IMPACT OF MICROBIAL INTERACTIONS ON INFECTIOUS DISEASES RELEASE DATE: March 11, 2002 RFA: AI-02-008 National Institute of Allergy and Infectious Diseases (NIAID) (http://www.niaid.nih.gov) LETTER OF INTENT RECEIPT DATE: May 21, 2002 APPLICATION RECEIPT DATE: June 21, 2002 THIS RFA CONTAINS THE FOLLOWING INFORMATION o Purpose of this RFA o Research Objectives o Mechanism(s) of Support o Funds Available o Eligible Institutions o Individuals Eligible to Become Principal Investigators o Where to Send Inquiries o Letter of Intent o Submitting an Application o Peer Review Process o Review Criteria o Receipt and Review Schedule o Award Criteria o Required Federal Citations: PURPOSE OF THIS RFA The Division of Microbiology and Infectious Diseases of the National Institute of Allergy and Infectious Diseases (NIAID) invites applications for research grants designed to develop innovative yet exploratory approaches that would contribute to our understanding of the mechanisms that impact on the virulence of infections involving two or more microorganisms or strains of microorganisms with the exception of HIV. Projects should include studies aimed at understanding the interactions of pathogens with the normal flora as well as the interactions among pathogens themselves, and how commensal organisms can be used to prevent or treat infections; however, this RFA is limited to those projects that involve or are based on intermicrobial interactions that have been well documented to occur in clinical settings. The development of co-infection models and the use of genomic and proteomic technologies to identify common virulence mechanisms and host response patterns is encouraged. The establishment of collaborative scientific teams with diverse backgrounds and approaches is strongly encouraged. Overall, a major focus of this RFA is an invitation to use new technology and to develop novel ideas for further studies. RESEARCH OBJECTIVES Background There is increasing evidence in the literature for the importance of polymicrobial infections in which microorganisms provide individual pathologies that may act in synergistic or inhibitory fashion, impacting on either tissue and host cell destruction, or the maintenance of health. Among these, bacteria-bacteria, virus-virus, parasite-parasite or virus-bacteria interactions have been well documented. For example, Helicobacter pylori can render individuals more or less susceptible to infection by certain enteric pathogens. Also, co-infection of Borrelia and Ehrlichia have been reported to enhance the severity and complicate the diagnosis of Lyme borreliosis. Further, the occurrence of multiple hepatotropic viruses influence the progression of the disease. In mice, schistosomiasis infections have been shown to be associated with exacerbated pathology during concomitant toxoplasmosis infections. Further, recent studies in mice support epidemiologic evidence of a synergistic interaction between Streptoccus pneumoniae and influenza virus; it has been suggested that such lethal synergy may account for excess mortality and meningitis during the influenza pandemics. It is conceivable that a viral or parasitic infection, for instance, may facilitate bacterial colonization and enhanced adherence to host cells paving the way for invasive disease. For example, a virus infection may induce host cell membrane changes such as the expression of viral glycoproteins that may serve as receptors for bacteria, or up-regulate platelet activating factor receptor thereby promoting increased bacterial adherence. Likewise, it is equally conceivable that a bacterial infection may pave the way for increased viral disease. Also, the ability of various bacteria in the microbial complex of the oral cavity to express surface molecules (e.g., bacteriocins) that specifically interact with other bacterial species and host cells has been suggested to be a critical determinant in plaque formation and structure. Indeed, a number of recent studies have focused on these research areas including those using experimental animal models; however, most of these studies are preliminary and need to be developed further. In future studies it will be important to examine the mechanisms associated with the actual pathogen-to-pathogen interaction within the same host environment that may lead to increased susceptibility. It is anticipated that a better understanding of the mechanisms involved in the observed clinical phenomena may provide opportunities to more critically evaluate the role of suspected virulence determinants involved in these mixed infections and the innate or specific host immune response patterns involved; these projects should also provide useful information for investigators in the development of more effective diagnostic, prevention and treatment strategies. Research Objectives and Scope A major focus of this RFA is to encourage investigators to develop novel yet exploratory approaches for examining polymicrobial interactions and to think beyond the one organism-one disease concept; it is hoped that the results of these projects would provide opportunities for future, more focused, research. Projects will be considered responsive to this RFA if the studies involve intermicrobial interactions (with the exception of HIV) that have been well- documented to occur in clinical settings or are based on clinically significant studies and are designed on the basis of sound scientific arguments with clearly defined endpoints such as profiles of immunological responses, synergizing metabolic activities or the inhibition/promotion of adherence to host cells. Thus, applications involving virus-virus, bacteria- bacteria, parasite-parasite, or virus-bacteria interactions, that demonstrate well-established links, would be considered responsive. Research studies to be investigated under this RFA are expected to develop new technologies and novel, mechanistic ideas for polymicrobial interactions. Projects to be examined include, but are not limited to the following: 1) Determination of whether an active viral or parasitic infection precedes a more severe bacterial infection or vice versa. 2) Definition of the environmental/physiological conditions that might contribute to the microbial synergy or inhibition. 3) Identification of microbial virulence genes and/or proteins that may be uniquely expressed during co-infection. 4) Evaluation of host response patterns, in response to single vs. multiple infections, required to elicit synergy or inhibition. 5) Characterization of the polymicrobial interactions associated with carriage of pathogens and those interactions that lead to invasion. 6) Examination of the use of commensal organisms in the prevention and treatment of infections (e.g. probiosis). MECHANISM OF SUPPORT The mechanism of support will be the Exploratory/Developmental Research Project Grant, R21. The total requested project period for an application submitted in response to this RFA may not exceed two years. As an applicant you will be solely responsible for planning, directing, and executing the proposed project. This RFA is a one-time solicitation. Future unsolicited, competing-continuation applications based on this project will compete with all investigator-initiated applications and will be reviewed according to the customary peer review procedures. NIAID uses R21 grants to provide short-duration support for preliminary studies of a highly speculative nature, which are expected to yield, within this time frame, sufficient information upon which to base a well-planned and rigorous series of further investigations. Applications will request direct costs in $25,000 modules. A typical modular grant application requests the same number of modules in each year. Funds and time requested should be appropriate for the research proposed. Applicants may not include travel or large equipment in the requested budget. It is hoped that successful grantees funded through this program will seek continuing support for research further through the R01 grant mechanism. Specific application instructions have been modified to reflect "MODULAR GRANT" and "JUST-IN-TIME" streamlining efforts that have been adopted by the NIH. Complete and detailed instructions and information on Modular Grant applications have been incorporated into the PHS 398 (rev. 5/01). Additional information on Modular Grants can be found at https://grants.nih.gov/grants/funding/modular/modular.htm. The anticipated award date is April 1, 2003. FUNDS AVAILABLE NIAID intends to commit approximately $3,000,000 in FY 2003 to fund 10 to 12 new and/or competitive continuation grants in response to this RFA. An applicant may request a project period of up to 2 years and a budget for direct costs of up to $150,000 per year. 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 NIAID 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 meritorious applications. At this time, it is not known if this RFA will be reissued. 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 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 inquiries concerning this RFA and welcome the opportunity to answer questions from potential applicants. Inquiries may fall into three areas: scientific/research, peer review, and financial or grants management issues: o Direct your questions about scientific/research issues to: Dr. Christopher E. Taylor Division of Microbiology and Infectious Diseases National Institute of Allergy and Infectious Diseases Room 3128, MSC-7630 6700-B Rockledge Drive Bethesda, MD 20892-7630 Telephone: (301) 496-5305 FAX: (301) 496-8030 E-Mail: ct18m@nih.gov o Direct your questions about peer review issues; address the letter of intent; mail two copies of the application and all five sets of appendices to: Gregory Jarosik, Ph.D. Division of Extramural Activities National Institute of Allergy and Infectious Diseases Room 2224, MSC-7616 6700-B Rockledge Drive Bethesda, MD 20892-7616 Telephone: (301) 496-0695 FAX: (301) 402-2698 E-Mail: gj67q@nih.gov o Direct your questions about financial or grants management matters to: Lesia Norwood Division of Extramural Activities National Institute of Allergy and Infectious Diseases Room 3221, MSC-7614 6700-B Rockledge Drive Bethesda, MD 20892-7614 Telephone: (301) 402-6581 Fax: (301) 480-3780 E-mail: ln5t@nih.gov LETTER OF INTENT Prospective applicants are asked to submit a letter of intent that includes the following information: o Descriptive title of the proposed research o Name, address, and telephone number of the Principal Investigator o Names of other key personnel o Participating institutions o Number and title of this RFA 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 IC staff to estimate the potential review workload and plan the review. The letter of intent is to be sent by the date listed at the beginning of this document. The letter of intent should be sent to: Gregory Jarosik, Ph.D. Division of Extramural Activities National Institute of Allergy and Infectious Diseases Room 2224, MSC-7616 6700-B Rockledge Drive Bethesda, MD 20892-7616 Telephone: (301) 496-0695 FAX: (301) 402-2698 E-Mail: gj67q@nih.gov SUBMITTING AN APPLICATION Applications must be prepared using the PHS 398 research grant application instructions and forms (rev. 5/2001). The PHS 398 is available at https://grants.nih.gov/grants/funding/phs398/phs398.html in an interactive format. For further assistance contact GrantsInfo, Telephone (301) 710-0267, Email: GrantsInfo@nih.gov. SUPPLEMENTAL INSTRUCTIONS FOR R21 APPLICATIONS: To apply, please follow NIH guidelines for submission of an R21 application as listed below: 1. The description (abstract) must include a brief explanation of the proposed activity, and how it is consistent with the exploratory/development nature of the R21 mechanism as described in this notice. 2. Although preliminary data are neither expected nor required for an R21 application, they may be included. 3. Sections a-d of the Research Plan may not exceed 10 pages, including tables and figures. 4. Appendix materials should be limited, as is consistent with the exploratory nature of the R21 mechanism, and should not be used to circumvent the page limit for the research plan. Copies of appendix material will only be provided to the primary reviewers of the application and will not be reproduced for wider distribution. The following materials may be included in the appendix: o Up to five publications, including manuscripts (submitted or accepted for publication), abstracts, patents, or other printed materials directly relevant to the project. These may be stapled as sets. o Surveys, questionnaires, data collection instruments, and clinical protocols. These may be stapled as sets. o Original glossy photographs or color images of gels, micrographs, etc., provided that a photocopy (may be reduced in size) is also included within the 10-page limit of items a-d of the research plan. Include five collated sets of all appendix material, in the same package with the application, following all copies of the application. Identify each item with the name of the principal investigator. SPECIFIC INSTRUCTIONS FOR MODULAR GRANT APPLICATIONS: Applications requesting up to $250,000 per year in direct costs must be submitted in a modular grant format. The modular 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 https://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 https://grants.nih.gov/grants/funding/modular/modular.htm. USING THE RFA LABEL: The RFA label available in the PHS 398 (rev. 5/2001) application form must be affixed to the bottom of the face page of the application. Type the RFA number on the label. 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 must be typed on line 2 of the face page of the application form and the YES box must be marked. The RFA label is also available at: https://grants.nih.gov/grants/funding/phs398/label-bk.pdf. SENDING AN APPLICATION TO THE NIH: Submit a signed, typewritten original of the application, including the Checklist, and three 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) At the time of submission, two additional exact copies of the grant application and all five sets of any appendix material must be sent to: Gregory Jarosik, Ph.D. Division of Extramural Activities National Institute of Allergy and Infectious Diseases Room 2224, MSC-7616 6700-B Rockledge Drive Bethesda, MD 20892-7616 APPLICATION PROCESSING: 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. PEER REVIEW PROCESS Upon receipt, applications will be reviewed for completeness by the CSR and responsiveness by NIAID. Incomplete applications will be returned to the applicant without further consideration. And, if the application is not responsive to the RFA, CSR staff may contact the applicant to determine whether to return the application to the applicant or submit it for review in competition with unsolicited applications at the next appropriate NIH review cycle. Applications that are complete and responsive to the RFA will be evaluated for scientific and technical merit by an appropriate peer review group convened by the NIAID in accordance with the review criteria stated below. As part of the initial merit review, all applications will: o Receive a written critique 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 second level review by the National Institute of Allergy and Infectious Diseases 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 your application in order to judge the likelihood that the proposed research will have a substantial impact on the pursuit of these goals: o Significance o Approach o Innovation o Investigator o Environment The scientific review group will address and consider each of these criteria in assigning your application's overall score, weighting them as appropriate for each application. Your 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. (1) SIGNIFICANCE: Does your study address an important problem? If the aims of your application are achieved, how do they advance scientific knowledge? 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? Do you acknowledge potential problem areas and consider alternative tactics? (3) INNOVATION: Does your project employ novel concepts, approaches or methods? Are the aims original and innovative? Does your project challenge existing paradigms or develop new methodologies or technologies? (4) INVESTIGATOR: Are you appropriately trained and well suited to carry out this work? Is the work proposed appropriate to your experience level as the principal investigator and to that of other researchers (if any)? (5) ENVIRONMENT: Does the scientific environment in which your 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? ADDITIONAL REVIEW CRITERIA: In addition to the above criteria, your application will also be reviewed with respect to the following: o PROTECTIONS: 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. o INCLUSION: 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. Plans for the recruitment and retention of subjects will also be evaluated. (See Inclusion Criteria included in the section on Federal Citations, below) o DATA SHARING: The adequacy of the proposed plan to share data. o BUDGET: The reasonableness of the proposed budget and the requested period of support in relation to the proposed research. RECEIPT AND REVIEW SCHEDULE Letter of Intent Receipt Date: May 21, 2002 Application Receipt Date: June 21, 2002 Scientific Peer Review Date: October, 2002 Advisory Council Date: January, 2003 Earliest Anticipated Award date: April, 2003 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. REQUIRED FEDERAL CITATIONS MONITORING PLAN AND DATA SAFETY AND MONITORING BOARD: Research components involving Phase I and II clinical trials must include provisions for assessment of patient eligibility and status, rigorous data management, quality assurance, and auditing procedures. In addition, it is NIH policy that all clinical trials require data and safety monitoring, with the method and degree of monitoring being commensurate with the risks (NIH Policy for Data Safety and Monitoring, NIH Guide for Grants and Contracts, June 12, 1998: https://grants.nih.gov/grants/guide/notice-files/not98-084.html). INCLUSION OF WOMEN AND MINORITIES IN CLINICAL RESEARCH: It is the policy of the NIH that women and members of minority groups and their sub-populations must be included in all NIH-supported clinical research projects unless a clear and compelling justification is provided indicating 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 clinical research should read the AMENDMENT "NIH Guidelines for Inclusion of Women and Minorities as Subjects in Clinical Research - Amended, October, 2001," published in the NIH Guide for Grants and Contracts on October 9, 2001 (https://grants.nih.gov/grants/guide/notice- files/NOT-OD-02-001.html); a complete copy of the updated Guidelines are available at https://grants.nih.gov/grants/funding/women_min/guidelines_amended_10_2001.htm. The amended policy incorporates: the use of an NIH definition of clinical research; updated racial and ethnic categories in compliance with the new OMB standards; clarification of language governing NIH-defined Phase III clinical trials consistent with the new PHS Form 398; and updated roles and responsibilities of NIH staff and the extramural community. The policy continues to require for all NIH-defined Phase III clinical trials that: a) all applications or proposals and/or protocols must provide a description of plans to conduct analyses, as appropriate, to address differences by sex/gender and/or racial/ethnic groups, including subgroups if applicable; and b) investigators must report annual accrual and progress in conducting analyses, as appropriate, by sex/gender and/or racial/ethnic group differences. INCLUSION OF CHILDREN AS PARTICIPANTS IN RESEARCH INVOLVING HUMAN SUBJECTS: ) The NIH maintains a policy 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 is available at https://grants.nih.gov/grants/funding/children/children.htm. REQUIRED EDUCATION ON THE PROTECTION OF HUMAN SUBJECT PARTICIPANTS: NIH policy requires education on the protection of human subject participants for all investigators submitting NIH proposals for research involving human subjects. You will find this policy announcement in the NIH Guide for Grants and Contracts Announcement, dated June 5, 2000, at https://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-039.html. HUMAN EMBRYONIC STEM CELLS (hESC): Criteria for federal funding of research on hESCs can be found at https://grants.nih.gov/grants/stem_cells.htm and at https://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-005.html. Only research using hESC lines that are registered in the NIH Human Embryonic Stem Cell Registry will be eligible for Federal funding (see http://escr.nih.gov). It is the responsibility of the applicant to provide the official NIH identifier(s)for the hESC line(s)to be used in the proposed research. Applications that do not provide this information will be returned without review. 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 https://grants.nih.gov/grants/policy/a110/a110_guidance_dec1999.htm. Applicants may wish to place data collected under this RFA 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 RFA, "Impact of Microbial Interactions on Infectious Diseases", is related to one or more of the priority areas. Potential applicants may obtain a copy of "Healthy People 2010" at http://www.health.gov/healthypeople. AUTHORITY AND REGULATIONS This program is described in the Catalogue of Federal Domestic Assistance in the following citations: No. 93.855, Immunology, Allergy, and Transplantation Research and No. 93.856, Microbiology and Infectious Diseases Research. 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 NIH Grants Policy Statement is available at https://grants.nih.gov/grants/policy/policy.htm. This document includes general information about the grant application and review process; information on the terms and conditions that apply to NIH Grants and cooperative agreements; and a listing of pertinent offices and officials at the NIH. 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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