Full Text PA-96-014 MODELS FOR HIV DISEASE AND AIDS-RELATED MALIGNANCIES NIH GUIDE, Volume 25, Number 1, January 26, 1996 PA NUMBER: PA-96-014 P.T. 34 Keywords: AIDS Disease Model Pathogenesis National Cancer Institute National Institute of Allergy and Infectious Diseases PURPOSE This Program Announcement (PA) is a reissuance of PA-95-021 with a similar title, which appeared in the NIH GUIDE, Vol. 24, No. 2, January 20, 1995. The purpose of the reissuance is to expand the scope to include refinement of mathematical models and new paradigms of HIV pathogenesis. This PA reflects a continuing joint effort by the National Cancer Institute (NCI) and the National Institute of Allergy and Infectious Diseases (NIAID) to encourage investigator-initiated grant applications for the development of useful and predictive biochemical, cellular, in vivo and mathematical models for the preclinical evaluation of new therapies against HIV disease and AIDS-related malignancies. The availability of well-characterized in vitro and in vivo models would accelerate the pace of evaluation of different paradigms of disease progression and would facilitate the discovery of successful treatments, including drugs, vaccines, gene therapy, and immune modulators. 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 PA, Models for HIV Disease and AIDS-Related Malignancies, is related to the priority areas of human immunodeficiency virus/AIDS and cancer. 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. Applications involving minority institutions are encouraged. Foreign institutions are not eligible for First Independent Research Support and Transition (FIRST) (R29) awards, but may participate in laboratory programs through subcontract or consortium arrangements. Racial/ethnic minority individuals, women, and persons with disabilities are encouraged to apply as principal investigators. MECHANISM OF SUPPORT Research support mechanisms for this PA are the investigator-initiated research project grant (R01) and FIRST (R29) award. R01 grants provide support for up to five years. R29 awards must request support for five years and are limited to $350,000 in direct costs over the entire project period. Collaborative arrangements involving more than one institution are encouraged, including participation of the pharmaceutical industry where appropriate. The NCI and NIAID have a continuing interest in the research areas of the PA and will give special consideration to the support of applications received in response to this initiative. The level of support is dependent on the receipt of a sufficient number and diversity of applications of high scientific merit and the availability of funds. Although the goal of this PA is to stimulate the development of diverse types of efficient and predictive biochemical, cellular, in vivo, and mathematical models for the evaluation of new agents for the treatment of HIV disease and AIDS-related malignancies, priority will be given to in vivo models if the number of meritorious applications exceeds funds available. Because the nature and scope of the research proposed in response to the PA may vary, it is anticipated that the sizes of awards will vary also. The total project period for applications submitted in response to this PA may not exceed five years. The NCI and NIAID have a continuing interest in the research areas of this PA. RESEARCH OBJECTIVES Background Despite advances in our knowledge of the molecular biology of HIV-1 (human immunodeficiency virus) and HIV-2 and increased understanding of HIV pathogenesis in the development of acquired immune deficiency syndrome (AIDS), no cure has been identified for HIV disease or AIDS-related malignancies, including high-grade B cell non-Hodgkin's lymphoma, Kaposi's sarcoma, Hodgkin's disease, and anogenital dysplasia and cancer. As of mid-1994, the World Health Organization (WHO) estimated that over four million AIDS cases have occurred worldwide, and that 16 million people are infected with HIV as the pandemic continues unabated. Objectives and Scope The goal of this PA is to foster the development of useful and predictive biochemical, cellular, in vivo and mathematical models for the evaluation of new therapies against HIV disease and AIDS- related malignancies. New relevant and cost-effective models are needed for various stages of preclinical therapy development, including lead discovery, lead optimization, and final evaluation of the most promising candidates for clinical trial. While progress has been made with cell-based and mechanism-based screens, such as those for reverse transcriptase and proteases, many other suitable targets exist but need to be employed in assays. There is an urgent need for simpler, safer, more relevant, and less expensive in vivo models to assess the in vivo efficacy of potential therapeutic candidates. Exploratory basic research studies on the mechanism of action of HIV genes, cellular genes involved in HIV gene replication, and gene products are excluded from this PA. The research scope encourages applications in the following areas, which are illustrated by but not limited to the examples provided: o Biochemical Assays. Rapid, resource efficient, and cost effective assays to block steps in HIV virus replication are encouraged. Models for well-studied targets such as reverse transcriptase and proteases are not advocated, whereas models for promising new targets such as the nef protein are encouraged. Applicants should consider high volume screens that would accommodate the needs of combinatorial chemistry programs. For those AIDS-related cancers in which a putative cofactor may be involved, such as the Kaposi's Sarcoma-Associated Herpesvirus (KSHV), approaches are sought to identify and define the precise role of the cofactor in the specific malignancy and to exploit this information for therapeutic advantage. o Cell Culture Assays. It is desirable that new cell culture models be developed for HIV replication and AIDS-related malignancies that more closely simulate the in vivo state. For example, models that mimic the three dimensional, multicellular environment or those based on single cycle replication kinetics would be of utility. For AIDS-related cancers, cell culture systems predictive of in vivo events that allow for studies of the mechanism(s) of action of specific cofactors and that would be useful for evaluating potential therapies are highly encouraged. o In Vivo Models. Models that reflect the current state of knowledge of HIV pathogenesis and are simpler, safer, more relevant and less expensive than currently available models are urgently needed for the evaluation of therapies for HIV disease and AIDS- related malignancies. Novel approaches using transgenic and gene knockout animals are especially encouraged. Although the use of small animals such as mice is most practical because of their availability and low cost, other animal models may be proposed. However, non-lentivirus models are not encouraged. For the models of both HIV disease and AIDS-related malignancies, the development of valid surrogate endpoints for survival is favored in the interest of conserving resources and reducing assay time and animal discomfort. o Mathematical Models. Refinement of mathematical models for viral levels, CD4+T cell counts, etc. that can be used as predictors of therapeutic efficacy and in conjunction with clinical studies will be considered. New paradigms of HIV pathogenesis that can provide alternative treatment strategies are encouraged. Applicants are reminded to provide a rationale for their model; to justify and demonstrate its potential utility over existing models, if applicable; to provide a research plan involving a testable hypothesis; and to use the model to demonstrate its utility. Relevance to the in vivo disease state, reproducibility using appropriate statistical analysis, and other important parameters of the assay should be documented. Although the intent of this PA is to restrict studies to those which are preclinical, clinical specimens may be used whenever required for the appropriate development of in vitro and animal models. 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 28, 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. APPLICATION PROCEDURES Applications are to be submitted on the grant application form PHS 398 (rev. 5/95) and will be accepted at the standard application deadlines as indicated in the application kit. Receipt dates for applications for AIDS-related research are January 2, May 1, and September 1. Application kits are available at most institutional offices of sponsored research and may be obtained from the Office of Grants Information, Division of Research Grants, National Institutes of Health, 6701 ROCKLEDGE DR MSC 7910, BETHESDA MD 20892-7910, telephone 301-710-0267. The title and number of the program announcement must be typed in Section 2 on the face page of the application. FIRST (R29) applications must include at least three sealed letters of reference attached to the face page of the original application. FIRST applications submitted without the required number of reference letters will be considered incomplete and will be returned without review. The completed original application and five legible copies must be sent or delivered to: DIVISION OF RESEARCH GRANTS NATIONAL INSTITUTES OF HEALTH 6701 ROCKLEDGE DRIVE SUITE 1040 MSC 7710 BETHESDA MD 20892-7710 BETHESDA, MD 20817 (for express/courier service) REVIEW CONSIDERATIONS Applications will be assigned on the basis of established PHS referral guidelines. Applications that are complete will be evaluated for scientific and technical merit by study sections of the Division of Research Grants, NIH, 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 appropriate national advisory council or board. Review Criteria o scientific, technical, or medical significance and originality of proposed research; o appropriateness and adequacy of the experimental approach and methodology proposed to carry out the research; o qualifications and research experience of the principal investigator and staff, particularly, but not exclusively, in the area of the proposed research; o availability of the resources necessary to perform the research; o appropriateness of the proposed budget and duration in relation to the proposed research; o adequacy of plans to include both genders and minorities and their subgroups as appropriate for the scientific goals of the research. Plans for the recruitment and retention of subjects will also be evaluated. The initial review group will also examine the provisions for the protection of human and animal subjects and the safety of the research environment. AWARD CRITERIA 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 are encouraged. The opportunity to clarify any issues or questions from potential applicants is welcome. Direct inquiries regarding programmatic issues to: Dr. Nava Sarver Division of AIDS National Institute of Allergy and Infectious Diseases Solar Building, Room 2C01 6003 EXECUTIVE BLVD MSC 7620 BETHESDA MD 20892-7620 Telephone: (301) 496-8197 FAX: (301) 402-3211 Email: ns18p@nih.gov Dr. Mary K. Wolpert Division of Cancer Treatment, Diagnosis, and Centers National Cancer Institute Executive Plaza North, Room 832 6130 EXECUTIVE BLVD MSC 7450 BETHESDA MD 20892-7450 Telephone: (301) 496-8783 FAX: (301) 496-8333 Email: mkwolper@helix.nih.gov Direct inquiries regarding fiscal matters to: Ms. Jane Unsworth Division of Extramural Activities National Institute of Allergy and Infectious Diseases Solar Building, Room 4B25 6003 Executive Boulevard, MSC 7610 BETHESDA MD 20892-7610 Telephone: (301) 496-7075 FAX: (301) 480-3780 Email: ju3a@nih.gov Ms. Michelle Burr Grants Administration Branch National Cancer Institute Executive Plaza South, Suite 243 6120 EXECUTIVE BLVD MSC 7150 BETHESDA MD 20892-7150 Telephone: (301) 496-7800, Ext. 231 FAX: (301) 496-8601 Email: BURRM@GAB.NCI.NIH.GOV AUTHORITY AND REGULATIONS This program is described in the Catalog of Federal Domestic Assistance No. 93.395, Cancer Treatment Research and 93.856, Microbiology and Infectious Diseases Research. 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 45 CFR Part 74 and 45 CFR Part 92. This program is not subject to the intergovernmental review requirements of Executive Order 12372 or Health System 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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