PA-01-094: MODELS FOR HIV DISEASE AND AIDS-RELATED MALIGNANCIES

Department of Health
and Human Services (HHS)

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MODELS FOR HIV DISEASE AND AIDS-RELATED MALIGNANCIES Release Date: May 16, 2001 PA NUMBER: PA-01-094 (see replacement PA-04-157) National Cancer Institute THIS PA 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 PA. This Program Announcement (PA) replaces PA-99-042, which was published in NIH Guide Volume 25, Number 1, January 29, 1999. PURPOSE The purpose of the this Program Announcement (PA) is 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 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. This PA will expire on September 3, 2003 unless reissued. NIH Grants policies apply to these awards. 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 is available for HIV associated 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 December 2000, the World Health Organization (WHO) estimated that more than 5.3 million new cases of AIDS occurred and 3.0 million people died of AIDS worldwide in the last year. More than 21.8 million people worldwide have died of AIDS since the beginning of the epidemic and more than 36 million people are infected and living with HIV/AIDS as the pandemic continues unabated. 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 HIV reverse transcriptase and proteases are not advocated, whereas models for promising new targets such as the nef or other HIV proteins 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 viral factors of 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 viral associated 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. MECHANISM OF SUPPORT Support of this program will be through the National Institutes of Health (NIH) research project grant (R01) mechanism and the exploratory/developmental grant (R21) mechanisms. Applicants will be responsible for the planning, direction, and execution of the proposed project. All PHS and NIH grants policies will apply to applications received and awards made in response to this PA.. The R21 mechanism supports pilot projects or feasibility studies. Accordingly, a sound rationale and a well designed research plan but not preliminary data are required. The R01 supports more advanced projects. Responsibility for the planning, direction, and execution of the proposed research for all applicable mechanisms of support will be solely that of the applicant. Applicants for the R21 grant mechanism may request up to $100,000 direct costs (four budget modules) per year unless the application includes consortium costs, in which case the limit is $125,000 direct costs (five budget modules) per year. For R21 grants, support may not exceed two years. Though the size of award may vary with the scope of research proposed, it is expected that R21 applications will stay within the budgetary guidelines for an exploratory/developmental project. The R21 grants are non-renewable, and competitive continuation of projects developed under this program will be through the R01 research grant mechanism. Applications for the R01 grant mechanism may not exceed five years. This PA 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. 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 http://grants.nih.gov/grants/funding/modular/modular.htm. 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 or local governments, and eligible agencies of the Federal government. 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. INQUIRIES Inquiries concerning this PA are encouraged. The opportunity to clarify any issues or questions from potential applicants is welcome. Direct inquiries regarding programmatic issues to: Dr. Kenneth Cremer Biological Carcinogenesis Branch Division of Cancer Biology National Cancer Institute Executive Plaza North, Room 5016 Bethesda, MD 20892-7398 Telephone: 301 496-6085 FAX: 301-496-2025 Email: cremerk@mail.nih.gov or kc47i@nih.gov Dr. Mary Wolpert Developmental Therapeutics Program Division of Cancer Treatment and Diagnosis National Cancer Institute Executive Plaza North, Room 8153 Bethesda, MD 20892-7456 Telephone: 301 496-8783 FAX: 301-402-5200 Email: wolpertm@mail.nih.gov or mw8u@nih.gov Direct inquiries regarding fiscal matters to: Ms. Eileen Natoli Grants Administration Branch National Cancer Institute 6120 Executive Blvd, Suite 243, MSC 7150 Bethesda, MD 20892-7150 Telephone: (301) 496-8791 FAX: 301-496-8601 Email: natoliea@gab.nci.nih.gov Mr. Bill Wells Grants Administration Branch National Cancer Institute 6120 Executive Blvd, Suite, 243 MSC 7150 Bethesda, MD 20892-7150 Telephone: (301) 496-8796 FAX: 301-496-8601 Email: ww14j@nih.gov or wellsw@gab.nci.nih.gov APPLICATION PROCEDURES 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. Applications 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. Applications kits are available at most institutional offices of sponsored research and may be obtained 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 title and number of the PA must be typed on line 2 of the face page of the application form and the YES box must be marked. For those applicants with Internet access, the 398 kit may be found at: http://grants.nih.gov/grants/forms.htm. Applicants are strongly encouraged to call the program contacts listed in INQUIRIES above with any questions regarding the adherence to the guidelines of their proposed project to the goals of this PA. SPECIFIC INSTRUCTIONS FOR MODULAR GRANT BUDGET INSTRUCTIONS Modular Grant applications will request direct costs in $25,000 modules, up to a total direct cost request of $250,000 per year for R01 and, up to a total direct cost request of $100,000 per year ($125,000 if there are consortium/contractual Cost) for R21. Applications that request more than $250,000 direct costs for an R01 in any year must follow the traditional PHS 398 application instructions. 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: 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. o NARRATIVE BUDGET JUSTIFICATION - Prepare a Modular Grant Budget Narrative page (see http://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 all project personnel, including their names, percent of effort, and roles 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. 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 all personnel, and the role on the project. Indicate whether the collaborating institution is domestic or foreign. 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. 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: http://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. 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. Submit a signed, typewritten original of the application, including the checklist, and five signed, exact, single-sided 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 will be evaluated for scientific and technical merit by an appropriate scientific review group convened in accordance with the standard 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 five criteria to be used in the evaluation of grant applications are listed below. 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. 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? Approach: Are the conceptual framework, design, methods, and analyzes adequately developed, well-integrated, and appropriate to the aims of the project? Does the applicant acknowledge potential problem areas and consider alternative tactics? 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? 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)? 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 adequacy of plans to include both genders and 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 This section must describe the factors, including the scientific and technical merit reflected in the priority score or percentile, that will be used to make award decisions. PAs can apply other criteria such as the geographical location of the applicant organization. The most common award criteria are: scientific merit as determined by peer review, availability of funds, and programmatic priorities. 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 sub- populations must be included in all NIH-supported biomedical and behavioral research projects involving human subjects, unless a clear and compelling rationale and justification are provided indicating 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 UPDATED "NIH Guidelines for Inclusion of Women and Minorities as Subjects in Clinical Research," published in the NIH Guide for Grants and Contracts on August 2, 2000 (http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00- 048.html), a complete copy of the updated Guidelines is available at http://grants.nih.gov/grants/funding/women_min/guidelines_update.htm: The revisions relate to NIH defined Phase III clinical trials and require: a) all applications or proposals and/or protocols to provide a description of plans to conduct analyses, as appropriate, to address differences by sex/gender and/or racial/ethnic groups, including subgroups if applicable, and b) all investigators to report accrual, and to conduct and report analyses, as appropriate, by sex/gender and/or racial/ethnic group differences. 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 clear and compelling 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://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. REQUIRED EDUCATION IN THE PROTECTION OF HUMAN RESEARCH PARTICIPANTS All investigators proposing research involving human subjects should read the NIH policy on education in the protection of human research participants now required for all investigators, which is published in the NIH Guide for Grants and Contracts, June 5, 2000 (Revised August 25, 2000), available at the following URL address: http://grants.nih.gov/grants/guide/notice-files/NOT- OD-00-039.html. A continuing education program in the protection of human participants in research is now available online at http://cme.nci.nih.gov/. 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. Reviewers are cautioned 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 PA, Models for HIV Disease and AIDS- Related Malignancies, is related to priority area of human immunodeficiency virus/AIDS and cancer Potential applicants may obtain a copy of "Healthy People 2010" at http://www.health.gov/healthypeople/. AUTHORITY AND REGULATIONS This program is described in the Catalog of Federal Domestic Assistance No. 93.399 Cancer Cause and Prevention Research and 93.395 Cancer Treatment Research. 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 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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