SIMIAN MODELS FOR THE ORAL BIOLOGY OF HIV INFECTION AND AIDS-RELATED ORAL COMPLICATIONS RELEASE DATE: February 24, 2004 PA NUMBER: PAS-04-066 May 1, 2007 - This PA has been reissued as (PA-07-369). March 2, 2006 (NOT-OD-06-046) – Effective with the June 1, 2006 submission date, all R03, R21, R33 and R34 applications must be submitted through Grants.gov using the electronic SF424 (R&R) application. This announcement will stay active for only the May 1, 2006 AIDS and AIDS-related application submission date. The non-AIDS portion of this funding opportunity expires on the date indicated below. A replacement R21 (PA-06-260) funding opportunity announcement has been issued for the submission date of June 1, 2006 and submission dates for AIDS and non-AIDS applications thereafter. EXPIRATION DATE for R21 Non-AIDS Applications: March 2, 2006 EXPIRATION DATE for R21 AIDS and AIDS-Related Applications: May 2, 2006 Department of Health and Human Services (DHHS) PARTICIPATING ORGANIZATION: National Institute of Health (NIH) (http://www.nih.gov) COMPONENT OF PARTICIPATING ORGANIZATION: National Institute of Dental and Craniofacial Research (NIDCR) (http://www.nidcr.nih.gov) CATALOG OF FEDERAL DOMESTIC ASSISTANCE NUMBER(S): No. 93.121, Oral Diseases and Disorders Research THIS PA CONTAINS THE FOLLOWING INFORMATION o Purpose of the PA o Research Objectives o Mechanism(s) of Support o Eligible Institutions o Individuals Eligible to Become Principal Investigators o Where to Send Inquiries o Submitting an Application o Supplementary Instructions o Peer Review Process o Review Criteria o Award Criteria o Required Federal Citations PURPOSE OF THIS PAS This Program Announcement with set-aside funds (PAS) solicits applications that will use nonhuman primate models to study the oral biology of HIV infection and the oral complications associated with AIDS. This is an exploratory/developmental award with limited funding that is designed to maximize the use of animals currently involved in ongoing studies. Studies that will increase our knowledge of the basic biology, pathogenic mechanisms, immunology, diagnosis, treatment, and prevention of oral HIV/AIDS in simian macaque models are requested. Exploratory projects in emerging areas of importance for oral manifestations of AIDS and other acquired immunodeficiencies are of particular interest. It is expected that investigators will base their studies on recent developments in the field and will make use of the new and emerging state of the art technologies. RESEARCH OBJECTIVES Background: Research on the oral biology of HIV infection and oral complications associated with immunosuppression in general, and AIDS in particular, has been hampered by the lack of reliable in vitro and in vivo models that recapitulate human infections. Nonhuman primate models for AIDS however, have been shown to be useful in mother-to-infant transmission studies and evaluation of novel vaccine approaches as well as early immunologic events following simian immunodeficiency virus (SIV) and simian-human immunodeficiency virus (SHIV) infection. SIV/SHIV can induce fatal immunosuppression in macaques, closely resembling AIDS in humans, but with a shorter incubation period and a more aggressive course (acute model). Certain variants and constructs of SHIV have been shown to induce simian AIDS after prolonged exposure (chronic model). The virus progeny become neutralization resistant, acquire the ability to replicate in macrophages and maintain CXCR4 usage at later stages of disease. The latter variants have the potential to induce a disease course with pathogenesis that approximates that induced by HIV in humans. The acute and chronic models serve different purposes and are potentially invaluable for studying the oral biology of HIV infection, the oral complications associated with AIDS, and the interaction of innate and adaptive immune regulatory networks in virally-induced immunosuppression. The majority of HIV infections are initiated at mucosal sites. This is followed by progressive loss of local and systemic immune responses, which eventually lead to opportunistic infections that primarily affect mucosal surfaces. These occur despite the considerable innate and adaptive immune mechanisms of resistance expressed at and within mucosal surfaces exposed to infection. Among the mucosal routes of transmission that HIV uses to infect the host is the oral mucosal tissue. This route of infection has been shown in both humans and primates. HIV RNA and proteins can be detected directly in the mucosa, as well as in the saliva from infected subjects. However, infectious HIV virions are rarely found in the saliva, suggesting that the oral mucosa is not permissive for efficient HIV replication. Our understanding of HIV pathogenesis is far from complete as is our understanding of how other opportunistic pathogens (HHV-8, CMV, EBV, HPV and Candida) infect and cause the oral complications associated with AIDS. The ability of the oral cavity to resist HIV infection and replication while providing a safe haven for other pathogens provides a unique opportunity to dissect the differential patterns of host defenses. Several of the complications associated with opportunistic infections occurring in HIV-infected individuals were reported to occur in non human primates. For example, rhesus lymphocryptovirus, a simian homologue of human EBV, was shown to cause an simian AIDS-associated lymphoma that closely resembles pathologically and histologically that caused by EBV in AIDS- associated non-Hodgkin’s lymphoma; retroperitoneal fibromatosis-associated herpesvirus (RFHV), a simian homolog of Kaposi's sarcoma-associated herpesvirus (KSHV), induces pathology in macaques that has similarities to Kaposi's sarcoma; and, rhesus cytomegalovirus, the simian homolog of human CMV, infection, accelerates the state of immunosuppression induced by SIV in macaques and induces pathological changes in the immunocompromised animals similar to those induced by human CMV in AIDS patients. Scope: Nonhuman primate animal models are especially useful as their biological systems and genetic composition closely resembles those of man. The objective of this PAS is to encourage the solicitation of high risk/high impact exploratory/developmental studies that address HIV oral biology and AIDS-related oral complications in non human primate models for AIDS. Multidisciplinary collaborations are encouraged to achieve the desired goals. Examples of research responsive to this PAS are listed below but are by no means inclusive: o Characterize the oral complications of AIDS in macaques; o Determine the immunological, virological and biochemical basis of lesions induced by chronic viral infections of the oral cavity (e.g. papilloma virus, Kaposi sarcoma herpes virus, cytomegalovirus, etc.) in the context of SIV/SHIV infection; o Determine the structural, biological and functional properties of oropharyngeal mucosa that makes it resistant to HIV but susceptible to other viral pathogens; o Compare the structural, biological and functional properties of oral mucosa from infants and adults to define the developmental impact on the susceptibility to HIV infection; o Determine the early events occurring in the oral mucosa and oropharyngeal lymphoid tissues following acute infection with SHIV and investigate whether the oral mucosa permits entry, transcytosis, harboring and shedding of SHIV; o Characterize and compare the genetic and protein profiles of oral epithelial cells in healthy macaques and the SIV macaque-model of immunodeficiency; o Investigate and compare innate and adaptive immune networks of oral, vaginal, and rectal mucosal epithelial surfaces as they relate to SIV/SHIV infection; o Identify and compare salivary components from infant and/or adult macaques that interact with SHIV and possibly control susceptibility of oral epithelium to SIV infection; o Determine the impact of co-infections, inflammatory diseases, and tissue injury on mucosal susceptibility to SIV and development of AIDS; and, o Apply genomic and/or proteomic approaches to determine gene expression in control and infected animals. Due to the limitations of the award, it is expected that the applicants will establish collaborations with investigators using the simian model for AIDS in ongoing studies. The applicants should submit evidence of the collaborative agreements to use the animals and perform the studies. Abstracts of currently NIH funded projects using macaque models are available from the CRISP Database: http://crisp.cit.nih.gov/ . MECHANISM OF SUPPORT Applicants responding to this PAS must use the NIH Exploratory/Developmental Research Grant (R21) award mechanism. The total project period for an application in response to this PAS may not exceed two years, with a combined budget for direct costs of up to $275,000 for the two year period. For example, the applicant may request $100,000 in the first year and $175,000 in the second year. The request should be tailored to the needs of the project. Normally, no more than $200,000 may be requested in any single year. This R21 cap may be exceeded by $25,000, direct costs per year to accommodate the facilities and administrative (indirect) costs associated with collaborative research at another institution. Because the nature and scope of the proposed research will vary from application to application, it is anticipated that the size and duration of each award will also vary. Although the financial plans of the NIDCR provide support for this program, awards pursuant to this PAS are contingent upon the availability of funds and the receipt of a sufficient number of meritorious applications. The applicant will be solely responsible for planning, directing, and executing the proposed project. This PAS uses just-in-time concepts. It also uses the modular budgeting format. (see http://grants.nih.gov/grants/funding/modular/modular.htm). All applications submitted in response to this announcement must use the modular budget format. This program does not require cost sharing as defined in the current NIH Grants Policy Statement at http://grants.nih.gov/archive/grants/policy/nihgps_2001/part_i_1.htm. Exploratory/developmental grant support is for new projects only; competing continuation applications will not be accepted. Two revisions of a previously reviewed exploratory/developmental grant application may be submitted as defined in NIH Policy at http://grants.nih.gov/grants/policy/amendedapps.htm. FUNDS AVAILABLE NIDCR intends to commit approximately $800,000 each year in FY2004, FY2005 and FY2006 to fund up to four grants per year in response to this PAS. The usual PHS policies governing grants administration and management will apply. Although this program is provided for in the financial plans of the NIDCR, awards pursuant to this PAS are contingent upon the availability of funds for this purpose and the receipt of a sufficient number of applications of high scientific merit. ELIGIBLE INSTITUTIONS You may submit (an) application(s) if your institution has any of the following characteristics: o For-profit or non-profit organizations o Public or private institutions, such as universities, colleges, hospitals, and laboratories o Units of State and local governments o Eligible agencies of the Federal government o Domestic or foreign institutions/organizations INDIVIDUALS ELIGIBLE TO BECOME PRINCIPAL INVESTIGATORS Any individual with the skills, knowledge, and resources necessary to carry out the proposed research is invited to work with their institution to develop an application for support. Individuals from underrepresented racial and ethnic groups as well as individuals with disabilities are always encouraged to apply for NIH programs. WHERE TO SEND INQUIRIES We encourage your inquiries concerning this PAS and welcome the opportunity to answer questions from potential applicants. Inquiries may fall into two areas: scientific/research and financial or grants management issues: o Direct your questions about scientific/research issues to: Isaac R. Rodriguez-Chavez, Ph.D., M.S., M.H.S. Director, AIDS and Immunosuppression Program Division of Extramural Research, Integrative Biology and Infectious Diseases Branch, National Institute of Dental and Craniofacial Research 6701 Democracy Blvd., Rm. 614 Bethesda, MD 20892-4878 Telephone: (301) 594-7985 Fax: (301) 480-8319 Email: firstname.lastname@example.org o Direct your questions about financial or grants management matters to: Mary Daley Grants Management Branch National Institute of Dental and Craniofacial Research 45 Center Drive MSC 6402 Building 45, Room 4AN-44B Bethesda, MD 20892-6402 Phone: (301) 594-4808 Fax: (301) 480-3562 Email: email@example.com SUBMITTING AN APPLICATION Applications must be prepared using the PHS 398 research grant application instructions and forms (rev. 5/2001). Applications must have a Dun and Bradstreet (D&B) Data Universal Numbering System (DUNS) number as the Universal Identifier when applying for Federal grants or cooperative agreements. The DUNS number can be obtained by calling (866) 705-5711 or through the web site at http://www.dunandbradstreet.com/. The DUNS number should be entered on line 11 of the face page of the PHS 398 form. The PHS 398 is available at http://grants.nih.gov/grants/funding/phs398/phs398.html in an interactive format. For further assistance contact Grants Info, Telephone (301) 435-0714, Email: GrantsInfo@nih.gov. The title and number of this program announcement must be typed on line 2 of the application form and the YES box must be checked. APPLICATION RECEIPT DATES: Applications submitted in response to this PAS will be accepted at the standard AIDS application deadlines, which are available at http://grants.nih.gov/grants/dates.htm. Application deadlines are also indicated in the PHS 398 application kit. SPECIFIC INSTRUCTIONS: The page and appendix limits for R21 applications should be followed 1. RESEARCH PLAN: Items a-d may not exceed fifteen (15) pages, including tables and figures. The following information should be taken into account for items a, b and c: o Item a, SPECIFIC AIMS--The instructions for this section suggest that the applicant state "the hypotheses to be tested". Since some applications submitted in response to this RFA may also be design- or problem-driven (e.g., development of novel technologies), or need- driven (initial research to develop a body of data upon which future research will build), hypothesis testing per se may not be the driving force in developing such a proposal and, therefore, may not be applicable. The application should state the hypotheses, design, problem and/or need which will drive the proposed research. o Item b, BACKGROUND AND SIGNIFICANCE--In this section, it is important to identify clearly how the application addresses the specific objectives of this RFA and the purpose of the R21 mechanism. o Item c, PRELIMINARY STUDIES/PROGRESS REPORT—No preliminary data are required for an R21 application. 2. APPENDIX. Up to five articles may be submitted as appendix materials. SPECIFIC INSTRUCTIONS FOR MODULAR BUDGET GRANT APPLICATIONS: Applications must be submitted in a modular budget grant format. The modular budget grant format simplifies the preparation of the budget in these applications by limiting the level of budgetary detail. Applicants request direct costs in $25,000 modules. Section C of the research grant application instructions for the PHS 398 (rev. 5/2001) at http://grants.nih.gov/grants/funding/phs398/phs398.html includes step-by-step guidance for preparing modular grants. Additional information on modular grants is available at http://grants.nih.gov/grants/funding/modular/modular.htm. SENDING AN APPLICATION TO THE NIH: Submit a signed, original of the application, including the checklist, and five signed 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) APPLICATION PROCESSING: Applications must be mailed on or before the receipt dates described at http://grants.nih.gov/grants/funding/submissionschedule.htm. The CSR will not accept any application in response to this PAS 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 a substantial revision of an unfunded version of an application already reviewed, but such application must include an Introduction addressing the previous critique. Although there is no immediate acknowledgement of the receipt of an application, applicants are generally notified of the review and funding assignment within 8 weeks of submission. PEER REVIEW PROCESS Applications submitted for this PAS will be assigned on the basis of established PHS referral guidelines. Appropriate scientific review groups convened in accordance with the standard NIH peer review procedures (http://www.csr.nih.gov/refrev.htm) will evaluate applications for scientific and technical merit. As part of the initial merit review, all applications will: o Undergo a selection process in which only those applications deemed to have the highest scientific merit, generally the top half of applications under review, will be discussed and assigned a priority score o Receive a written critique o Receive a second level review by the appropriate national advisory council or board. 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 evaluate applications in order to judge the likelihood that the proposed research will have a substantial impact on the pursuit of these goals. The scientific review group will address and consider each of the following criteria in assigning the application’s overall score, weighting them as appropriate for each application: o Significance o Approach o Innovation o Investigator o Environment 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. 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? PROTECTION OF HUMAN SUBJECTS FROM RESEARCH RISK: The involvement of human subjects and protections from research risk relating to their participation in the proposed research will be assessed. (See criteria included in the section on Federal Citations, below). http://www.hhs.gov/ohrp/humansubjects/guidance/45cfr46.htm INCLUSION OF WOMEN, MINORITIES AND CHILDREN IN RESEARCH: The adequacy of plans to include subjects from both genders, all racial and ethnic groups (and subgroups), and children as appropriate for the scientific goals of the research will be assessed. Plans for the recruitment and retention of subjects will also be evaluated. (See Inclusion Criteria in the sections on Federal Citations, below). CARE AND USE OF VERTEBRATE ANIMALS IN RESEARCH: If vertebrate animals are to be used in the project, the five items described under Section f of the PHS 398 research grant application instructions (rev. 5/2001) will be assessed. ADDITIONAL REVIEW CONSIDERATIONS BUDGET: The reasonableness of the proposed budget and the requested period of support in relation to the proposed research. AWARD CRITERIA Funding decisions for this PAS will be based on: o Scientific merit of the proposed project as determined by peer review o Availability of funds o Relevance to program priorities o Evidence of collaborative agreements to use the animals and perform the studies REQUIRED FEDERAL CITATIONS ANIMAL WELFARE PROTECTION: Recipients of PHS support for activities involving live, vertebrate animals must comply with PHS Policy on Humane Care and Use of Laboratory Animals (http://grants.nih.gov/grants/olaw/references/PHSPolicyLabAnimals.pdf), as mandated by the Health Research Extension Act of 1985 (http://grants.nih.gov/grants/olaw/references/hrea1985.htm), and the USDA Animal Welfare Regulations (http://www.nal.usda.gov/awic/legislat/usdaleg1.htm), as applicable. PUBLIC ACCESS TO RESEARCH DATA THROUGH THE FREEDOM OF INFORMATION ACT: The Office of Management and Budget (OMB) Circular A-110 has been revised to provide public access to research data through the Freedom of Information Act (FOIA) under some circumstances. Data that are (1) first produced in a project that is supported in whole or in part with Federal funds and (2) cited publicly and officially by a Federal agency in support of an action that has the force and effect of law (i.e., a regulation) may be accessed through FOIA. It is important for applicants to understand the basic scope of this amendment. NIH has provided guidance at http://grants.nih.gov/grants/policy/a110/a110_guidance_dec1999.htm. Applicants may wish to place data collected under this PAS in a public archive, which can provide protections for the data and manage the distribution for an indefinite period of time. If so, the application should include a description of the archiving plan in the study design and include information about this in the budget justification section of the application. In addition, applicants should think about how to structure informed consent statements and other human subjects procedures given the potential for wider use of data collected under this award. 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. Furthermore, we caution reviewers 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 PAS is related to one or more of the priority areas. Potential applicants may obtain a copy of "Healthy People 2010" at http://www.healthypeople.gov/. AUTHORITY AND REGULATIONS: This program is described in the Catalog of Federal Domestic Assistance at http://www.cfda.gov/ and is not subject to the intergovernmental review requirements of Executive Order 12372 or Health Systems Agency review. Awards are made under the authorization of Sections 301 and 405 of the Public Health Service Act as amended (42 USC 241 and 284) and under Federal Regulations 42 CFR 52 and 45 CFR Parts 74 and 92. All awards are subject to the terms and conditions, cost principles, and other considerations described in the NIH Grants Policy Statement. The NIH Grants Policy Statement can be found at http://grants.nih.gov/grants/policy/policy.htm. The PHS strongly encourages all grant recipients to provide a smoke-free workplace and discourage the 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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