MODELS FOR HIV DISEASE AND AIDS-RELATED MALIGNANCIES Release Date: January 20, 1999 PA NUMBER: PA-99-042 P.T. National Cancer Institute National Institute of Dental and Craniofacial Research This Program Announcement (PA) is a reissuance of PA-96-014, which appeared in the NIH GUIDE, Vol. 25, No.1, January 26, 1996. PURPOSE This PA from the National Cancer Institute (NCI) and the National Institute of Dental and Craniofacial Research (NIDCR) encourages 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 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), or at http://www.crisny.org/health/us/health7.html. ELIGIBILITY REQUIREMENTS Applications may be submitted by domestic and foreign for-profit and nonprofit 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 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 mechanism for this PA is the investigator-initiated research project grant (R01). Collaborative arrangements involving more than one institution are encouraged, including participation of the pharmaceutical industry where appropriate. 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. Awards will be administered under NIH grants policy as stated in the NIH Grants Policy Statement 10/1/98. RESEARCH OBJECTIVES Background Despite many recent advances in our knowledge of the molecular biology of HIV-1 (human immunodeficiency virus) and HIV-2 and our 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 Kaposi's sarcoma, high-grade B cell non-Hodgkin's lymphoma, Hodgkin's disease, Castleman's Disease and anogenital dysplasia and cancer. As of June 1998, the World Health Organization (WHO) estimated that more than 5.8 million new cases of AIDS occurred and 2.3 million people died of AIDS worldwide in the last year. Nearly 12 million people worldwide have died of AIDS since the beginning of the epidemic and more than 30 million people are infected and living with HIV/AIDS 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. However, 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 in any way 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/HHV-8), Epstein-Barr Virus (EBV) or Human Papilloma Viruses (HPV), 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, retroviral animal 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/or viral resistance 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 that are preclinical in nature, 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 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 have been published in the Federal Register of March 28, 1994 (FR 59 14508-14513) and in the NIH Guide for Grants and Contracts, Volume 23, Number 11, March 18, 1994, available at the following URL address: http://www.nih.gov/grants/guide/notice-files/not94-105.html. Investigators also may obtain copies of the policy from the program staff listed under INQUIRES. Program staff may also provide additional relevant information concerning the policy. 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: http://www.nih.gov/grants/guide/notice-files/not98-024.html Investigators also may obtain copies of the policy from the program staff listed under INQUIRES. 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. 4/98) 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 Division of Extramural Outreach and Information Resources, National Institutes of Health, 6701 Rockledge Drive, MSC 7910, Bethesda, MD 20892-7910, telephone 301/710-0267, E-mail: grantsinfo@nih.gov. Application kits are also available on the Internet at: http://www.nih.gov/grants/forms.htm Applicants planning to submit an investigator-initiated new (type 1), competing continuation (type 2), competing supplement, or any amended/revised version of the preceding grant application types requesting $500,000 or more in direct costs for any year are advised that they must contact Institute/Center program staff before submitting the application, while plans for the study are being developed. Furthermore, the applicant must obtain agreement from the Institute that it will accept the application for consideration for award. Finally, the applicant must identify, in a cover letter sent with the application, the staff member (and Institute) who agreed to accept assignment of the application. This policy requires an applicant to obtain agreement for acceptance from both for any such application and any such subsequent amendment. Refer to the NIH Guide for Grants and Contracts, March 20, 1998 at: http://www.nih.gov/grants/guide/notice-files/not98-030.html. The title and number of this Program Announcement must be typed on line 2 of the face page of the application form and the YES box must be marked. Submit a signed, typewritten original of the application, including the Checklist, and five identical, 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) 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 Center for Scientific Review, 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 The goals of NIH-supported research are to advance our understanding of biological systems, improve the control of disease, and enhance health. The reviewers will comment on the following aspects of the application in their written critiques 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 by the reviewers 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 a 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 analysis 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 methods? 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? The initial review group will also examine: the appropriateness of proposed project budget and duration; the adequacy of plans to include both genders, minorities and their subgroups, and children as appropriate for the scientific goals of the research and plans for the recruitment and retention of subjects; 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. Mary K. Wolpert Division of Cancer Treatment and Diagnosis National Cancer Institute 6130 Executive Boulevard, Room 841, MSC 7456 Bethesda, MD 20892-7456 Telephone: (301) 496-8783 FAX: (301) 402-5200 Email: mw8u@nih.gov Dr. Kenneth J. Cremer Division of Cancer Biology National Cancer Institute 6130 Executive Boulevard, Room 540, MSC 7398 Bethesda, MD 20892-7398 Telephone: (301) 496-6085 FAX: (301) 496-2025 Email: kc47i@nih.gov Dennis F. Mangan, Ph.D. Division of Extramural Research, National Institute of Dental and Craniofacial Research 45 Center Drive, Room 4AN-32F, MSC 6402 Bethesda, MD 20892-6402 Telephone: (301) 594-2421 FAX: (301) 480-8318 Email: Dennis.Mangan@nih.gov Direct inquiries regarding fiscal matters to: Ms. Michelle Burr Grants Administration Branch National Cancer Institute 6120 Executive Boulevard, Suite 243, MSC 7150 Bethesda, MD 20892-7150 Telephone: (301) 496-7800, Ext. 231 FAX: (301) 496-8601 Email: mb94r@nih.gov Mr. Kevin Crist Division of Extramural Research National Institute of Dental and Craniofacial Research Natcher Building, Room 4AS-44 Bethesda, MD 20892-6402 Telephone: (301) 594-4800 FAX: (301) 480-8301 Email: Kevin.Crist@nih.gov AUTHORITY AND REGULATIONS This program is described in the Catalog of Federal Domestic Assistance No. 93.399 - Cancer Cause and Prevention Research, 93.395 - Cancer Treatment Research and No. 93.121 - Oral Diseases and Disorders Research Awards. 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 HHS policies and grant regulations. This program is not subject to the intergovernmental review requirements of Executive Order 12372 or Health Systems 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. 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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