Full Text PA-96-068 INNOVATIVE DRUG DISCOVERY RESEARCH IN AIDS OPPORTUNISTIC INFECTIONS NIH Guide, Volume 25, Number 26, August 2, 1996 PA NUMBER: PA-96-068 P.T. 34 Keywords: AIDS Drug Design Pathophysiology Infectious Diseases/Agents National Institute of Allergy and Infectious Diseases Application Receipt Dates: January 2, May 1, September 1 PURPOSE The National Institute of Allergy and Infectious Diseases gives special consideration for funding to scientifically meritorious applications in response to Program Announcements. Program Announcements (PA) identify areas of ongoing research emphasis for the NIAID. The purpose of this PA is to seek research grant applications aimed at novel approaches to discovery and preclinical development of therapeutic agents and strategies against opportunistic infections (OIs) in people with AIDS. The intent of this Program Announcement is to encourage investigator-initiated grant applications that involve creative and original preclinical research that emphasizes under-exploited facets of the basic biology, biochemistry, and pathophysiology of the opportunistic pathogens necessary to propel advances in improved therapies. No clinical trials will be supported under this PA. Another Program Announcement, "Collaborations for Advanced Strategies in Opportunistic Infections," soliciting research projects that encompass laboratory research linked to proof-of-concept clinical studies will be announced at a later date. 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, Innovative Drug Discovery Research for Opportunistic Infections Associated with AIDS, is related to the priority area of human HIV infection. 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. Racial/ethnic minority individuals, women, and persons with disabilities are encouraged to apply as Principal Investigators. Foreign institutions are not eligible for First Independent Research Support and Transition (FIRST) (R29) awards. MECHANISM OF SUPPORT Traditional research project grant (R01), FIRST award (R29), small research (R03) grant, and Interactive Research Project Grants (IRPG), awards may be submitted in response to this PA. Applications for R01 grants may request up to five years of support. Applications for R29 grants must request five years of support and are limited to $350,000 in direct costs over the entire project period. The NIAID uses R03 grants to support small highly innovative or pilot projects. Applicants for R03 grants may request up to $50,000 (direct costs) per year for a period not to exceed three years. Funds and time requested should be appropriate for the research proposed. Applicants for R03 grants must follow the special application guidelines and Terms and Conditions of Award for NIAID SMALL RESEARCH GRANTS, which appeared in the NIH Guide for Grants and Contracts, Vol. 25, No. 9, March 22, 1996. If an IRPG is proposed, it must consist of a minimum of two independent applications (see PA-96-001, NIH Guide for Grants and Contracts, Vol. 24, No. 35, October 6, 1995). 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. RESEARCH OBJECTIVES Background The principal causes of morbidity and mortality in AIDS are opportunistic infections (OIs). Although HIV is the primary cause of the progressive immunological deterioration seen in AIDS, the OIs account for the vast majority of all AIDS-related deaths as well as diminishing quality of life. Individuals infected with HIV are susceptible to a range of viral, bacterial, protozoal, and fungal infections. The pathologic consequences associated with OIs in AIDS are debilitating oral lesions, retinitis (cytomegalovirus), progressive multifocal leukoencephalopathy (JC virus),, disseminated nontuberculosis mycobacterial disease (M. avium), pulmonary disease (Pneumocystis carinii), protracted diarrhea (Cryptosporidium parvum, Enterocytozoon bieneusi), and meningitis (Cryptococcus neoformans). Whereas the available treatments for OIs have improved and prolonged the lives of people living with AIDS, the management of OIs in AIDS patients remains difficult and complicated due to toxicity and adverse side effects of therapeutic agents, long-term drug use leading to patient intolerance or drug resistance, frequent relapses, drug-drug interactions, and/or lack of standard treatments for newly emerging OIs (e.g., JC virus, C. parvum, E. bieneusi). New ideas and novel approaches are urgently needed to overcome the lack of therapeutic options available to people with AIDS-associated OIs. Research Objectives and Experimental Approaches The principal objective of this PA is to stimulate drug discovery through original and innovative research focused on key metabolic and pathophysiologic features between pathogen and host that will lead to the discovery and development of safe, better tolerated and effective new therapies for AIDS-associated OIs. Equally important is the need for rapid, non-invasive detection methods for early and specific diagnosis and for evaluation of responses to therapy. Research responsive to this PA includes studies to identify therapies and evaluation strategies for the following infectious agents: human cytomegalovirus (HCMV), JC virus, Mycobacterium avium, Pneumocystis carinii, Cryptosporidium parvum, the Microsporida, and Cryptococcus neoformans. Areas of study on these organisms include, but are not restricted to, the following: o discovery of efficacious new antibiotics for treatment and prevention of AIDS-associated disease; o basic cellular and molecular biology of the pathogens (virulence factors, genome structure, and gene expression) leading to identification of potential new chemo-or immuno-therapeutic targets; o pathogen physiology, biochemistry and metabolism leading to a better understanding of drug susceptibility and resistance; o development of improved in vitro (cell culture) and in vivo (animal model) systems for drug evaluations; o identification and evaluation of promising new drugs from natural products and synthetic chemical compounds, and elucidation of their mechanism of action; o early development and preclinical validation/standardization of rapid, non-invasive diagnostic methods for the specific and quantifiable detection of the infectious organism and for monitoring response to therapy; o development of improved delivery systems for therapeutic agents. 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 printed 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). Applications kits are available at most institutional offices of sponsored research and may be obtained from the Grants Information Office, Office of Extramural Outreach and Information Resources, National Institutes of Health, 6701 Rockledge Drive, MSC 7910, Bethesda, MD 20892-7910, telephone 301/710-0267, email: ASKNIH@odrockm1.od.nih.gov. Specific guidelines for R03 applications are provided in the notice, "NIAID Small Research Grants," NIH Guide, Vol. 25, No. 9, March 22, 1996; which is available from program staff listed under INQUIRIES. Specific guidelines for IRPG applications are provided in PA-96-001, NIH Guide, Vol. 24, No. 25, October 6, 1995. Specific guidelines for FIRST (R29) awards are provided in "First Award Guidelines (rev. 6/96). Applications for FIRST (R29) awards must include at least three sealed letters of reference attached to the face page of the original application. FIRST (R29) applications submitted without the required number of reference letters will be considered incomplete and will be returned without review. Applications must be identified by checking "YES" on line 2 of the PHS face page, and the number and title of this program announcement must be typed in. Submit a signed, typewritten original of the application, including the Checklist, and five signed, exact photocopies in one package 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) R03 applicants should submit an original typewritten application and three exact signed copies to the Division of Research Grants at the above address, and two copies to: Stanley Oaks, Ph.D. Division of Extramural Activities National Institute of Allergy and Infectious Diseases Solar Building, Room 4C06 6003 Executive Boulevard Bethesda, MD 20892 Telephone: (301) 496-7042 FAX: (301) 402-2638 Email: stanley_oaks@nih.gov Applicants from institutions that have a General clinical Research Center (GCRC) funded by the NIH National Center for Research Resources may wish to identify the Center as a resource for conducting the proposed research. If so, a letter of agreement from the GCRC Program Director must be included in the application material. The Small Business Innovation Research Program (SBIR) and the Small Business Technology Transfer Research Program (STTR) also solicit applications in this research area. SBIR and STTR solicitation packages are available from: MTL, Inc. 13687 Baltimore Avenue Laurel, MD 20707-5096 Telephone: (301) 206-9385 FAX: (301) 206-9722 Email: a2y@cu.nih.gov The National Heart, Lung, and Blood Institute (NHLBI) and the National Institute of Dental Research (NIDR) also have interests in the basic biology, biochemistry, and pathophysiology of opportunistic pathogens; in particular, how these organisms interact with host lung cells and affect the respiratory system (NHLBI), or how they interact with tissues and defense mechanisms of the oral cavity (NIDR). Therefore, applications that are of mutual interest are likely to be given a secondary assignment to NHLBI or NIDR in accordance with the NIH referral guidelines. REVIEW CONSIDERATIONS R03 APPLICANTS ONLY: Review considerations and procedures are contained in the NIAID SMALL RESEARCH GRANTS notice which appeared in the NIH Guide for Grants and Contracts, Vol. 25, No. 9, March 22, 1996. Applications will be assigned on the basis of established PHS referral guidelines. Program staff will be responsible for determining whether an application is responsive to the goals of the PA. Applications will be reviewed for scientific and technical merit in accordance with the standard NIH peer review procedures. As part of the initial merit review, all applications may 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 the applications under review will be discussed, assigned a priority score, and receive a second-level review by the appropriate national advisory council. Review Criteria o scientific, technical, or medical significance and originality of the proposed research; o appropriateness and adequacy of the experimental approach and methodology proposed to carry out the research; o interactive nature of the component and overall program of the IRPG (where applicable); 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 favorably recommended applications. The following will be considered when making funding decisions: quality of the proposed project as determined by peer review, program balance among research areas of the announcement, availability of funds. INQUIRIES Written and telephone inquiries are encouraged. The opportunity to clarify any issues or questions from potential applicants is welcome. Direct inquiries regarding programmatic (eligibility, responsiveness, and choice of funding mechanism) issues to: Chris Lambros, Ph.D. Division of AIDS National Institute of Allergy and Infectious Diseases 6003 Executive Boulevard, Room 2C40, MSC 7620 Bethesda, MD 20892-7620 Telephone: (301) 402-2304 FAX: (301) 402-3171 Email: chris_lambros@nih.gov R03 APPLICANTS ONLY: Direct inquiries regarding review issues and special instructions for application preparation to Dr. Stanley Oaks at the address listed under APPLICATION PROCEDURES. Direct inquiries regarding fiscal and administrative matters to: Ms. Jane W. Unsworth Division of Extramural Activities National Institute of Allergy and Infectious Diseases 6003 Executive Boulevard, Room 4B25, MSC 7610 Bethesda, MD 20892-7610 Telephone: (301) 402-6824 FAX: (301) 480-3780 Email: jane_unsworth@nih.gov AUTHORITY AND REGULATIONS This program is described in the Catalogue of Federal Domestic Assistance No. 93.856. 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 Part 52 and 45 CFR Part 74. This program is not subject to the intergovernmental review requirements of the Executive Order 12372 or Health Systems 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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