INFLAMMATION IN THE PATHOGENESIS OF COPD Release Date: November 2, 1999 RFA: HL-00-006 National Heart, Lung, and Blood Institute Letter of Intent Receipt Date: February 1, 2000 Application Receipt Date: March 10, 2000 THIS RFA USES "MODULAR GRANT" AND "JUST-IN-TIME" CONCEPTS. IT INCLUDES DETAILED MODIFICATIONS TO STANDARD APPLICATION INSTRUCTIONS THAT MUST BE FOLLOWED WHEN PREPARING APPLICATIONS IN RESPONSE TO THIS RFA. PURPOSE The National Heart, Lung, and Blood Institute (NHLBI) invites research grant applications to conduct studies on the role of inflammation in the pathogenesis of chronic obstructive pulmonary disease (COPD). The overall goal of this program is to establish the cellular and molecular mechanisms of inflammatory and immune processes which play a role in the pathogenesis and progression of COPD. Toward this goal, this initiative strongly encourages scientific collaborations among investigators with interest in COPD, inflammation and immunology. 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), "Inflammation in the Pathogenesis of COPD", is related to one or more of the priority areas. Potential applicants may obtain a copy of "Healthy People 2000" at http://odphp.osophs.dhhs.gov/pubs/hp2000. ELIGIBILITY REQUIREMENTS Applications may be submitted by domestic and foreign, for-profit and non-profit organizations, public and private, such as universities, colleges, hospitals, laboratories, units of State or local governments, and eligible agencies of the Federal government. Awards under this RFA to foreign institutions will be made only for research of very unusual merit, need, and promise, and in accordance with PHS policy governing such awards. Racial/ethnic minority individuals, women, and persons with disabilities are encouraged to apply as Principal Investigators. MECHANISM OF SUPPORT This RFA will use the National Institutes of Health (NIH) research project grant (R01) award mechanism. Responsibility for the planning, direction, and execution of the proposed project will be solely that of the applicant. The total project period for an application submitted in response to this RFA may not exceed 4 years. 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. The anticipated award date is September 29, 2000. 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 https://grants.nih.gov/grants/funding/modular/modular.htm. 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 either from the GCRC program director or principal investigator should be included with the application. FUNDS AVAILABLE The NHLBI intends to commit approximately $3,200,000 total costs in fiscal year 2000 to fund 6 to 8 new grants in response to this RFA. An applicant may request a project period of up to 4 years and a budget for direct costs of up to $225,000 per year, including facilities and administrative costs (F&A) on consortium arrangements. The total cost for a consortium arrangement is included in the overall requested modular direct cost amount. Because the nature and scope of the research proposed may vary, it is anticipated that the size of each award will also vary. Although the financial plans of the National Heart, Lung and Blood Institute provide support for this program, awards pursuant to this RFA are contingent upon the availability of funds and the receipt of a sufficient number of applications of strong scientific and technical merit. RESEARCH OBJECTIVES Background Chronic obstructive pulmonary disease (COPD), which includes chronic bronchitis and emphysema, is characterized by chronic and progressive airflow limitation. It affects more than 16 million Americans, is the fourth leading cause of death in the USA, and costs the nation billions of dollars for direct and indirect health care. Although cigarette smoking has been recognized as a major causal factor in the majority of cases, it remains a major societal issue and both mortality and prevalence rates of COPD are continuing to rise. COPD is most likely a complex of conditions with multiple initiating and effector pathways. Research in COPD has primarily focused on the role of proteases and antiproteases in the generation of emphysema, a subset of COPD. Although inflammation has always been considered a prominent feature in COPD, there has been little work describing the specific inflammatory and immune events in COPD and their role in the pathogenesis of disease. Recently, several studies have shown steroids, so effective in treatment of asthma, to be of limited therapeutic value in COPD. This has underscored the need to characterize and elucidate the inflammatory pathways in COPD. This includes initiating events, regulatory mechanisms and subsequent underlying cellular and molecular processes which lead to inflammation, tissue damage and remodeling. These insights should lead to a better understanding of the pathogenic mechanisms of COPD and provide a basis for the development of therapeutic modalities specific to COPD as distinguished from other obstructive pulmonary diseases. Other Preliminary descriptions report that the lymphocytic infiltrate in COPD appears to vary with specific syndrome, severity and stability versus exacerbation. Furthermore, while most smokers will have some degree of inflammation in their airways, only about 15 percent will go on to develop the clinical syndrome of COPD. Rigorous identification, at the cellular and molecular level, of the various inflammatory and immune pathways present in COPD and how they may differ from smokers who do not get disease is an important goal in understanding pathogenesis at the mechanistic level. While cigarette smoke or other environmental stimuli are thought to be the primary initiators of the inflammatory response, the mechanisms involved and other co-initiators have not been identified. It is possible that smokers exist in a heightened local inflammatory state that, in some, leads to long term damage and remodeling of the airways that may be further exacerbated by infection or other events. Proinflammatory molecules such as endotoxin and lipopolysaccharide (LPS), as well as the adenovirus protein E1A, are known to play a role in the upregulation of inflammation. Specific cells and factors, such as cytokines, chemokines, along with initiating events, regulatory mechanisms, need to be identified and characterized to determine their role in COPD. Cellular migration, infiltration and activation state also need to be investigated. It is also necessary to determine the potential influence of the involved pathways and their components on resident airway cell function and extracellular matrix (ECM). Inflammatory cytokines and cells may be involved in goblet cell hyperplasia and the appearance and increase of goblet cells in the small airways. This relationship needs to be investigated and defined. Elucidation of these molecular events is critical to defining the mechanisms which underlie development and progression of COPD. Additionally, the relationships among inflammation, cell activation and cell- cell and cell-matrix interactions as they relate to altered airway function in COPD are poorly understood and require further study. The role of inflammatory cells and cytokines as they relate to the structural integrity of the airways needs to be investigated. For example, enzymes which play a role in the activation of matrix metalloproteinases (MMPs) have been identified, and are known to be upregulated, in alveolar macrophages from COPD patients. Cellular events that are required for increased expression and activation of these enzymes need to be identified. ECM fragments have been demonstrated to be chemotactic for inflammatory cells and contact with disrupted ECM is known to activate multiple signaling pathways triggering many cellular responses. It will be important to determine the relationship between inflammation, MMP activation and ECM degradation and also to further investigate the potential role of MMPs and ECM fragmentation in remodeling of the airways and perpetuation of the inflammatory process. THESE ARE EXAMPLES ONLY. INVESTIGATORS SHOULD NOT FEEL LIMITED TO THE EXAMPLES MENTIONED ABOVE AND ARE ENCOURAGED TO SUBMIT OTHER TOPICS PERTINENT TO THE OBJECTIVES OF THE RFA. SPECIAL REQUIREMENTS Applications that propose descriptive studies and do not contain hypothesis driven studies directed at understanding the mechanisms associated with inflammatory and immune events and their relationship with the pathogenesis of COPD will not be responsive to the RFA. The intent of this initiative is to focus on the pathogenesis of COPD. Applications using in vitro, cellular, or animal models, including humans, to study inflammatory mechanisms as they relate to COPD will be considered responsive. Applicants who propose to test hypotheses in animal or in vitro models must demonstrate relevance to inflammation and/or immunology and its relationship with COPD pathogenesis and/or disease progression. Studies directed solely at inflammatory and/or immune events, without relevance to COPD, will not be responsive to this initiative. Multidisciplinary investigations bringing together investigators with expertise in COPD, immunology, inflammation and molecular and cellular biology are strongly encouraged. Large clinical studies or epidemiologic studies are not within the scope of this RFA. Upon initiation of the program, the NHLBI will sponsor periodic meetings to encourage exchange of information among investigators who participate in this program. 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 application indicating their willingness to participate in these meetings and to interact openly with other study participants so as to provide the greatest promise for scientific advances from the approved research scope of the awards. 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 new 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, Volume 23, Number 11, March 18, 1994, available on the web at: https://grants.nih.gov/grants/guide/notice-files/not94-100.html. INCLUSION OF CHILDREN AS PARTICIPANTS IN RESEARCH INVOLVING HUMAN SUBJECTS It is the policy of the NIH that children (i.e., individuals under the age of 21) must be included in all human subjects research, conducted or supported by the NIH, unless there are scientific and ethical reasons not to include them. This policy applies to all initial (Type 1) applications submitted for receipt dates after October 1, 1998. All investigators proposing research involving human subjects should read the "NIH Policy and Guidelines" on the Inclusion of Children as Participants in Research Involving Human Subjects that was published in the NIH Guide for Grants and Contracts, March 6, 1998, and is available at the following URL address: https://grants.nih.gov/grants/guide/notice-files/not98-024.html. Investigators also may obtain copies of these policies from the program staff listed under INQUIRIES. Program staff may also provide additional relevant information concerning the policy. LETTER OF INTENT Prospective applicants are asked to submit a letter of intent that includes a descriptive title of the proposed research, the name, address, and telephone number of the Principal Investigator, the identities of other key personnel and participating institutions, and the number and title of the RFA in response to which the application may be submitted. Although a letter of intent is not required, is not binding, and does not enter into the review of subsequent applications, the information that it contains allows NHLBI 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 mailed to Dr. C. James Scheirer as the address listed under INQUIRIES. APPLICATION PROCEDURES The modular grant concept establishes specific modules in which direct costs* may be requested as well as a maximum level for requested budgets. Only limited budgetary information is required under this approach. The just-in-time concept allows the applicant 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. BUDGET INSTRUCTIONS Modular Grant applications will request direct costs in $25,000 modules, up to a maximum total direct cost request of $225,000 per year. An R01 grant application may include research activities that involve institutions other than the sponsoring organization, creating a consortium effort. The consortium costs should be included in the direct cost limit ($225,000). 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 $225,000) and Total Costs [Modular Total Direct plus 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-DD of the PHS 398 (rev 4/98). It is not required nor will it be accepted at the time of application. o BUDGET FOR THE ENTIRE PROPOSED PERIOD OF SUPPORT - Do not complete the categorical budget table on Form Page 5 of the PHS 398. It is not required and will not be accepted with the application. o NARRATIVE BUDGET JUSTIFICATION - Prepare a Modular Grant Budget Narrative page. (See https://grants.nih.gov/grants/funding/modular/modular.htm for sample pages). At the top of the page, enter the total direct costs requested for each year. This is not a Form page. o Under Personnel, list key project personnel, including their names, percent of effort and roles on the project. No individual salary information should be provided. However, the applicant should use the NIH appropriation language salary cap and the NIH policy for graduate student compensation in developing the budget request For Consortium/Contractual Costs, provide an estimate of total costs (direct plus facilities and administrative) for each year, each rounded to the nearest $1,000. For this RFA, the consortium costs should be included in the $225,000 cost limit. 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 collaborative 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 modified instructions below. No more than three pages may be used for each person. A sample biographical sketch may be viewed at: https://grants.nih.gov/grants/funding/modular/modular.htm - Complete the educational block at the top of the form page; - List position(s) and any honors; - Provide information, including overall goals and responsibilities, on research projects ongoing or completed during the last three years; - List selected peer-reviewed publications, with full citation; o CHECKLIST - This page should be completed and submitted with the application. If the F&A rate agreement has been established, indicate the type of agreement and the date. All appropriate exclusions must be applied in the calculation of the F&A costs for the initial budget period and all future budget years. o The applicant should provide the name and phone number of the individual to contact concerning fiscal and administrative issues if additional information is necessary following the initial review. The research grant application form PHS 398 (rev. 4/98) is to be used in applying for these grants. These forms are available at most institutional offices of sponsored research and from the Division of Extramural Outreach and Information Resources, National Institutes of Health, 6701 Rockledge Drive, MSC 7910, Bethesda, MD 20892-7910, telephone 301/710-0267, email: GrantsInfo@nih.gov. The RFA label found in the PHS 398 (rev. 4/98) application form must be affixed to the bottom of the face page of the application. Failure to use this label could result in delayed processing of the application such that it may not reach the review committee in time for review. In addition, the RFA title (Inflammation in the Pathogenesis of COPD) and number (HL-00-006) must be typed on line 2 of the face page of the application form and the YES box must be marked. Please be sure to include the RFA number (HL-00-006) on the label. The sample RFA label available at: https://grants.nih.gov/grants/funding/phs398/label-bk.pdf has been modified to allow for this change. Please note this is in pdf format. 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 copies of the application must be sent to Dr. C. James Scheirer, at the listing under INQUIRIES. APPLICATIONS MUST BE RECEIVED BY MARCH 10, 2000. IF AN APPLICATION IS RECEIVED AFTER THAT DATE, IT WILL BE RETURNED TO THE APPLICANT WITHOUT REVIEW. The Center for Scientific Review (CSR) will not accept any application in response to this RFA that is essentially the same as one currently pending initial review, unless the applicant withdraws the pending application. The CSR will not accept any application that is essentially the same as one already reviewed. This does not preclude the submission of substantial revisions of applications already reviewed, but such applications must include an introduction addressing the previous critique. REVIEW CONSIDERATIONS Upon receipt, applications will be reviewed for completeness by CSR and responsiveness by NHLBI. Incomplete and/or non-responsive applications will be returned to the applicant without further consideration. Applications that are complete and responsive to the RFA will be evaluated for scientific and technical merit by an appropriate peer review group convened by the NHLBI in accordance with the review criteria stated below. As part of the initial merit review, a process will be used by the initial review group in which applications receive a written critique and undergo a process in which only those applications deemed to have the highest scientific merit, generally the top half of the applications under review, will be discussed, assigned a priority score, and receive a second level review by the National Heart, Lung, and Blood Advisory Council. Review Criteria The goals of NIH-supported research are to advance our understanding of biological systems, improve the control of disease, and enhance health. In the written comments, reviewers will be asked to discuss the following aspects of the application in order to judge the likelihood that the proposed research will have a substantial impact on the pursuit of these goals. Each of these criteria will be addressed and considered in the assigning the overall score, weighing them as appropriate for each application. Note that the application does not need to be strong in all categories to be judged to have major scientific impact and thus deserve a high priority score. For example, an investigator may propose to carry out important work that by its nature is not innovative but is essential to move a field forward. 1) Significance. Does this study address an important problem? If the aims of the application are achieved, how will scientific knowledge be advanced? What will be the effect of these studies on the concepts or methods that drive this field? 2) Approach. Are the conceptual framework, design, methods, and analyses adequately developed, well integrated, and appropriate to the aims of the project? Does the applicant acknowledge potential problem areas and consider alternative tactics? 3) Innovation. Does the project employ novel concepts, approaches or method? Are the aims original and innovative? Does the project challenge existing paradigms or develop new methodologies or technologies? 4) Investigator. Is the investigator appropriately trained and well suited to carry out this work? Is the work proposed appropriate to the experience level of the principal investigator and other researchers (if any)? 5) Environment. Does the scientific environment in which the work will be done contribute to the probability of success? Do the proposed experiments take advantage of unique features of the scientific environment or employ useful collaborative arrangements? Is there evidence of institutional support? In addition to the above criteria, in accordance with NIH policy, all applications will also be reviewed with respect to the following: o The adequacy of the research plans to include both genders, minorities and their subgroups, and children as appropriate for the scientific goals of the research. Plans for the recruitment and retention of subjects will also be evaluated. o The reasonableness of the proposed budget and duration in relation to the proposed research. o The adequacy of the proposed protection for humans, animals or the environment, to the extent that may be adversely affected by the project proposed in the application. The personnel category will be reviewed for appropriate staffing based on the requested percent effort and justification provided. The direct costs budget request will be reviewed for consistency with the proposed methods and specific aims. Any 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 requested scope of the project. Schedule Letter of Intent Receipt Date: February 1, 2000 Application Receipt Date: March 10, 2000 Date of Initial Review: May/June 2000 Review by NHLBI Advisory Council: September 7-8, 2000 Anticipated Award Date: September 2000 AWARD CRITERIA Award criteria that will be used to make award decisions include: o Scientific merit (as determined by peer review) o Availability of funds o Programmatic priorities and program balance INQUIRIES Inquiries concerning this RFA are encouraged. The opportunity to clarify any issues or questions from potential applicants is welcome. Direct inquiries regarding programmatic issues to: Patricia Noel, Ph.D. Division of Lung Diseases National Heart, Lung, and Blood Institute 6701 Rockledge Drive, Room10018, MSC 7952 Bethesda, Maryland 20892-7952 Telephone: (301) 435-0202 FAX: (301) 480-3557 Email: noelp@nih.gov or Gail Weinmann, M.D. Division of Lung Diseases National Heart, Lung, and Blood Institute 6701 Rockledge Drive, Room10018, MSC 7952 Bethesda, Maryland 20892-7952 Telephone: (301) 435-0202 FAX: (301) 480-3557 E-mail: weinmang@nih.gov Direct inquiries regarding review matters and address the letter of intent to: C. James Schreirer, Ph.D. Division of Extramural Affairs National Heart, Lung, and Blood Institute 6701 Rockledge Drive, Room 7220, MSC 7924 Bethesda, Maryland 20892-7924 Telephone: (301) 435-0266 FAX: (301) 480-3541 E-mail: JS110J@nih.gov Direct inquiries regarding fiscal matters to: Raymond L. Zimmerman Division of Extramural Affairs National Heart, Lung, and Blood Institute 6701 Rockledge Drive, Room 7154, MSC 7926 Bethesda, MD 20892-7926 Telephone: (301) 435-0171 FAX: (301) 480-3310 E-mail: ZimmermR@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 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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