Full Text HL-97-010 ROLE OF RESPIRATORY INFECTIONS IN CHILDHOOD ASTHMA NIH GUIDE, Volume 26, Number 21, June 20, 1997 RFA: HL-97-010 P.T. 34, AA Keywords: Asthma Pulmonary Diseases Immunology Biology, Cellular Biology, Molecular National Heart, Lung, and Blood Institute National Institute of Allergy and Infectious Diseases Letter of Intent Receipt Date: October 24, 1997 Application Receipt Date: December 11, 1997 This RFA uses "Modular Grant" and "Just-In-Time" concepts. This full RFA includes detailed modifications to standard application instructions and must be used when preparing applications in response to this RFA. PURPOSE The National Heart, Lung, and Blood Institute (NHLBI) and the National Institute of Allergy and Infectious Diseases (NIAID) invite grant applications for research on the cellular and molecular mechanisms by which respiratory pathogens contribute to the development of, exacerbation of, or protection from childhood asthma. 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), "Role of Respiratory Infections in Childhood Asthma," is related to the priority area of Chronic Disabling Conditions. Potential applicants may obtain a copy of "Healthy People 2000" (Full Report: Stock No.017-001-00474-0 or Summary Report: Stock No. 017-001-00473-1) through the Superintendent of Documents, Government Printing Office, Washington, DC 20402-9325 (telephone 202-512-1800). ELIGIBILITY REQUIREMENTS Among the disciplines and expertise that may be appropriate for this research program are microbiology, virology, molecular biology, cell biology, immunology, molecular immunology, infectious diseases, allergy, asthma, genetics, pulmonary medicine, pulmonary physiology, and pediatrics. Applications may be submitted by domestic and foreign, for-profit and non-profit organizations, public and private, such as universities, colleges, hospitals, laboratories, units of State or local governments, and eligible agencies of the Federal government. Racial/ethnic minority individuals, women, and persons with disabilities are encouraged to apply as Principal Investigators. All current policies and requirements that govern the research grant programs of the National Institutes of Health (NIH) will apply to grants awarded under this RFA. Awards under this RFA to foreign institutions will be made only in accordance with PHS policy governing such awards. MECHANISM OF SUPPORT This RFA will use the NIH individual research project grant (R01) mechanism of support. Investigators without prior R29 or R01 support are encouraged to apply for this RFA and to state this in a cover letter. Specific R01 application instructions have been modified to reflect "Modular Grant" and "Just-In-Time" streamlining efforts being examined by the NIH. 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, applicant institutions, reviewers, and Institute staff. While multidisciplinary approaches are encouraged, it is not the intent of this announcement to solicit applications for large studies encompassing a variety of individual subprojects, i.e., program projects. If collaborative arrangements through subcontracts with other institutions are planned, consult the program staff listed under Inquiries. For this RFA, funds must be requested in $25,000 direct cost modules and a maximum of nine modules ($225,000 direct costs) per year may be requested. A feature of the modular grant concept is that no escalation is provided for future years, and all anticipated expenses for all years of the project must be included within the number of modules being requested. Only limited budgetary information will be required and any budget adjustments made by the Initial Review Group will be in modules of $25,000. Instructions for completing the Biographical Sketch have also been modified. In addition, Other Support information and the application Checklist page are not required as part of the initial application. If there is a possibility for an award, necessary budget, Other Support and Checklist information will be requested by NHLBI or NIAID staff following the initial review. The Application Procedures section of this RFA provides specific details of modifications to standard PHS 398 application kit instructions. Applicants are expected to furnish their own estimates of time required to achieve the objectives of the proposed research project. Since a variety of approaches would represent valid responses to this RFA, it is anticipated that there will be a range of costs among individual grants awarded. Up to 5 years of support may be requested on R01 applications. This RFA is a 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. It is anticipated that support for this program will begin in July, 1998. Administrative adjustments in project period and/or amount may be required at the time of the award. Applicants from institutions that have a General Clinical Research Center (GCRC) funded by the NIH National Center for Research Resources may wish to identify the GCRC as a resource for conducting the proposed research. If so, a letter of agreement from either the GCRC program director or principal investigator should be included with the application. FUNDS AVAILABLE It is anticipated that for fiscal year 1998, $ 2.4 million (total costs) will be committed by the NHLBI and $0.5 million will be committed by NIAID to fund applications submitted in response to this RFA. Award of grants pursuant to this RFA is contingent upon availability of such funds for this purpose. It is anticipated that approximately 8 new grants will be awarded under this program. The specific number to be funded will, however, depend on the merit and scope of the applications received and on the availability of funds. Direct costs will be awarded in modules of $25,000, less any overlap or other necessary administrative adjustments. Indirect costs will be awarded based on the negotiated rates. Applicants may request up to 5 years of support. RESEARCH OBJECTIVES Background Asthma often starts early in life; however, the characteristic features of childhood asthma have not been clearly defined. Important clues to the etiology of the disease are missing. A major issue in childhood asthma relates to the role of infections in the development and persistence of asthma. Clinical and epidemiologic data suggest that viral respiratory infections and exposure to allergens, together with the genetic background of the host, are the most important risk factors early in life that may lead to wheezing, prolonged alterations in airway function, and the development of persistent asthma. Once asthma is established, recurrent viral infections are a major cause of asthma exacerbations in children and adults. Since most children who develop asthma have elevated IgE levels and have a history of early respiratory infections, an interplay between respiratory infections and allergens may operate in the development of asthma. On the other hand, it has been suggested that the immune response to childhood tuberculosis and other infections may actually protect against asthma and allergic disease. Alternatively, some individuals may be genetically predisposed to mount strong protective immune responses on exposure to certain infectious agents and these same individuals may be genetically predisposed to have a reduced capacity to develop allergic responses. The timing, duration, and frequency of exposure to infectious agents may affect the capacity of these agents to act as protagonists or protectors in the development and persistence of asthma. With currently available techniques in cellular and molecular biology, it is now possible to study the mechanisms by which some infections trigger asthma while other infections protect against the development of asthma. Also, studies on the role of respiratory infections in the development of asthma may shed light on whether respiratory infections have different functional and/or pathologic consequences, depending on whether they occur early or late in life. Research Scope: This RFA is designed to address the cellular and molecular mechanisms by which respiratory pathogens trigger or protect from the exacerbation and/or development of asthma. Areas of investigation relevant to the objectives of this RFA include, but are not limited to, the following: (1) Molecular mechanisms of infection-induced airways inflammation and remodeling. The precise pathway(s) of pathogen-induced airways inflammation and remodeling including the production of cytokines, adhesion molecules, and other inflammatory mediators in airway and nasal target tissues should be characterized. Among the specific questions that need to be addressed are: What are the mechanisms underlying the a) development, b) exacerbation, and/or c) protection from asthma by respiratory pathogens? Are there distinct mechanisms and biochemical pathways that distinguish respiratory infectious agents that mediate protection from versus exacerbation of asthma? Are there definable signal transduction and/or transcriptional activation pathways that mediate the induction of inflammation and/or airway wall remodeling that lead to or protect from asthma that are specific for particular respiratory pathogens? Will inhibition of the biochemical pathways induced by the infectious agents alter tissue inflammation, remodeling or physiologic function ? What are the precise pathway(s) of pathogen entry? What is the profile of pathogen gene expression, and what mechanisms regulate its expression? How does interaction of the pathogen with the host lead to the development of, exacerbation of, or protection from asthma? (2) The effect of pathogen-allergen interactions on sensitization, inflammation, and airway wall remodeling. Allergens may induce quantitatively or qualitatively different immune and inflammatory responses in the setting of respiratory infection. The mechanisms by which pathogens modulate either the production of Th1 versus Th2 cytokines, or other events in sensitization, should be evaluated in atopic and non-atopic individuals and appropriate animal models. The mechanisms by which interactions of pathogen with allergen modulate pathogen-induced and/or allergen-induced inflammatory responses and airway remodeling should also be evaluated. What interrelationships exist between the allergic diathesis and respiratory infections? Does the timing of an infection(s) make a difference? Does the dose and type of allergen presented modulate the immune/inflammatory (Th1 versus Th2) pathway? Do differing exposures to respiratory pathogens, and their frequency, modify the immune response? Do particular infections predispose to the development of a Th2-type response leading to asthma? Do others lead to protection from asthma? Do pathogen-induced airway inflammation and remodeling influence the generation of the asthmatic diathesis? If so, what are the mechanisms of these pathogen-induced effects, what are the temporal requirements for their elicitation and their regulatory mechanisms? These are examples only. Investigators are not limited to the subjects mentioned above and are encouraged to submit other topics pertinent to the objectives of the RFA. While studies involving children are desirable, investigations with young adults or with mammalian models will also be suitable for addressing the mechanistic information sought in this RFA. Investigators proposing studies using animal models must provide evidence that they are relevant to both asthma and human respiratory infections. An application addressing fundamental aspects of pathogen gene expression will be responsive to this RFA only if it can demonstrate relevance to the development of, exacerbation of, or protection from asthma. Special Requirements Upon initiation of the program, the NHLBI and NIAID will co-sponsor periodic meetings to encourage exchange of information among investigators who participate in this program. In the budget of the grant application, travel funds for a one day meeting each year, most likely to be held in Bethesda, Maryland, should be included in the modules. Applicants should also include a statement in their applications indicating their willingness to participate in these meetings. Applications that are primarily descriptive or epidemiological that do not propose hypothesis driven studies directed at understanding the mechanisms by which respiratory infections trigger or protect from asthma will not be acceptable. Applications that focus on these mechanisms at the molecular level are of particular interest. Although studies in human subjects are strongly encouraged, large clinical studies are not within the scope of this RFA. Applicants who propose to test hypotheses in animal or in vitro models must provide a strong rationale for relevance to the human host. This program will not support studies directed at development of animal models alone. INCLUSION OF WOMEN AND MINORITIES IN RESEARCH INVOLVING HUMAN SUBJECTS It is the policy of the NIH that women and members of minority groups and their subpopulations must be included in all NIH supported biomedical and behavioral research projects involving human subjects, unless a clear and compelling rationale and justification is provided that inclusion is inappropriate with respect to the health of the subjects or the purpose of the research. This policy results from the NIH Revitalization Act of 1993 (Section 492B of Public Law 103-43). All investigators proposing research involving human subjects should follow the "NIH Guidelines for Inclusion of Women and Minorities as Subjects in Clinical Research", which have been published in the Federal Register of March 28, 1994 (FR 59 14508-14513), and in the NIH Guide for Grants and Contracts of March 18, 1994, Volume 23, Number 11. LETTER OF INTENT Prospective applicants are asked to submit, by October 24, 1997, 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 subsequent applications, the information that it contains allows NIH staff to estimate the potential review workload and to avoid conflict of interest in the review. The letter of intent is to be faxed or sent to: C. James Scheirer, Ph.D. Division of Extramural Affairs National Heart, Lung, and Blood Institute 6701 Rockledge Drive, Room 7220 Bethesda, MD 20892-7924 Telephone: (301) 435-0266 FAX: (301) 480-3541 APPLICATION PROCEDURES The research grant application form PHS 398 (rev 5/95) is to be used in applying for these grants. Applications kits are available at most institutional offices of sponsored research and may be obtained from the Division of Extramural Outreach and Information Resources, National Institutes of Health, 6701 Rockledge Drive, MSC 7910, Bethesda, MD 20892-7910, telephone 301/710-0267, email: ASKNIH@odrockm1.od.nih.gov. The RFA label found in the phs 398 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 must be typed on line 2 of the face page of the application form and the yes box must be marked. This RFA is restricted to R01 grants. All will be awarded as modular grants. The modular grant concept establishes specific modules (increments) in which direct costs may be requested and a maximum level for requested direct cost. Only limited budgetary information is required in the application; a detailed budget need not be provided. Sample budgets and justification page will be provided upon request or following the submission of a letter of intent. Budget 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: Detailed budget for the initial budget period Do not complete Form Page 4 of the PHS 398 (rev 5/95). It is not required nor will it be accepted at the time of application. Budget for the entire proposed period of support Do not complete the categorical budget tables on Form page 5 of the PHS 398 (rev. 5/95). Only the requested total direct costs line for each year must be completed based on the number of $25,000 modules being requested. Applicants may not request a change in the amount of each module. A maximum of Nine modules ($225,000 direct costs) per year may be requested and each applicant may request up to Five years of support for this RFA. Direct cost budgets will remain constant throughout the life of the project (i.e., the same number of modules requested for all budget periods). Any necessary escalation should be considered when determining the number of modules to be requested. However, in the event that the number of modules requested must change in any future year due to the nature of the research proposed, appropriate justification must be provided. Total Direct Costs for the Entire Proposed Project Period should be shown in the box provided. Budget Justification Budget justifications should be provided under "Justifications" on Form Page 5 of the PHS 398. List the names, role on the project and proposed percent effort for all project personnel (salaried or unsalaried)and provide a narrative justification for each person based on his/her role on the project. Identify all consultants by name and organizational affiliation and describe the services to be performed. Provide a general narrative justification for individual categories (equipment, supplies, etc.) required to complete the work proposed. More detailed justifications should be provided for high cost items. Any large one-time purchases, such as large equipment requests, must be accommodated within these limits. Consortium/contractual costs - If collaborations or subcontracts are involved that require transfer of funds from the grantee to other institutions, it is necessary to establish formal subcontract agreements with each collaborating institution. A letter of intent from each collaborating institution should be submitted with the application. Only the percentage of the consortium/contractual Total Costs (direct and indirect) relative to the total Direct Costs of the overall project needs to be stated at this time. The following example should be used to indicate the percentage cost of the consortium, "The consortium agreement represents 27% of overall $175,000 direct costs requested in the first year." A budget justification for the consortium should be provided as described in the "Budget Justification" section above (no Form Page 5 required for the consortium). Please indicate whether the consortium will be in place for the entire project period and identify any future year changes in the percentage relative to the parent grant. If there is a possibility for an award, the applicant will be requested to identify actual direct and indirect costs for all years of the consortium. Please note that total subcontract costs need not be calculated in $25,000 modules. However, when subcontract funds are added to the parent grant budget, the total direct cost amount must be included in the number of $25,000 modules requested. Biographical Sketch - A biographical sketch is required for all key personnel, following the modified instructions below. Do not exceed the two-page limit for each person. Complete the educational block at the top of the form page; List current position(s) and those previous positions directly relevant to the application; List selected peer-reviewed publications directly relevant to the proposed project, with full citation; The applicant has the option to provide information on research projects completed and/or research grants participated in during the last five years that are relevant to the proposed project. Other Support - Do not complete the "Other Support" pages (Form Page 7). Selected other support information relevant to the proposed research may be included in the Biographical Sketch as indicated above. Complete Other Support information will be requested by NHLBI or NIAID staff if there is a possibility for an award. Checklist - No "Checklist" page is required as part of the initial application. A completed Checklist will be requested by NHLBI or NIAID staff if there is a possibility for an award. 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. Applications not conforming to these guidelines will be considered unresponsive to this RFA and will be returned without further review. Submit a signed, typewritten original of the application and three signed, photocopies, in one package to: Division of Research Grants National Institutes of Health 6701 Rockledge Drive, room 1040 - MSC 7710 Bethesda, MD 20892-7710 Bethesda, MD 20817 (for express courier service) At the time of submission, two additional copies of the application must be sent to Dr. C. James Scheirer, at the address listed under LETTER OF INTENT. Applications must be received by December 11, 1997. If an application is received after that date, it will be returned to the applicant without review. The Division of Research Grants (DRG) 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 DRG 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. If an application is determined to be unresponsive to the RFA, the principal investigator will be notified and may request that the application be returned or sent to DRG where it will be processed in the next available cycle as a regular grant application. A sample budget is available upon request from Ms. Tanya McCoy at the number listed under Inquiries. Review Considerations Applications that are complete and responsive to the RFA will be evaluated for scientific and technical merit by a peer review group convened by the NHLBI, in accordance with NIH peer review procedures. As part of the initial merit review, all applications will receive a written critique and undergo a review in which only those applications deemed to have the highest scientific merit of the applications under review (usually two to three times the number of applications that the NHLBI and NIAID anticipate being able to fund under the program) will be discussed, assigned a priority score, and receive a second level review by the National Heart, Lung, and Blood Advisory Council or the National Institute of Allergy and Infectious Diseases Advisory Council. The personnel category will be reviewed for appropriate staffing based on the requested percent effort. The direct costs budget request will be reviewed for consistency with the proposed methods and specific aims. Total budgetary adjustments recommended by the reviewers will be in $25,000 modules. The duration of support will be reviewed to determine if it is appropriate to ensure successful completion of the recommended scope of the project. Review Criteria 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 method? Are the aims original and innovative? Does the project challenge existing paradigms or develop new methodologies or technologies? Investigator: is the investigator appropriately trained and well suited to carry out this work? Is the work proposed appropriate to the experience level of the principal investigator and other researchers (if any)? Environment: Does the scientific environment in which the work will be done contribute to the probability of success? Do the proposed experiments take advantage of unique features of the scientific environment or employ useful collaborative arrangements? Is there evidence of institutional support?~ The initial review group will also examine: the adequacy of plans to include both genders and minorities and their subgroups as appropriate for the scientific goals of the research and plans for the recruitment and retention of subjects; the provisions for the protection of human and animal subjects; and the safety of the research environment. Award Criteria The following will be considered in making funding decisions: quality of the proposed project as determined by peer review, availability of funds, and program priority. The anticipated date of award is July 1, 1998. INQUIRIES Inquiries concerning this RFA are encouraged. Potential applicants may request a copy of sample budget pages. The opportunity to clarify any issues or questions from potential applicants is welcome. Direct inquiries regarding programmatic issues to: Susan Banks-Schlegel, Ph.D. Division of Lung Diseases National Heart, Lung, and Blood Institute 6701 Rockledge Drive, Suite 10018, MSC 7952 Bethesda, Maryland 20892-7952 Telephone: (301) 435-0202 FAX: (301) 480-3557 E-mail: Schleges@gwgate.nhlbi.nih.gov Daniel Rotrosen, M.D. Acting Director Division of Allergy, Immunology and Transplantation National Institute of Allergy and Infectious Diseases Solar Building, Room 4A24 6003 Executive Boulevard Bethesda, MD 20892-7640 Telephone: (301) 496-8974 FAX: (301) 402-0175 E-mail: dr17g@nih.gov Direct inquiries regarding fiscal matters to: Tanya McCoy Grants Operations Branch Division of Extramural Affairs National Heart, Lung, and Blood Institute Two Rockledge Centre, Suite 7154, MSC 7926 6701 Rockledge Drive Bethesda, MD 20892-7926 Telephone: (301) 435-0171 FAX: (301) 480-3310 E-mail: mccoyt@gwgate.nhlbi.nih.gov Pamela Fleming Grants Management Branch Division of Extramural Activities National Institute of Allergy and Infectious Diseases Solar Building, Room 4C25 6003 Executive Boulevard Bethesda, MD 20892-7610 Telephone: (301) 402-6580 FAX: (301) 480-3780 E-mail: pf49e@nih.gov Authority and Regulations This program is described in the Catalog of Federal Domestic Assistance, No. 93.838. Awards are made under authorization of the Public Health Service Act, Title IV, Part A (Public Law 78-410, amended by Public Law 99-158, 42 USC 241 and 285) and administered under PHS grants policies and Federal Regulations 42 CFR 52 and 45 CFR Part 74. This program is not subject to the intergovernmental review requirements of Executive Order 12372 or a Health Systems Agency Review. The PHS strongly encourages all grant and contract recipients to provide a smoke-free workplace and promote the non-use of all tobacco products. In addition, Public Law 103-227, the Pro-Children Act of 1994, prohibits smoking in certain facilities (or in some cases, any portion of a facility) in which regular or routine education, library, day care, health care or early childhood development services are provided to children. This is consistent with the PHS mission to protect and advance the physical and mental health of the American people. .
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