MYCOLOGY RESEARCH UNITS Release Date: February 2, 1998 RFA: AI-98-002 P.T. National Institute of Allergy and Infectious Diseases Letter of Intent Receipt Date: March 9, 1998 Application Receipt Date: June 16, 1998 APPLICATIONS IN RESPONSE TO THIS REQUEST FOR APPLICATIONS (RFA) MUST BE PREPARED USING A MULTI-PROJECT GRANT APPLICATION FORMAT; SPECIFIC INSTRUCTIONS FOR COMPLETING THE APPLICATION ARE IN AN NIAID BROCHURE ENTITLED "INSTRUCTIONS FOR APPLICATIONS FOR MULTI- PROJECT AWARDS." PURPOSE The National Institute of Allergy and Infectious Diseases (NIAID) invites applications for program project (P01) grants to conduct interdisciplinary research to increase understanding of the biology and host-pathogen interactions of the medically important fungi. This fundamental knowledge will be applied to the development of new and improved strategies for the prevention, diagnosis, and therapy of the mycoses. Therefore, research must be focused on the identification and validation of targets for the development of diagnostics, vaccines or therapeutics for systemic mycotic infections. 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 RFA, Mycology Research Units, is related to the priority area of immunization and infectious diseases. 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 for-profit and non-profit organizations, public and private institutions, such as universities, colleges, hospitals, laboratories, units of State and local governments, and eligible agencies of the Federal government. Foreign organizations are not eligible to apply. Racial/ethnic minority individuals, women, and persons with disabilities are encouraged to apply as Principal Investigators. MECHANISM OF SUPPORT The mechanism of support will be the program project (P01) grant. This type of award supports broadly based multidisciplinary research programs that have a well-defined central research focus or objective. An important feature is that the interrelationships among the individual scientifically meritorious projects will result in a greater contribution to the overall program goals than if each project was pursued individually. The program project grant consists of a minimum of three interrelated individual research projects that contribute to the program objective. The award also can provide support for certain common resources termed cores. Such resources should be utilized by two or more projects within the award. Responsibility for the planning, direction, and execution of the proposed projects will be solely that of the applicant. The total project period may not exceed five years. At this time, the NIAID is administratively limiting the duration of P01 grants to four years; this administrative limitation may change in the future. The earliest anticipated award date is January 2, 1999. FUNDS AVAILABLE The estimated total funds (direct and indirect) available for the first year of support for this RFA will be $2.5 million. In fiscal year 1999, the NIAID plans to make approximately three awards related to this RFA. This level of support is dependent on the receipt of a sufficient number of applications of high scientific merit. Applications may not request budgets in excess of $830,000 in total (direct and indirect) costs in the first year. The usual PHS policies governing grants administration and management will apply. Although this program is provided for in the financial plans of the NIAID, awards pursuant to this RFA are contingent upon the availability of funds for this purpose. Funding beyond the first and subsequent years of the grant will be contingent upon satisfactory progress during the preceding years and availability of funds. At this time, the NIAID has not determined whether or how this solicitation will be continued beyond the present RFA. RESEARCH OBJECTIVES Background Fungal infections are being recognized with increasing frequency as an important cause of both morbidity and mortality in immunocompromised as well as immunocompetent hosts. As the use of immunosuppressive therapies increases in the treatment of patients with malignant disease or with organ transplants, the frequency of systemic mycoses undoubtedly will increase. Current antifungal therapy is less than optimal, and there is evidence that resistance to available drugs is developing. The fungi of medical importance include, but are not limited to, Aspergillus fumigatus, A. flavus, Blastomyces dermatitidis, Candida albicans, Coccidioides immitis, Cryptococcus neoformans, Histoplasma capsulatum, Pseudallescheria boydii, Sporothrix schenckii, and Trichosporon beigelii. Currently, 10% of all nosocomial bloodstream infections are caused by Candida species, with an attributable mortality of 38%. Patients at high risk for these infections include those neutropenic or likely to become neutropenic because of treatment for leukemia, solid tumors, or bone marrow transplants. Systemic candidiasis is also increasing in non-neutropenic patients including premature infants, burn patients, surgical and trauma patients. Similarly, Aspergillus species carry a high attributable mortality and are a significant cause of nosocomial pneumonia, especially in bone marrow transplant patients. It was estimated in the early 1980's, on the basis of skin tests, that there are between 25,000 and 100,000 new infections with Coccidioides immitis each year. An epidemic of coccidioidomycosis occurred in highly endemic areas of the American Southwest beginning in 1991. Direct medical costs between 1991 and 1993 were estimated at approximately $45 million in Kern County, California alone. In Arizona from 1990 to 1995 the incidence of coccidioidomycosis increased 144%, with a disproportionate number of cases occurring in persons >65 years of age and persons infected with HIV. Estimates of direct medical costs in 1993 based on the Arizona Hospital Discharge Database were approximately $19 million, with an estimated average cost per hospitalization of $23,889. Increased incidence also has been documented for infections with Cryptococcus neoformans. The majority of cases occur in immunocompromised patients such as those with AIDS or those undergoing immunosuppression for renal allografts, however, a subset of patients has no identified underlying disease. A study from the Centers for Disease Control and Prevention found that the incidence of cryptococcal disease in the U.S. increased nearly 5 fold from 1980 to 1989. The annual prevalence of cryptococcosis among HIV infected patients in New York City in 1991 was estimated to be 6.1 - 8.5%. Currently the mycology program in the Division of Microbiology and Infectious Diseases, NIAID, where projects resulting from this RFA will be based, consists primarily of investigator initiated research project grants focusing on the biology (molecular biology, immunology, biochemistry and cell biology) of the medically important fungi. An infrastructure, the Mycoses Study Group, dedicated to clinical trials of antifungal agents in invasive mycoses is supported through the contract mechanism. An active basic research program in mycology is of crucial importance to help resolve the serious public health problem of fungal disease. The Division of AIDS, NIAID, also supports pre-clinical and clinical research on AIDS-associated pathogenic fungi (Pneumocystis carinii, Candida albicans, Cryptococcus neoformans) with an emphasis on drug development. The NIAID workshop series in medical mycology has identified opportunities for basic and clinically relevant research. Investigator initiated research project grants are ideally suited to address most of the research needs. Progress in medical mycology has been made through individual and collaborative efforts in the areas of cellular and molecular biology, genetic systems, host-pathogen interactions, and application of new technology and knowledge to address virulence, mechanisms of pathogenesis, and mechanisms of immune protection. Comments from the 20-23 August 1997 NIAID Mycology Workshop, Immunology in Medical Mycology: Host Responses to Fungi, indicated a need for more rapid translation of basic research observations into clinical application and a need for the field of mycology to capitalize on preliminary success by building on initial observations. The program project mechanism provides an excellent opportunity to extend beyond the capabilities of single project grants with collaborations to link multiple projects with a yield of synergy. Research Objectives and Scope The NIAID recognizes the importance of maintaining its programmatic emphasis in mycology and fungal disease research. The goal of this program is to increase understanding of the biology and host- pathogen interactions of the medically important fungi. This fundamental knowledge will be applied to the development of new and improved strategies for the prevention, diagnosis, and therapy of the mycoses. The 8-11 June 1994 NIAID Mycology Workshop on Molecular and Immunologic Approaches to the Diagnosis and Treatment of Systemic Mycoses identified the particular need for better diagnostic tests for invasive candidiasis and aspergillosis. Similarly, these diseases were identified as priorities for drug development. These two diseases are exemplary of some common issues surrounding the opportunistic systemic mycoses. Limitations in treatment are confounded by limitations in diagnosis. Blood cultures are usually negative in disseminated aspergillosis and often negative in systemic candidiasis. Clinical trials evaluating new antimicrobials or new regimens of existing antimicrobials in high risk groups often must be constructed around empiric treatment before a microbiologic diagnosis is proven, and measurement of successful outcome can involve interpretation of a complex including signs and symptoms of disease, and indirect evidence of infection. Accordingly, the workshop recommended development of new and improved methods for diagnosing fungal infections including but not limited to methods adapting immunological, nucleic acid, physiological, or metabolic methods or markers. The 7-9 September 1995 NIAID Mycology Workshop on Antigenic Peptides, Glycobiology and Vaccines assessed opportunities in fungal vaccine research. Key advances were described in vaccine- related research with the systemic mycoses and even for the more conceptually difficult, opportunistic mycoses such as cryptococcosis and candidiasis (Dixon et al., 1996. Researchers use molecular immunology and technology to combat fungal pathogens. ASM News, 62(2)81-84). The interdisciplinary nature of developing a preventive or therapeutic vaccine is well suited to the program project mechanism. The NIAID wishes to develop multidisciplinary mycology research units to serve as foci for innovative new research in fungal diseases. These units will be funded as program project grants. To achieve medical and public health relevance, studies should involve the use of clinical isolates and, where appropriate, clinical materials, including human cells. For projects to be deemed responsive, a biological process or entity must be identified as a potential target for prevention, diagnosis, or treatment. Processes or entities that could serve as potential targets include but are not limited to: cellular and molecular biology (cell biology, genetics, genome structure, gene expression, gene manipulation; genomics); virulence factors and mechanisms of pathogenesis; host-pathogen interactions (including the role of the immune system in resistance, pathogenesis, and recovery); and fungal physiology, biochemistry and metabolism. Research drawing on the preceding disciplines may form the foundation of the application, but a central focus must be on the identification and validation of targets for the development of diagnostics, vaccines or therapeutics for systemic mycotic infections. The utility must evaluated in an appropriate in vitro or in vivo model that demonstrates clinical relevance. o Diagnostics. Examples of targets and validation steps could include identification of a fungal antigen for a systemic fungal pathogen or related group of pathogens. Specific research aims should include steps for qualitative and quantitative analysis of the target antigen in an in vitro system. Clinical relevance should be demonstrated by an appropriate preclinical model or by application to patient samples. Ideally, the target would serve not only to identify a specific infection, but also to track the course of infection in response to treatment. Multiple courses of basic research could be integrated and applied to culminate in a specific aim that validates the entity or target as a legitimate diagnostic candidate. o Vaccines. The goal is to identify antigens that are immunoprotective or immunotherapeutic for the systemic mycoses. Multiple approaches are encouraged, but the one(s) selected for study must contain a validation step whereby acquisition of infection or modification of the course of disease in an appropriate preclinical model is assessed. Parallel courses of study to address methods or models of evaluating vaccine efficacy for the systemic mycoses are also acceptable. o Therapeutics. Project directors for projects focusing on therapeutics are encouraged to address or document how the research approaches are unique or underexploited and are not duplicative of approaches under extensive industrial development. The areas of particular interest to the NIAID include, but are not restricted to: immune based therapy, including antibody; novel approaches to enhancing antifungal efficacy; and novel approaches to enhancing antifungal delivery. Novel antimicrobial compounds may be a component of study if emphasis is to validate new classes or approaches, but downstream (post validation) drug development and drug screening are not areas of interest for the purposes of this RFA. It is anticipated that, in order to achieve these research goals, a given program project would involve three to five projects and common resources provided by the cores. The orientation could be either organism-specific, with multiple individuals and disciplines focused on a single fungus of medical importance, or theme specific, with different medically important fungi serving as models to address closely related areas of research emphasis. For example, a program project focused on development of approaches to fungal vaccines would have a common goal, would allow for interdisciplinary projects to draw upon discipline-specific strengths, requires key components from the above research areas, and has the potential to demonstrate true synergy where the project sum is greater than the addition of individual project components. Projects may involve collaboration among investigators at several institutions. Consortium arrangements should follow the NIH Guide outlined in "Guidelines for Establishing & Operating Consortium Grants, January, 1989." These are available from the individuals listed under INQUIRIES, below. SPECIAL REQUIREMENTS Budget for an annual one day progress review meeting of the Project Directors at a site to be designated (either in Bethesda or in association with a relevant national meeting). 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 are provided that inclusion is inappropriate with respect to the health of the subjects of 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 the NIH Guide for Grants and Contracts, Vol. 23, No. 11, March 18, 1994. Investigators may obtain copies from these sources or from Dr. Dennis M. Dixon (listed in INQUIRIES below) who may also provide additional relevant information concerning the policy. LETTER OF INTENT Prospective applicants are asked to submit, by March 9, 1998, a letter of intent that includes a descriptive title of the overall proposed research, the name, address and telephone number of the Principal Investigator, and the number and title of this RFA. Although the letter of intent is not required, is not binding, does not commit the sender to submit an application, and does not enter into the review of subsequent applications, the information that it contains allows NIAID staff to estimate the potential review workload and to avoid conflict of interest in the review. The letter of intent is to be sent to Dr. Madelon Halula at the address listed under INQUIRIES. APPLICATION PROCEDURES Applicants for P01 grants must follow special application guidelines in the NIAID Brochure entitled INSTRUCTIONS FOR APPLICATIONS FOR MULTI-PROJECT AWARDS (September 1997); this brochure is available from NIAID staff listed under INQUIRIES, and via the WWW at: http://www.niaid.nih.gov/ncn/grants/multibron.htm Applications are to be submitted on the standard research grant application form PHS 398 (rev. 5/95). Application kits are available at most institutional offices of sponsored research and may be obtained from the Division of Extramural Outreach and Information, National Institutes of Health, 6701 Rockledge Drive, MSC 7910, Bethesda, MD 20892-7910, telephone (301) 710-0267, email: asknih@od.nih.gov. For purposes of identification and processing, item 2a on the face page of the application must be marked "YES" and the RFA number AI-98-002 and the words "Mycology Research Units (MRUs)" must be typed in. Applications must be received by June 16, 1998. Applications that are not received as a single package on the receipt date or that do not conform to the instructions contained in PHS 398 (rev. 5/95) Application Kit (as modified in, and superseded by, the NIAID BROCHURE ENTITLED "INSTRUCTIONS FOR APPLICATIONS FOR MULTI-PROJECT AWARDS"), will be judged non-responsive and will be returned to the applicant. The RFA label available in the application form PHS 398 must be affixed to the bottom of the face page. Failure to use this label could result in delayed processing of the application such that it may not reach the review committee in time for review. 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 GCRC as a resource for conducting the proposed research. If so, a letter of agreement from either the GCRC program director or principal investigator could be included with the application. It is highly recommended that the appropriate NIAID program contact be consulted before submitting the letter of intent and during the early stages of preparation of the application. (See program contact under INQUIRIES). Submit a signed, typewritten original of the application, including the checklist, and three 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) At the time of submission, two additional exact copies of the grant application and all five sets of any appendix material must be sent to Dr. Madelon Halula at the address listed under INQUIRIES. Concurrent submission of an R01 and a Component Project of a Multi- project Application: Current NIH policy permits a component research project of a multi-project grant application to be concurrently submitted as a traditional individual research project (R01) application. If, following review, both the multi-project application and the R01 application are found to be in the fundable range, the investigator must relinquish the R01 and will not have the option to withdraw from the multi-project grant. This is an NIH policy intended to preserve the scientific integrity of a multi-project grant, which may be seriously compromised if a strong component project(s) is removed from the program. Investigators wishing to participate in a multi-project grant must be aware of this policy before making a commitment to the Principal Investigator and awarding institution. SPECIAL INSTRUCTIONS FOR COMPLETION OF APPLICATIONS IN RESPONSE TO THIS RFA Applicants for P01 grants must follow special application guidelines in the NIAID Brochure entitled INSTRUCTIONS FOR APPLICATIONS FOR MULTI-PROJECT AWARDS (September 1997); this brochure is available via the WWW at: http://www.niaid.nih.gov/ncn/grants/multibron.htm. The brochure presents specific instructions for sections of the PHS 398 (rev. 5/95) application form that should be completed differently than usual. For all other items in the application, follow the usual instructions on pages 5-20 of the PHS 398 booklet. REVIEW CONSIDERATIONS Review Procedures Upon receipt, applications will be reviewed for completeness by the NIH Center for Scientific Review and for responsiveness by NIAID staff. Incomplete and/or non-responsive applications will be returned to the applicant without further consideration. Applications that are complete and responsive to the RFA will be evaluated for scientific and technical merit by an appropriate peer review group convened by the NIAID in accordance with the review criteria stated below. 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 received in response to the RFA. 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. The second level of review will be provided by the National Advisory Allergy and Infectious Diseases Council. Review Criteria The general criteria for P01 grant applications are presented in the NIAID brochure entitled INSTRUCTIONS FOR APPLICATIONS FOR MULTI-PROJECT AWARDS (September 1997). AWARD CRITERIA Funding decisions will be made on the basis of scientific and technical merit as determined by peer review, program balance, and the availability of funds. INQUIRIES Written and telephone inquiries concerning this RFA are encouraged. The opportunity to clarify any issues or questions from potential applicants is welcome. Requests for the NIAID brochure "INSTRUCTIONS FOR APPLICATIONS FOR MULTI-PROJECT AWARDS" as well as inquiries regarding programmatic (eligibility and research scope) issues, may be directed to: Dennis M. Dixon, Ph.D. Division of Bacteriology and Mycology Branch National Institute of Allergy and Infectious Diseases 6003 Executive Boulevard, Room 3A06 - MSC 7630 Bethesda, MD 20892- 7630 Telephone: (301) 496-7728 FAX: (301) 402-2508 Email: dd24a@nih.gov Direct inquiries regarding preparation of the application and review issues, and address the letter of intent to, and mail two copies of the application and all five sets of appendices to: Dr. Madelon Halula Division of Extramural Activities National Institute of Allergy and Infectious Diseases 6003 Executive Boulevard, Room 4C-16 Bethesda, MD 20892-7610 Telephone: (301) 496-2550 FAX: (301) 402-2638 Email: mh30x@nih.gov Direct inquiries regarding fiscal matters to: Mr. Todd Ball Division of Extramural Activities National Institute of Allergy and Infectious Diseases 6003 Executive Boulevard, Room 4B-35 Bethesda, MD 20892-7610 Telephone: (301) 496-7075 Email: tb22j@nih.gov Schedule Letter of Intent Receipt Date: March 9, 1998 Application Receipt Date: June 16, 1998 Scientific Review Date: October 1998 Advisory Council Date: December 1998 Earliest Date of Award: January 2, 1999 AUTHORITY AND REGULATIONS This program is supported under authorization of the Public Health Service Act, Sec. 301 (c), Public Law 78-410, as amended. The Catalogue of Federal Domestic Assistance Citation is Sec. 93.856, Microbiology and Infectious Diseases Research. Awards will be 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 Executive Order 12372 or Health Systems 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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