Full Text PA-95-021 MODELS FOR AIDS AND AIDS-RELATED MALIGNANCIES NIH GUIDE, Volume 24, Number 2, January 20, 1995 PA NUMBER: PA-95-021 P.T. Keywords: National Cancer Institute National Institute of Allergy and Infectious Diseases PURPOSE This Program Announcement (PA) is a joint effort by the National Cancer Institute (NCI) and the National Institute of Allergy and Infectious Diseases (NIAID) to encourage investigators to develop useful and predictive biochemical, cellular, and in vivo models that could be used for the preclinical evaluation of new therapies against HIV disease and AIDS-related malignancies. The development of well- characterized in vitro and in vivo models would accelerate and 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 AIDS 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 "Healthy People 2000" (Summary Report: Stock No. 017-001-00473-1) through the Superintendent of Documents, Government Printing Office, Washington, DC 20402-9325 (telephone 202-783-3238). 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 may be submitted from one institution or may include arrangements with several institutions, if appropriate. Applications involving minority institutions are encouraged. Foreign institutions are not eligible for First Independent Research Support and Transition (FIRST) (R29) awards. Racial/ethnic minority individuals, women, and persons with disabilities are encouraged to apply as Principal Investigators. MECHANISM OF SUPPORT Support for the PA will be by the investigator-initiated research project grant (R01), FIRST (R29) award, or the Interactive Research Project Grants (IRPG) mechanisms. If an IRPG is proposed, it must consist of a minimum of two independent applications (see PA-94-086, NIH Guide for Grants and Contracts, Vol. 23, No. 28, July 29, 1994). An IRPG may consist of a combination of R01s and R29s or R01s only, but may not consist solely of R29 applications. An IRPG may also contain shared interactive resources (Cores), which must serve at least two of the research projects in order to facilitate achievement of the Group's common research goals. Collaborative arrangements involving more than one institution are especially encouraged, including participation of the pharmaceutical industry where appropriate. FUNDS AVAILABLE The NCI has set aside approximately $2.0 million total costs in Fiscal Year 1995 for the first year of funding and NIAID will give special consideration for 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, and in vivo models that could be used 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. Although the NCI and NIAID have a continuing interest in the research areas of this PA, the latest anticipated award date with set aside funds is September 30, 1995. 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 immunodeficiency syndrome (AIDS), no cure has been identified for AIDS or AIDS-related malignancies, including high-grade B cell non-Hodgkin's lymphoma, Kaposi's sarcoma, Hodgkin's disease, anogenital dysplasia and cancer, and basal cell carcinoma. 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, and in vivo models that could be used 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. 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. Since considerable effort is being expended on reverse transcriptase and proteases, applications on these enzymes are not encouraged for this initiative. However, applicants should consider high volume screens which would accommodate the needs of combinatorial chemistry programs. For those AIDS-related cancers in which a putative cofactor may be involved, 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 AIDS pathogenesis and are simpler, safer and less expensive than currently available models are urgently needed for the evaluation of therapies for AIDS and AIDS-related malignancies. Novel approaches using transgenic and gene knockout animals are especially encouraged. While the use of small animals such as mice is most practical because of their availability and low cost, other animal models can be proposed. However, non-lentivirus models are not encouraged. For the models of both AIDS 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. Applicants are reminded to provide a rationale for their model; to justify and perhaps demonstrate its potential utility over existing models, if applicable; and to provide a research plan involving a testable hypothesis. Relevance to the in vivo disease state, reproducibility and other important parameters of the assay should be documented using appropriate statistical analysis. 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. 9/91) 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, Westwood Building, Room 449, Bethesda, MD 20892, telephone 301/710-0267. The title and number of the announcement must be typed in Section 2a 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. If an IRPG is proposed, each application must be identified along with the number of the PA and the phrase "Investigator-initiated IRPG." All R01 or R29 applications constituting the proposed IRPG cohort must be submitted in a single package, whether or not the applications arise from the same institutions. For detailed instructions for preparation and submission of IRPG applications, refer to PA-94-086, NIH Guide for Grants and Contracts, Volume 23, Number 28, July 29, 1994. The complete original application and five legible copies must be sent or delivered to: Division of Research Grants National Institutes of Health Westwood Building, Room 240 Bethesda, MD 20892** REVIEW CONSIDERATIONS Applications will be assigned on the basis of established PHS referral guidelines. Applications will be reviewed for scientific and technical merit by study sections of the Division of Research Grants, NIH, in accordance with the standard NIH peer review procedures. Following scientific-technical review, the applications will receive a second-level review by an appropriate national advisory board/council. As part of the initial merit review, a process (triage) may be used by the initial review group in which applications will be determined to be competitive or non-competitive based on their scientific merit relative to other applications. Applications judged to be competitive will be discussed and be assigned a priority score. Applications determined to be non-competitive will be withdrawn from further consideration and the Principal Investigator and the official signing for the applicant organization will be notified. 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. For Fiscal Year 1995, the NCI has set aside $2 million for this initiative. 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 Boulevard 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 National Cancer Institute Executive Plaza North, Room 832 6130 Executive Boulevard 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 242 6120 Executive Boulevard MSC 7150 Bethesda, MD 20892-7150 Telephone: (301) 496-7800, Ext. 231 FAX: (301) 496-8601 Email: MICHELLE BURR@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 42 CFR 52 and 45 CFR Part 74. This program is not subject to the intergovernmental review requirements of Executive Order 12372 or Health System Agency review. The Public Health Service (PHS) strongly encourages all grant recipients to provide a smoke-free workplace and promote the non- use of all tobacco products. This is consistent with the PHS mission to protect and advance the physical and mental health of the American people. .
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