COMPETITIVE SUPPLEMENTS: ORAL DIMENSIONS OF HIV TRANSMISSION, THERAPIES, AND OUTCOMES NIH GUIDE, Volume 26, Number 40, December 19, 1997 RFA: DE-98-001 P.T. National Institute of Dental Research Letter of Intent Receipt Date: March 1, 1998 Application Receipt Date: March 26, 1998 PURPOSE The National Institute of Dental Research (NIDR) invites competitive grant supplement applications to address critical gaps in knowledge concerning the role of the oral environment in HIV transmission, the etiology and treatment of HIV- related oral symptoms and neuropathic pain, and dental interventions which may contribute to treatment adherence or clinical outcomes. These supplements are expected to enrich scientifically or to extend the scope of relevant NIH-funded research grants supporting biological, biomedical, behavioral, or epidemiological studies. The primary (parent) grants being supplemented may be funded by any of the Institutes or Centers of the National Institutes of Health (NIH). Through this Request for Applications (RFA) NIDR seeks to stimulate collaborative studies capitalizing on current NIH- wide investments in HIV research by building upon resources already available (e.g., tissue samples, cohorts of HIV+ or high risk subjects with well- delineated medical data, pediatric or adult clinical trials testing drugs or drug combinations). Studies are specifically encouraged on oral mucosal immunity, mechanisms underlying the development of HIV-related oral opportunistic infections, prevention of oral HIV transmission, improved therapies for oral opportunistic infections, mechanisms underlying and treatments for HIV-related neuropathic pain, and dental care-based interventions to enhance prevention, symptom management, or clinical outcomes in HIV. 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, Competitive Supplements: Oral Dimensions of HIV Transmission, Therapies, and Outcomes, is related to the priority areas of HIV infection and oral health. 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 Office, Washington, DC 20402-9325 (telephone 202-512-1800. ELIGIBILITY REQUIREMENTS Supplements may only be made to NIH-supported research project (R01), program project (P01), and cooperative agreement (U01) grants. The principal investigator for the grant identified for supplementation (i.e., "parent" grant) must provide assurances that the proposed project is technically and administratively feasible as an adjunct to the ongoing project. For example, if collaborative expertise or research resources (e.g., tissue samples, data sets, or access to HIV+ or high-risk cohorts) are required to implement the supplement project successfully, documentation of the characteristics, quality, and availability of these resources must be fully addressed in the application. The minimum number of years remaining on the parent grant should be no less than one year at the award date for the supplement application (March 26, 1998). Projects are expected to fit within the broad aims of the approved, funded parent grant and extend to dental/oral research. Grants related to dental/oral research topics may also be supplemented (e.g., to expand the specific aims or use new methods), although supplement applications that merely propose minor methodological changes or expansions in sample size will not be considered responsive. 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 organizations that have current NIH-support grants are eligible to apply, and domestic applications may include international components. The NIDR encourages applications that include investigators who are racial/ethnic minority individuals, women, and persons with disabilities. MECHANISM OF SUPPORT The competitive supplement (S1) mechanism will be utilized. Total costs are expected to be significantly less than they would be if the proposed project were an independent R01. Supplement applications proposing secondary analyses of existing data, pilot studies, small clinical studies or any projects with total budgets (direct and indirect) less than $50,000 may follow an abbreviated application format outlined under Application Procedures. All other competitive supplement applications will be expected to utilize the usual application format for R01 submissions, irrespective of the size or duration of the requested support. This RFA may be re-issued in FY 1999. FUNDS AVAILABLE The estimated total costs (directs plus indirect costs) available for applications submitted in response to this RFA will be up to $1.5 million. The NIDR plans to support a total of up to 15 competitive supplements in response to this RFA in FYs 1998. The total number of awards will be contingent on the receipt of high quality competitive supplement applications and the availability of funds. Applications may not request more than three percent annual increases for inflation over subsequent years. Usual PHS policies governing grants administration and management will apply. Funding beyond the first and subsequent years of the supplement grant will be contingent upon satisfactory progress during the preceding year and the availability of funds. RESEARCH OBJECTIVES Background The HIV pandemic has already had a major impact on health and health care demands both world-wide and in the U.S. According to the World Health Organization, 22 million men, women and children are infected with HIV-1 worldwide, and the number of infected people is expected to exceed 40 million by the year 2000. It is estimated that 8,500 new HIV infections occur every day. The NIDR is already committed to supporting research projects on the oral manifestations of HIV infection and AIDS. Specifically, the Institute supports a modest number of studies examining biological mechanisms underlying the establishment of oral pathologies associated with HIV infection, as well as studies on the progression of the infection to AIDS in different patient groups. NIDR also supports studies characterizing the inhibitory salivary proteins and the importance of oral fluids as sources of HIV inhibitory factors and non-invasive diagnostic tests for HIV, identifying oral diagnostic markers for HIV, investigating the molecular events that transform candida and other oral organisms from non-pathogenic to pathogenic forms, sequencing the C. albicans genome, and developing new therapeutic strategies to combat reoccurrence of Candida infections. Also supported are studies on oral mucosal immunity, salivary leukocyte protease inhibitor (SLPI), mechanisms of retrovirus infection in exocrine tissue, and the use of transgenic mice and other methods to elucidate the effect of HIV infections on selected oral tissues. In order to identify future opportunities in the areas of AIDS research relevant to the mission of the NIDR an Ad Hoc Panel on AIDS Research was convened April 24-25, 1997. Panel members were drawn from academia, industry, NIDR Council, other NIH Institutes and Federal agencies. The panel indicated that the NIDR is uniquely positioned to pursue three important areas of AIDS research, namely those involving oral transmission of HIV, opportunistic infections of the oral cavity, and mucosal immunity and the development of vaccines. In addition, supplements to HIV and non-HIV grants to apply reagents, technologies and models for HIV were recommended. Research Objectives and Scope The overall objective of this RFA is to expand our understanding of the role of oral factors in HIV transmission, therapies, and outcomes by supplementing ongoing research grants. The following research topics are provided as examples that would extend research been funded by NIH in related areas. They are not listed in any priority order and are not intended to be inclusive or restrictive. Examine the role(s) that oral pathogens and oral co-morbidities play in potentiating infection with HIV or in influencing treatment outcomes, including response to the new antiretroviral therapies. Assess tissue responses in bronchial, vaginal, rectal and other mucosal sites as compared with the oral cavity in order to characterize unique and common immunological parameters critical to HIV infection and HIV-associated pathologies; explore the presence of chemokine receptors as well as the levels of cytokines in these sites. Assess viral load in oral fluids and compare with other body fluids (e.g., cervical/vaginal, breast milk, blood, semen) during both primary and chronic HIV infection to determine whether or not it is sufficient to provide a significant risk for infection via the oral route. Develop improved measures to prevent or reduce risks for oral HIV transmission (e.g., vertical transmission from HIV positive mothers to breast- feeding infants). Examine molecular mechanisms underlying HIV- associated immunosuppression resulting in oral complications; elucidate the molecular mechanisms by which HIV or HIV-associated immunosupression might affect the phenotypic variability and pathogenesis of candida and the reactivation of HCMV, HSV, HPV, EBV, and HHV8. Determine effects of antiretroviral therapies as related to oral manifestations of HIV infection or the expression of salivary genes and proteins; determine whether tonsilar or other oral tissues serve as a reservoir of HIV and monitor viral loads in specific oral tissues during antiretroviral therapies. Develop appropriate animal models and experimental strategies to assess events underlying characteristics of HIV infection within oral tissues and HIV- associated oral pathologies. Determine the pathogenesis of opportunistic oral infections and analyze select genomes (e.g., Candida and HHV8). Determine the prevalence and clinical correlates of neuropathic pain in medically and immunologically well-defined populations of HIV patients. Elucidate underlying mechanisms and test promising preventive or therapeutic interventions. Determine associations or common mechanisms which may exist between central manifestations of neurotoxicity, such as HIV-related dementia and the development of HIV-related neuropathic pain. Develop innovative, improved measures to prevent or treat oral symptoms impairing quality of life or causing discomfort/pain in patients undergoing therapies for HIV or living with HIV; characterize relationships between oral symptom relief and adherence to oral or systemic therapies. Develop appropriate, effective palliative measures for oral symptom management at the end of life or for use in settings such as hospices. Develop and test interventions utilizing oral health care settings or oral health personnel to deliver and reinforce health education messages pertinent to HIV prevention or risk reduction. Determine how oral symptoms (oral opportunistic infections, oral lesions, xerostomia) or dental treatments influence eating behaviors, nutritional status, or systemic health outcomes in HIV positive individuals. Characterize the roles of socioeconomic status, age, dental hygiene, behaviors, and poor nutrition in oral transmission. 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 of March 18, 1994, Volume 23, Number 11. LETTER OF INTENT Prospective applicants are asked to submit, by March 1, 1998, a letter of intent that includes a descriptive title of the proposed research; the name, mailing address, FAX number, email address, and telephone number of the Principal Investigator; the identifies of other key personnel and participating institutions and departments; and the number and title of this program announcement. Although a letter of intent is not required, is not binding, and does not enter into the review of a subsequent application, the information that it contains is helpful in planning for the timely review of the applications. It helps NIDR staff to estimate the potential review workload and to avoid possible conflicts of interest in the review. The letter of intent is to be addressed to Dr. Eleni Kousvelari at the address listed under INQUIRIES. APPLICATION PROCEDURES The grant application form PHS 398 (rev. 5/95) is to be used in applying for these competitive supplement grants. These forms are available at most institutional offices of sponsored research and may also 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 ASKNIH@od.nih.gov. The forms are also available on the NIH World Wide Web Home Page at https://grants.nih.gov/grants/funding/phs398/phs398.html. The RFA label available in the PHS 398 application kit must be affixed to the bottom of the face page of the original and the original must be placed on top of the entire package. Failure to use this label could result in delayed processing of the application such that it may no reach the review committee in time for review. In addition, in order to identify the application as a response to the RFA, the RFA title (Competitive Supplements: Oral Dimensions of HIV Transmission, Therapies, and Outcomes) and the number DE-98-001 must be typed in item 2 of the face page of the application form and the face page of the application form and the YES box must be checked. The instructions accompanying Form PHS 398 must be followed as far as possible. However, applicants submitting competitive supplements with direct costs budgets totaling less than $50,000 may follow an abbreviated application format as summarized below: o the research plan (specific aims, background, significance, preliminary studies, and research design and methods) may not exceed ten pages; o brief statements must be included indicating how the proposed supplement will utilize resources available through the parent project and providing assurance of access to collaborations or research resources available through the parent grant; o graphs, diagrams, tables, charts and photographs must be included in the body of the application. Applicants must attach a letter from the program official of the Institute or Center responsible for the parent grant indicating concurrence with the request for consideration of the supplement. Submit a signed, typewritten original of the application, including the Checklist, and three signed photocopies, in one package to: CENTER FOR SCIENTIFIC REVIEW (formerly Division of Research Grants) 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 copies of the application must also be sent to: Dr. H. George Hausch Extramural Program National Institute of Dental Research Natcher Building, Room 4AN-38D 45 Center Drive MSC 6402 Bethesda, MD 20892-6402 Applications must be received by the receipt date (March 26, 1998) in order to receive consideration for funding in FY98. REVIEW CONSIDERATIONS Review Procedures Upon receipt, applications will be reviewed for completeness by the Center for Scientific Review (CSR), NIH. Incomplete and/or unresponsive applications will be returned without further consideration. Applications that are complete and fit the requirements specified in this RFA will be evaluated for scientific and technical merit by a special emphasis panel convened by the Scientific Review Branch, NIDR. 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 the applications under review will be discussed, assigned a priority score, and receive a second level review by the National Advisory Dental Research Council. Review Criteria The five criteria to be used in the evaluation of grant applications are listed below (see NIH GUIDE, Vol. 26, No. 22, June 27, 1997). An additional criterion, specific for this RFA, evaluates the relevance of the supplement to overall aims of the parent grant, as well as the likelihood of integrating the supplemental study successfully into the ongoing research of the parent grant. To put the criteria in context, the following information is provided to the peer reviewers. 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 and 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. Relevance to the parent grant: Is this proposed competitive supplement relevant to the overall aims the parent grant? Are the plans for integrating the parent project and the supplement feasible? Is there evidence that the principal investigator of the parent project will provide appropriate cooperation and support to the investigator conducting the oral research component(s) supported by the supplement? Does the investigator proposing the supplement demonstrate an understanding of the strengths or limitations of data from the parent study, as directly pertinent to the proposed study? 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 analyses 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 methods? 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 will also examine the appropriateness of proposed budget and duration, the adequacy of plans to include both genders and minorities and their subgroups 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 The earliest anticipated date of award is September 30, 1998. Applicants should be aware that, in addition to scientific merit, program priorities and program balance, the total cost of the proposed project and the availability of funds will be considered by the NIDR staff and the National Advisory Dental Research Council in making funding recommendations. In addition, the NIDR values complementary funding from other public and private sources including foundations and industrial concerns. When applications have similar scientific merit, but vary in cost- competitiveness, the NIDR is likely to select the more cost-competitive application for funding. INQUIRIES Written, email, and telephone inquiries concerning this RFA are encouraged. The opportunity to clarify any issues or questions from potential applicants is welcome. For information concerning supplements which aim to focus on genetic, molecular, or biological aspects of oral response to HIV/AIDS please contact: Dr. Eleni Kousvelari Division of Extramural Research National Institute of Dental Research Natcher Building, Room 4AN 18A Bethesda, MD 20892-6402 Telephone: (301) 594-2427 FAX: (301) 480-8318 Email: kousvelari@de45.nidr.nih.gov Inquiries regarding applications on interventions within oral health care settings, of prevention and management of oral symptoms, including pain or inquires regarding applications addressing social, behavioral, cultural, epidemiological, economic, or environmental issues relevant to oral complications of HIV or HIV-associated neuropathies may contact: Dr. Patricia Bryant Division of Extramural Research National Institute of Dental Research Natcher Building, Room 4AN-24E Bethesda, MD 20892-6500 Telephone: (301) 594-2095 FAX: (301) 480-8318 Email: BryantP@DE45.nidr.nih.gov Inquiries regards grants management issues should be directed to: Mr. Martin R. Rubinstein Division of Extramural Research National Institute of Dental Research 45 Center Drive, Room 4AN-44A, MSC 6402 Bethesda, MD 20892-6402 Telephone: (301) 594-4800 Email: RubinsteinM@DE45.nidr.nih.gov Schedule Letter of Intent Receipt Date: March 1, 1998 Application Receipt Date: March 26, 1998 Scientific Review Date: June 1998 Advisory Council Date: September 1998 Earliest Award Date: September 30, 1998 AUTHORITY AND REGULATIONS This program is described in the Catalog of Federal Domestic Assistance No. 93.121. 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 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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