PAS-00-067: MEMBRANE PROPERTIES: EXPLORATION OF SPERM/MICROBE SUSCEPTIBILITY

Department of Health
and Human Services (HHS)

NIH... Turning Discovery Into Health^®

Note: For help accessing PDF, RTF, MS Word, Excel, PowerPoint, Audio or Video files, see Help Downloading Files.

MEMBRANE PROPERTIES: EXPLORATION OF SPERM/MICROBE SUSCEPTIBILITY Release Date: February 24, 2000 PA NUMBER: PAS-00-067 National Institute of Child Health and Human Development THIS PA 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 PA. PURPOSE The purpose of this program announcement is to encourage research to explore the similarities between membranes of spermatozoa and pathogens, and the properties that contribute to differential fusibility of membranes at the molecular level. The results may have implications for design of spermicidal microbicides for contraception and prevention of HIV and other viral or bacterial infections. The goal of this initiative is to discover membrane properties that spermatozoa share with a variety of pathogens, including HIV, that render them susceptible to attack by naturally occurring and synthetic antimicrobial peptides and other non-surfactant compounds. It has been hypothesized that these properties or components are related to spermatozoa and pathogens having externally fusible membranes, and that such properties are lacking in membranes that are resistant to external fusion. Research supported under this announcement would identify the components that cause spermatozoa, HIV, and other pathogens to be targets of antimicrobial agents that spare epithelial cells. Such information would be useful in the design of spermicides with microbicidal activity. Additionally, research to assess, at a molecular level, the process involved in cell fusion and the properties of membranes that aid in viral adsorption is encouraged. The intent is to develop a better understanding of the basic science of membrane fusion that could lead to more targeted drug design for antiviral/antibacterial spermicidal compounds. 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 Program Announcement (PA) is related to one or more of the priority areas. Potential applicants may obtain "Healthy People 2010" 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. MECHANISM OF SUPPORT This PA will use the National Institutes of Health (NIH) research project grant (R01) and small grant (R03) award mechanisms. 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 PA may not exceed five years for an R01 and two years for an R03. Specific application instructions have been modified to reflect "MODULAR GRANT" and "JUST-IN-TIME" streamlining efforts being examined by the NIH. Complete and detailed instructions and information on Modular Grant applications can be found at http://grants.nih.gov/grants/funding/modular/modular.htm. FUNDS AVAILABLE The NICHD intends to commit up to a total of $1 million per year in total costs (direct plus facilities and administrative [F&A] costs) to fund new grants in response to this PA. Awards are contingent upon the availability of funds and the receipt of a sufficient number of meritorious applications. This PA will remain active for three years, through the June 2003 application receipt date. RESEARCH OBJECTIVES Background Sexually transmitted diseases (STDs) are a major health problem throughout the world and human immunodeficiency virus type-1 (HIV-1) infection is spreading most rapidly due to heterosexual transmission to women. Thus, there is a need for more woman-controlled methods for prevention of infection with HIV and other STDs. Microbicides offer a potential alternative to physical barrier methods for prevention of HIV transmission. Development of effective microbicidal agents has been hindered by a variety of factors, including the lack of reliable animal models and constraints experienced in clinical testing. The challenge is to generate agents that target pathogens without damaging healthy tissue. Currently marketed spermicides are surfactants that dissolve cell membranes indiscriminately, affecting pathogens, sperm, and epithelial cells alike, often irritating or damaging vaginal epithelium. The ideal spermicidal microbicide would not affect epithelial cells while killing spermatozoa and pathogens. There may be similarities among spermatozoa, bacteria, and enveloped viruses that can be used to advantage. All have membranes that are capable of external membrane fusion, membrane fusion is an integral process for both fertilization and infection of cells, i.e., the sperm head is designed to fuse with the egg during fertilization, while bacteria and enveloped viruses fuse with somatic cell membranes. Additionally, infection of cells by some viruses alters the nature of the infected cell membrane, resulting in fusion between fusion-resistant cell types. In humans, for example, epithelial and other non-germ cells normally do not fuse with each other, although infection with some strains of syncytium-inducing viruses (including HIV), as well as other viruses, can cause cell fusion under one set of circumstances and not under others. Since the mechanism by which cell membranes are differentially susceptible to external fusion is not well understood, research on models of membrane fusion may offer opportunities to identify the critical components involved in the process. Additionally, research to identify the factors involving entry of the virus into cells, including the process of cell fusion, is needed. Theoretically, a substance that attacks cells with externally fusible membranes as well as enveloped viruses, while sparing cells with fusion- resistant membranes, could be an excellent spermicide/microbicide. Similarly, a compound that prevents viral fusion could be an effective antiviral agent. Thus, an understanding of the fusion mechanism could lead to a more rational drug design that is specifically directed toward fusion-enabling elements in cell, viral, and bacterial membranes. Scope of Research Applications are solicited for research designed to elucidate properties that account for differential fusibility of membranes. Factors that are common to membranes of spermatozoa and pathogenic organisms, but are absent in somatic cell membranes, are of special interest, because identification of such factors may lead to effective drug development. Possible candidates for such factors include glycosaminoglycans, lipid content, protein receptors, or other components. Additionally, factors that transform fusion-resistant membranes into fusible membranes, and mechanisms by which this occurs, could be explored. Research to develop model systems for sperm-egg, bacteria-cell, and virus-cell fusion may be supported within the scope of this program. Appropriate topics for investigation include, but are not limited to: o Membrane properties that spermatozoa share with a variety of pathogens, including HIV, that render these cells susceptible to attack by antimicrobial peptides or other non-surfactant compounds. o Factors that are common to membranes of spermatozoa and pathogens, but are absent in somatic cell membranes. o Differences between fusion-capable and fusion-resistant membranes in terms of glycosaminoglycans, lipid content, protein receptors, etc. o Properties of membranes that aid in viral or bacterial adsorption. o Factors, in addition to known fusion proteins, that transform fusion- resistant membranes into fusion-competent membranes, and mechanisms by which this transformation occurs. o Membrane properties that determine cell type dependence on induction of syncytia formation as a result of infection. 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 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 of March 18, 1994, Volume 23, Number 11, and available at: http://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/or 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," published in the NIH Guide for Grants and Contracts, March 6, 1998, and available at: http://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 also may provide additional relevant information concerning the policy. 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. Reviewers are cautioned that their anonymity may be compromised when they directly access an Internet site. APPLICATION PROCEDURES Applications are to be submitted on the grant application form PHS 398 (rev. 4/98) and will be accepted at the standard AIDS-related application receipt dates as indicated in the application kit. Application kits are available at most institutional offices of sponsored research, on the Internet at http://grants.nih.gov/grants/funding/phs398/phs398.html, and from the Division of Extramural Outreach and Information Resources, National Institutes of Health, 6701 Rockledge Drive, MSC 7910, Bethesda, MD 20892-7910, telephone 301-435-0714, E-mail: GrantsInfo@nih.gov. An applicant planning to submit an investigator-initiated new (Type 1), competing continuation (Type 2), competing supplement (Type 3), or any amended/revised version of the preceding grant application types, requesting $500,000 or more in direct costs for any year are advised that he or she must contact the Institute or Center (IC) program staff before submitting the application, i.e., as plans for the study are being developed. Furthermore, the applicant must obtain agreement from the IC staff that the institute will accept the application for consideration for award. Finally, the applicant must identify, in a cover letter sent with the application, the staff member and Institute or Center who agreed to accept assignment of the application. This policy requires an applicant to obtain agreement for acceptance of both any such application and any such subsequent amendment. Refer to the NIH Guide for Grants and Contracts, March 20, 1998 at http://grants.nih.gov/grants/guide/notice-files/not98-030.html. Special Instructions for Modular Grant 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 (rev. 4/98) is to be used in applying for these grants, with the modifications noted below. Modular Grant applications will request direct costs in $25,000 modules, up to a total direct cost request of $250,000 per year. (Applications that request more than $250,000 direct costs in any year must follow the traditional PHS 398 application instructions.) The total direct costs must be requested in accordance with the program guidelines and the modifications made to the standard PHS 398 application instructions described below: o FACE PAGE: Items 7a and 7b should be completed, indicating Direct Costs (in $25,000 increments up to a maximum of $250,000) 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 http://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. 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 F & A) 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 the 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: http://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. Submission Instructions The title and number of this program announcement must be typed on line 2 of the face page of the application form and the YES box must be marked. Submit a signed, typewritten 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) REVIEW CONSIDERATIONS Applications will be assigned on the basis of established PHS referral guidelines. Applications will be evaluated for scientific and technical merit by an appropriate scientific review group convened in accordance with the standard NIH peer review procedures. 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 applications under review, will be discussed, assigned a priority score, and 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 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 also will 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 also will 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. AWARD CRITERIA Applications will compete for available funds with all other recommended applications assigned to the NICHD. The following will be considered in making funding decisions: quality of the proposed project as determined by peer review, availability of funds, and program priority. INQUIRIES Inquiries are encouraged. The opportunity to clarify any issues or questions from potential applicants is welcome. Direct inquiries regarding programmatic issues to: Steven Kaufman, M.D., M.S. Center for Population Research National Institute of Child Health and Human Development 6100 Executive Blvd., Room 8B13, MSC 7510 Bethesda, MD 20892-7510 Telephone: 301-496-4924 FAX: 301-480-1972 E-mail: sck@nih.gov Diana Blithe, Ph.D. Center for Population Research National Institute of Child Health and Human Development 6100 Executive Blvd., Room 8B13, MSC 7510 Bethesda, MD 20892-7510 Telephone: 301-435-6990 FAX: 301-480-1972 E-mail: blithed@nih.gov Direct inquiries regarding fiscal matters to: Michael Loewe Grants Management Branch National Institute of Child Health and Human Development 6100 Executive Blvd., Room 8A17, MSC 7510 Bethesda, MD 20892-7510 Telephone: 301- 435-7008 FAX: 301-402-0915 E-mail: ml70m@nih.gov AUTHORITY AND REGULATIONS This program is described in the Catalog of Federal Domestic Assistance Nos. 93.866 and 93.864. Awards are made under authorization of Sections 301 and 405 of the Public Health Service Act, as amended (42 USC 241 and 284) 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 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, and 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.

Weekly TOC for this Announcement
NIH Funding Opportunities and Notices