HOST IMMUNE RESPONSE TO OROPHARYNGEAL CANDIDIASIS Release Date: December 15, 1999 RFA: DE-00-001 National Institute of Dental and Craniofacial Research http://www.nidr.nih.gov/ Letter of Intent Receipt Date: February 15, 2000 Application Receipt Date: March 15, 2000 THIS RFA 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 RFA. PURPOSE The National Institute of Dental and Craniofacial Research (NIDCR) invites experienced and new investigators to submit research grant applications for basic and clinical investigations to further the understanding of the host immune response to oropharyngeal candidiasis (OPC). Research in this targeted area will improve our understanding of infection, virulence and host responses to OPC, and lead to improved diagnosis, prevention and treatment strategies. Collaborative projects that bring together investigators studying OPC in diverse scientific disciplines including microbiology, mycology, yeast genetics, innate and acquired immunology, biochemistry, pathology, genomic sequencing, imaging technology, and mathematical modeling are encouraged. Applications that include collaboration with foreign scientists conducting unique research on OPC are also encouraged. 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 Request for Applications (RFA), Host Immune Response to Oropharyngeal Candidiasis, is related to the priority area of Oral Health. Potential applicants may obtain a copy of "Healthy People 2000" at http://odphp.osophs.dhhs.gov/pubs/hp2000. 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. Although an application must be submitted from a single institution, collaborative arrangements with other institutions are encouraged MECHANISM OF SUPPORT This RFA will use the National Institutes of Health (NIH) research project grant (R01) award mechanism. Responsibility for the planning, direction, and execution of the proposed project will be solely that of the applicant. The total project period for an application submitted in response to this RFA may not exceed 5 years. This RFA 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. New investigators are strongly encouraged to apply. They should identify their status on the cover page for the application. The anticipated award date is September 29, 2000. FUNDS AVAILABLE The NIDCR intends to commit approximately $2 million in FY 2000 to fund 6 or 7 new and/or competitive continuation grants in response to this RFA. An applicant may request a project period of up to 5 years and a budget for direct costs of up to $200,000 per year. Applicants with collaborative agreements at other domestic universities can apply for direct costs of up to $225,000, since facilities and administrative (F&A) costs on the consortium are included in the direct costs of the applicant. Because the nature and scope of the research proposed may vary, it is anticipated that the size of each award will also vary. Although the financial plans of the NIDCR provide support for this program, awards pursuant to this RFA are contingent upon the availability of funds and the receipt of a sufficient number of applications of outstanding scientific and technical merit. RESEARCH OBJECTIVES Background Oropharyngeal candidiasis (OPC) (oral candidiasis, or thrush) occurs as an overgrowth of Candida, a yeast normally found in low numbers on the mucus membranes of the mouth and throat. Disturbance in the commensal flora of the oral cavity or inadequate host immunity provides favorable conditions for OPC to occur. Those at highest risk of OPC include persons with immunodeficiency (e.g. HIV-infected, AIDS), patients receiving antibiotics, or chemotherapy, neonates, diabetics, smokers and denture wearers. OPC can lead to blood stream infections with subsequent severe and even fatal systemic diseases such as endocarditis, septicemia and meningitis. OPC affects quality of life in that the white patches in the mouth are not only esthetically displeasing but also are associated with painful lesions that causes difficulty in chewing and swallowing, and thus affect nutrition. An increase in the incidence of OPC was seen during the first part of the last decade as a result of the human immunodeficiency virus (HIV) type 1 epidemic. In one prospective study 84% of HIV infected patients had oropharyngeal colonization by Candida species on at least one occasion and 55% developed clinical thrush. Candida albicans is the organism isolated from most patients although other yeasts may sometimes cause clinical disease. Most OPC infections are endogenously acquired, although in some cases, Candida can be transmitted from person to person. While the incidence of OPC has decreased as a result of combined therapy, OPC is still an independent predictor of immunodeficiency in patients who have AIDS and may also be a predictor in patients with debilitated immune systems due to other disease processes. OPC is commonly treated with topical or systemic antifungal agents that ameliorate the disease, but do not necessarily eradicate colonization. Thus, clinical recurrence of the disease is common. It has been recently reported that azole drugs are failing to contain recurrent cases of OPC indicating that some Candida organisms may be developing drug resistance. Other factors that might play a role in clinical resistance are diminished cellular immunity, drug interactions, or decreased drug absorption. Re-establishment of cellular immunity reduces the incidence of OPC, providing hope that immunotherapies can be used to control this disease. The infective Candida strains tend to be genetically identical over time. It has been reported that the same strain of Candida was isolated from 11 of 17 patients with recurrent OPC infections, as measured by DNA probe analysis. Another study has shown that 60% of patients were colonized with one dominant strain of C. albicans and 74% of those patients were re-colonized with the same strain even after fungal therapy. The strain of Candida that most commonly infects HIV positive patients also causes disease in those patients who do not have HIV infection. These findings suggest that effective therapies, including immunization, might be targeted against selected strains of Candida that cause OPC. The precise immunologic processes that control OPC in humans are not known. Research shows that innate immunity, including complement, histatins, defensins, and neutrophils, as well as adaptive immunity (antibodies and cellular immunity) are involved in host protection. Immunological responses might also participate in the pathogenesis of OPC. Inflammation and tissue damage can also occur as a result of allergic or specific immune responses to Candida antigens. Host immunity to OPC represents an important yet understudied area for new research. An improved awareness of the underlying mechanisms of host defense to Candida should lead to more effective diagnostic approaches and provide a better means of prevention and treatment for these organisms. The studies might ultimately lead to development of safe and effective vaccines. Understanding the host response may lead to new ideas about the management of this disease through immunotherapy or stem cell reconstitution. Research Objectives and Scope Research proposals submitted in response to this RFA must demonstrate that they are relevant to OPC and one or more of the following immunological topics: ? Candida antigenicity ? Candida genetics (as it relates to immunity) ? Inflammation or wound healing ? Neutrophils, macrophages, or other leukocytes ? Innate immunity ? Humoral immunity ? Cellular immunity ? Mucosal immunity ? Hypersensitivities/allergies ? Tolerance ? Autoimmunity ? Immunization (passive or active) ? Immunodeficiency ? Immunogenetics Basic, clinical, epidemiological and behavioral research could be responsive to this RFA. Although appropriate animal models may be used to acquire and evaluate the experimental data obtained, the development of a new animal model should not be the major focus of proposals submitted in response to this RFA. Studies addressing solely the structure, physiology or genetics of Candida albicans would not be responsive to this RFA. SPECIAL REQUIREMENTS Awardees will be invited to attend a meeting to present the progress of the work funded under this program. Details of this meeting will be provided post-award. Applicants should include travel funds in their budgets for a two-day meeting every year, most likely to be held in Bethesda, Maryland, to meet with other NIDCR-supported researchers studying the oral complications of HIV-infection and AIDS. Applicants should also include a statement in their applications indicating their willingness to participate in these meetings. INCLUSION OF WOMEN AND MINORITIES IN RESEARCH INVOLVING HUMAN SUBJECTS It is the policy of the NIH that women, 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 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", published in the Federal Register of March 28, 1994 (FR 59 14508-14513), and in the NIH Guide for Grants and Contracts, Vol. 23, No. 11, March 18, 1994, available on the web at: https://grants.nih.gov/grants/guide/notice-files/not94-100.html. 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: https://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. LETTER OF INTENT Prospective applicants are asked to submit a letter of intent that includes a descriptive title of the proposed research, the name, address, and telephone number of the Principal Investigator, the identities of other key personnel and participating institutions, and the number and title of the RFA in response to which the application may be submitted. 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 allows NIDCR staff to estimate the potential review workload and avoid conflict of interest in the review process. The letter of intent receipt date is listed in the heading of this RFA and is to be sent to the program staff listed under INQUIRIES. 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 (revised 4/98) is to be used in applying for these grants, with the modifications noted below. BUDGET INSTRUCTIONS Modular Grant applications will request direct costs in $25,000 modules, up to a total direct cost request of $200,000 per year ($225,000 for applicants with consortium arrangements with other domestic universities.) The modular budget request must be in accordance with the modifications made to the standard PHS 398 application instructions described below: PHS 398 o FACE PAGE: Items 7a and 7b should be completed, indicating Direct Costs (in $25,000 increments up to a maximum of $200,000) 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 https://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 key 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 key personnel, and the role on the project. Indicate whether the collaborating institution is foreign or domestic. The total cost for a consortium/contractual arrangement is included in the overall requested modular direct cost amount. Include a 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: https://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. o 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. The RFA label available in the PHS 398 (rev. 4/98) application form must be affixed to the bottom of the face page of the application. 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. In addition, the RFA title and number (DE-00-001) must be typed on line 2 of the face page of the application form and the YES box must be marked. The RFA number must be typed on the label as well. The sample RFA label is available at: https://grants.nih.gov/grants/funding/phs398/label-bk.pdf has been modified to allow for this change. Please note this is in pdf format. The NIAID also has active basic and clinical research programs focused on candidiasis, and will accept assignments in accordance with referral guidelines. Submit a signed, typewritten original of the application, including the Checklist, and three (3) signed, photocopies, in one package to: CENTER FOR SCIENTIFIC REVIEW NATIONAL INSTITUTES OF HEALTH SUITE 1040 6701 ROCKLEDGE DRIVE, MSC 7710 BETHESDA, MD 20892-7710 BETHESDA, MD 20817 (for express/courier service) The telephone number is (301) 435-0715. At the time of submission, two (2) additional copies of the application must be sent to: Dr. H. George Hausch Scientific Review Branch Division of Extramural Research National institute for Dental and Craniofacial Research 45 Center Drive, Room 4AN-38D- MSC 6402 Bethesda, MD 20892-6402 Applications must be received by the application receipt date listed in the heading of this RFA. If an application is received after that date, it will be returned to the applicant without review. The Center for Scientific Review (CSR) will not accept any application in response to this RFA that is essentially the same as one currently pending initial review, unless the applicant withdraws the pending application. The CSR will not accept any application that is essentially the same as one already reviewed. This does not preclude the submission of substantial revisions of applications already reviewed, but such applications must include an introduction addressing the previous critique. REVIEW CONSIDERATIONS Upon receipt, applications will be reviewed for completeness and responsiveness by the CSR and NIDCR. 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 NIDCR in accordance with the review criteria stated below. As part of the initial merit review, a process will be used by the initial review group in which applications 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 and Craniofacial Research Council. Review Criteria The goals of NIH-supported research are to advance our understanding of biological systems, improve the control of disease, and enhance health. In the written comments reviewers will be asked to discuss the following aspects of the application 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 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 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 analyses 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 method? 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? In addition to the above criteria, in accordance with NIH policy, all applications will also be reviewed with respect to the following: o The adequacy of plans to include both genders, minorities and their subgroups, and children as appropriate for the scientific goals of the research. Plans for the recruitment and retention of subjects will also be evaluated. o The reasonableness of the proposed budget and duration in relation to the proposed research o The adequacy of the proposed protection for humans, animals or the environment, to the extent they may be adversely affected by the project proposed in the application. SCHEDULE: Letter of Intent Receipt Date: February 15, 2000 Application Receipt Date: March 15, 2000 Peer Review Date: May 2000 Council Review: August 2000 Earliest Anticipated Start Date: September 29, 2000 AWARD CRITERIA Award criteria that will be used to make award decisions include: o-scientific merit (as determined by peer review) o-availability of funds o-programmatic priorities. INQUIRIES Inquiries concerning this RFA are encouraged. The opportunity to clarify any issues or questions from potential applicants is welcome. Direct inquiries regarding programmatic issues to: Denise Anne Russo, Ph.D. Infectious Diseases and Immunity Branch Division of Extramural Research, National Institute of Dental and Craniofacial Research 45 Center Drive, Room 4AN-18B Bethesda, MD 20892-6402 Telephone: (301) 594-2617 FAX: (301) 480-8318 Email: Denise.Russo@nih.gov Direct inquiries regarding fiscal matters to: Mr. Kevin Crist Grants Management Branch Division of Extramural Research National Institute of Dental and Craniofacial Research 45 Center Drive, Room 4AN-44A, MSC 6402 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. 93.121, 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 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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