TNF-alpha) inhibitors, used for the management of diseases like rheumatoid arthritis and Crohn's disease, can re-activate latent Mtb infection and promote the development of extrapulmonary tuberculosis o Analysis of the status of the different bone marrow components during the course of SIV/SHIV infection and progression to simian AIDS MECHANISM OF SUPPORT This RFA will use the R01 (investigator-initiated research project grant) award mechanism. As an applicant, you will be solely responsible for planning, directing, and executing the proposed project. This RFA is a one-time solicitation. Future unsolicited, competing-continuation applications based on this project will compete with all investigator-initiated applications and will be reviewed according to the customary peer review procedures. The anticipated award date is September 30, 2003. This RFA uses just-in-time concepts (e.g., for documentation of appropriate animal welfare requirements). It also uses the modular as well as the non-modular budgeting formats (see Specifically, if you are submitting an application with direct costs in each year of $250,000 or less, use the modular format. Otherwise, follow the instructions for non-modular research grant applications. Since the total costs for a subcontract or consortium are included in the direct cost request, one additional module of $25,000 above the cap may be requested for the facilities and administrative costs associated with third party agreements A module requested for this purpose must be clearly identified in the budget justification section of the application, and will be restricted for this purpose only at the time of award. FUNDS AVAILABLE The NHLBI intends to commit approximately $3.8M in FY 2003 to fund five to seven new and/or competitive continuation grants in response to this RFA. An applicant may request a project period of up to 5 years and a budget for direct costs of up to $500,000 per year. We recognize that a dramatic shortage of primates available for research exists at present in this country; because of this, collaborations with institutions outside of the United States may be considered. Because the nature and scope of the proposed research will vary from application to application, it is anticipated that the size and duration of each award will also vary. Although the financial plans of the NHLBI provide support for this program, awards pursuant to this RFA are contingent upon the availability of funds and the receipt of a sufficient number of meritorious applications. Although interested in this area of research, the National Institute of Allergy and Infectious Diseases (NIAID) is not participating in this initiative. ELIGIBLE INSTITUTIONS You may submit (an) application(s) if your institution has any of the following characteristics: o For-profit or non-profit organizations o Public or private institutions, such as universities, colleges, hospitals, and laboratories o Units of State and local governments o Eligible agencies of the Federal government o Domestic or foreign o Faith-based or community-based organizations INDIVIDUALS ELIGIBLE TO BECOME PRINCIPAL INVESTIGATORS Any individual with the skills, knowledge, and resources necessary to carry out the proposed research is invited to work with their institution to develop an application for support. Individuals from under-represented racial and ethnic groups as well as individuals with disabilities are always encouraged to apply for NIH programs. SPECIAL REQUIREMENTS Inclusions o Optimal utilization of the resources generated under this RFA is strongly recommended; therefore, a plan for proper acquisition and storage of non human primate tissue, to be made available to interested and qualified investigators for further study, is required as part of the application. Investigators should include a request for funds in the budget for this purpose. o Furthermore, investigators should indicate their willingness to participate in a meeting to determine how to standardize tissue collection and storage and to develop criteria for fair distribution of the samples; funds should be set-aside for this purpose. o The applicants should also state their willingness to provide detailed descriptions of protocols and phenotypes. o To be responsive to this announcement, applications must propose collaborations between scientists devoted to studies of SIV/SHIV disease in primates, as a model for human AIDS, and investigators who are documented experts in lung, cardiovascular, or blood diseases. Exclusions o Applications that lack a statement of willingness to share tissues and data with other investigators. o The establishment of new primate facilities will not be supported by this RFA. Grantees' Meetings Upon initiation of the program, the NHLBI will sponsor annual meetings to encourage exchange of information and dissemination of results among investigators who participate in this program. In their budgets, applicants should include funds for annual one-day grantees' meetings, to be held, most likely, in Bethesda, Maryland. Applicants should also include a statement in their applications that indicates their willingness to participate in these meetings. WHERE TO SEND INQUIRIES We encourage inquiries concerning this RFA and we welcome the opportunity to answer questions from potential applicants. Inquiries may fall into three areas: scientific/research, peer review, and financial or grants management issues. Please direct your questions about scientific/research issues to: Sandra Colombini Hatch, M.D. Division of Lung Diseases National Heart, Lung, and Blood Institute 6701 Rockledge Drive, MSC 7956 Bethesda, MD 20892-7956 Telephone: (301) 435-0222 FAX: (301)-480 3557 Luiz Barbosa Ph.D. Division of Blood Disease Research National Heart Lung and Blood Institute 6701 Rockledge Drive, MSC 7950 Bethesda, MD 20892-7950 Telephone: (301) 435-0075 Fax: (301) 480-0868 Email: Diane Reid M.D. Division of Heart and Vascular Diseases National Heart, Lung, and Blood Institute 6701 Rockledge Drive, MSC 7940 Bethesda, MD 20982-7940 Telephone: (301) 435-0515 Fax: (301) 480-1336 Email: Please direct your questions about peer review issues to: Anne P. Clark, Ph.D. Chief, Review Branch Division of Extramural Affairs National Heart, Lung, and Blood Institute 6701 Rockledge Drive 7214, MSC 7924 Bethesda, MD 20892-7924 (20817 for express/courier service) Telephone: (301)435-0270 FAX: (301)480-0730 Email: Please direct your questions about financial or grants management matters to: Robert A. Pike Division of Extramural Affairs Grant Operation Branch National Heart, Lung, and Blood Institute 6701 Rockledge Drive 7214, MSC 7924 Bethesda, MD 20892-7924 (20817 for express/courier service) Telephone: (301) 480-0182 FAX: (301) 4803310 Email: LETTER OF INTENT Prospective applicants are asked to submit a letter of intent that includes the following information: o Descriptive title of the proposed research; o Name, address, telephone number, and e-mail address of the Principal Investigator; o Names of other key personnel; o Participating institutions; and o Number and title of this RFA Although a letter of intent is not a requirement, is not binding, and does not enter into the review of a subsequent application, the information that it contains allows IC staff members to estimate the potential review workload and to plan the review. Letters of intent should be sent by the date listed at the beginning of this document to Dr. Anne Clark at the address listed under WHERE TO SEND INQUIRIES. SUBMITTING AN APPLICATION Applications must be prepared using the PHS 398 research grant application instructions and forms (rev. 5/2001). The PHS 398 is available at in an interactive format. For further assistance contact GrantsInfo, Telephone (301) 710-0267, E-mail: SUPPLEMENTAL INSTRUCTIONS: SPECIFIC INSTRUCTIONS FOR MODULAR GRANT APPLICATIONS: Applications requesting up to $250,000 per year in direct costs must be submitted in a modular grant format. The modular grant format simplifies the preparation of the budget in these applications by limiting the level of budgetary detail. Applicants request direct costs in $25,000 modules. Section C of the research grant application instructions for the PHS 398 (rev. 5/2001) at includes step- by-step guidance for preparing modular grants. Additional information on modular grants is available at Applications requesting up to $250,000 per year in direct costs must be submitted in a modular grant format. Applications requesting one module ($25,000) above the cap due to subcontract or consortium facilities and administrative costs associated with third party agreements must also be submitted in modular format and may request up to $275,000 per year in direct costs. USING THE RFA LABEL: The RFA label available in the PHS 398 (rev. 5/2001) application form must be affixed to the bottom of the face page of the application. Type the RFA number on the label. Failure to use this label could result in delayed processing of the application such that it may not reach the review committee in time for review. In addition, the RFA title and number must be typed on line 2 of the face page of the application form and the YES box must be marked. The RFA label is also available at: SENDING AN APPLICATION TO THE NIH: Submit a signed, typewritten original of the application, including the Checklist, and three signed, photocopies, in one package to: Center For Scientific Review National Institutes Of Health 6701 Rockledge Drive, Room 1040, MSC 7710 Bethesda, MD 20892-7710 Bethesda, MD 20817 (for express/courier service) At the time of submission, two additional copies of the application and all five collated sets of appendix material must be sent to Dr. Anne Clark at the address listed under WHERE TO SEND INQUIRIES. Please note that applications delivered by individuals are no longer accepted; all applications must either come via courier delivery or the United States Postal Service ( APPLICATION PROCESSING: 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. Principal investigators should not send supplementary material without first contacting the Scientific Review Administrator (SRA). The SRA will be identified in the letter sent to you indicating that your application has been received. If you have not received such a letter within three weeks after submitting the application, contact Dr. Anne Clark at the address listed under WHERE TO SEND INQUIRIES. PEER REVIEW PROCESS Upon receipt, applications will be reviewed for completeness by the CSR and responsiveness by the (IC). 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 (IC) in accordance with the review criteria stated below. As part of the initial merit review, all applications will: o Receive a written critique o Undergo a process in which only those applications deemed to have the highest scientific merit, generally the top half of the applications under review, will be discussed and assigned a priority score o Receive a second level review by the NHLBI National 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 your application in order to judge the likelihood that the proposed research will have a substantial impact on the pursuit of these goals: o Significance o Approach o Innovation o Investigator o Environment The scientific review group will address and consider each of these criteria in assigning your application's overall score, weighting them as appropriate for each application. Your 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, you 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 your study address an important problem? If the aims of your application are achieved, how do they advance scientific knowledge? 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? Do you acknowledge potential problem areas and consider alternative tactics? (3) INNOVATION: Does your project employ novel concepts, approaches or methods? Are the aims original and innovative? Does your project challenge existing paradigms or develop new methodologies or technologies? (4) INVESTIGATOR: Are you appropriately trained and well suited to carry out this work? Is the work proposed appropriate to your experience level as the principal investigator and to that of other researchers (if any)? (5) ENVIRONMENT: Does the scientific environment in which your 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? ADDITIONAL REVIEW CRITERIA: In addition to the above criteria, your application will also be reviewed with respect to the following: o PROTECTIONS: The adequacy of the proposed protection for animals, or the environment, to the extent they may be adversely affected by the project proposed in the application. o DATA SHARING: The adequacy of the proposed plan to share tissue and data. o The capacity to show an optimal utilization of the resources (e.a. a plan to utilize the same experimental animals and controls to answer multiple biological questions and a plan for storage of tissue as indicated in the Special Requirement section of this RFA). BUDGET: The reasonableness of the proposed budget and the requested period of support in relation to the proposed research. RECEIPT AND REVIEW SCHEDULE Letter of Intent Receipt Date: Feb 20 2003 Application Receipt Date: March 20 2003 Peer Review Date: June/July 2003 Council Review: September 4-5, 2003 Earliest Anticipated Start Date: September 30, 2003 AWARD CRITERIA Award criteria that will be used to make award decisions include: o Scientific merit (as determined by peer review) o Availability of funds o Programmatic priorities. REQUIRED FEDERAL CITATIONS PUBLIC ACCESS TO RESEARCH DATA THROUGH THE FREEDOM OF INFORMATION ACT: The Office of Management and Budget (OMB) Circular A-110 has been revised to provide public access to research data through the Freedom of Information Act (FOIA) under some circumstances. Data that are (1) first produced in a project that is supported in whole or in part with Federal funds and (2) cited publicly and officially by a Federal agency in support of an action that has the force and effect of law (i.e., a regulation) may be accessed through FOIA. It is important for applicants to understand the basic scope of this amendment. NIH has provided guidance at Applicants may wish to place data collected under this RFA in a public archive, which can provide protections for the data and manage the distribution for an indefinite period of time. If so, the application should include a description of the archiving plan in the study design and include information about this in the budget justification section of the application. In addition, applicants should think about how to structure informed consent statements and other human subjects procedures given the potential for wider use of data collected under this award. URLs IN NIH GRANT APPLICATIONS OR APPENDICES: All applications and proposals for NIH funding must be self-contained within specified page limitations. Unless otherwise specified in an NIH solicitation, Internet addresses (URLs) should not be used to provide information necessary to the review because reviewers are under no obligation to view the Internet sites Furthermore, we caution reviewers that their anonymity may be compromised when they directly access an Internet site. HEALTHY PEOPLE 2010: The Public Health Service (PHS) is committed to achieving the health promotion and disease prevention objectives of "Healthy People 2010," a PHS-led national activity for setting priority areas. This RFA is related to one or more of the priority areas. Potential applicants may obtain a copy of "Healthy People 2010" at AUTHORITY AND REGULATIONS: This program is described in the Catalog of Federal Domestic Assistance No. 93.838 and is not subject to the intergovernmental review requirements of Executive Order 12372 or Health Systems Agency review. Awards are made under authorization of Sections 301 and 405 of the Public Health Service Act as amended (42 USC 241 and 284) and administered under NIH grants policies described at and under Federal Regulations 42 CFR 52 and 45 CFR Parts 74 and 92. The PHS strongly encourages all grant recipients to provide a smoke- free workplace and discourage the use of all tobacco products. In addition, Public Law 103-227, the Pro-Children Act of 1994, prohibits smoking in certain facilities (or in some cases, any portion of a facility) in which regular or routine education, library, day care, health care, or early childhood development services are provided to children. This is consistent with the PHS mission to protect and advance the physical and mental health of the American people.

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