RFA-HL-04-009: GRANULOMATOUS LUNG INFLAMMATION IN SARCOIDOSIS

Department of Health
and Human Services (HHS)

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GRANULOMATOUS LUNG INFLAMMATION IN SARCOIDOSIS RELEASE DATE: July 28, 2003 RFA: HL-04-009 National Heart, Lung, and Blood Institute (NHLBI) (http://www.nhlbi.nih.gov) CATALOG OF FEDERAL DOMESTIC ASSISTANCE NUMBER(S): 93.838 LETTER OF INTENT RECEIPT DATE: September 22, 2003 APPLICATION RECEIPT DATE: October 20, 2003 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 Special Requirements 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 purpose of this Request for Applications (RFA) is to initiate a broad research effort to support novel work on the inciting immunopathogenic mechanisms leading to nontuberculous granulomatous inflammation in the lungs pertaining to sarcoidosis. Investigators new to sarcoidosis research are particularly encouraged to develop projects in this area. Research involving human tissues or biological samples is encouraged. RESEARCH OBJECTIVES Sarcoidosis, an illness of unknown cause, usually affects the respiratory tract, but often involves many other organs as well. Although many patients have only intrathoracic illness, others unpredictably can experience a severe multi-organ disease. However, the unknown inciting stimulus can elicit an immunologic host response, the non-caseating granuloma, in almost every organ. While this stimulus can be widespread throughout the body, the biology of the disease is variable. For sarcoidosis, the cause remains unknown, its course is variable, and treatment (usually with corticosteroids) is nonspecific and has side effects. Sarcoidosis remains an important public health issue. Its incidence in the United States is approximately 10 per 100,000 in the white population but higher (35 per 100,000) among Blacks. In the US about 40,000 people are affected with sarcoidosis. Moreover, the illness is more severe in those diagnosed at a more advanced radiologic stage of lung involvement and impairment of forced vital capacity, in persons of low socioeconomic status who are medically underinsured, and in Blacks. The NHLBI convened a working group on "Future Research Directions in Sarcoidosis" in August 2002. The group advised that in addition to seeking the etiology of sarcoidosis and determining susceptibility factors, the initial components in the innate and/or adaptive immune pathways that affect lung lymph nodes or tissue in early disease must be identified. The immunopathogenesis of granulomatous inflammation similar to that found in sarcoidosis needs to be studied in relevant animal models and in human tissues to identify therapeutic targets appropriate for clinical trials. This approach would include the role of predisposing factors, the immune components involved in the formation of granuloma and the defective regulatory immune response (TH1 pathway) all of which need to be evaluated with innovative projects. The research objectives and scope of this initiative are to: 1) solicit and support innovative approaches for producing granulomatous inflammation in the lungs that resembles the histopathological appearance of sarcoidosis and 2) encourage investigators working in other areas of research to bring novel perspectives and expertise to this field. Animal models or human sarcoidosis tissue may be utilized. High risk, high impact projects are sought that have potential to significantly increase present understanding of the mechanisms that induce granulomatous lung changes. Studies on the role of innate immunity, antigen presentation, dendritic cell antigen processing, T-cell regulation and hypersensitivity in granulomatous lung inflammation are pertinent. The characterization of specific immunoregulatory cytokines in the setting of chronic granulomatous lung inflammation is also of interest. Moreover, murine models of inflammatory bowel disease, if they have associated lung inflammation, might pertain to mechanisms relevant for sarcoidosis. Examples of innovative lung projects to evaluate new concepts of granulomatous lung inflammation may include, but are not limited to, research in the following areas: o mechanistic basis for different immune responses induced by systemic versus mucosal routes; o identification and characterization of promising antigen-presenting cell molecular targets and T-cell pathways; o detection of airway antigens non-peptide self antigens, alloantigens, allergens, and relevant infectious agents; o novel technologies to assess innate or adaptive immunity for T or B cell reactivity; o development or application of cell and tissue engineering methods to induce immune tolerance; o characterization of novel, antigen-specific immunosuppressive cell types. Studies with tissue or biologic samples from sarcoidosis patients are encouraged, and may include: o analysis of bronchoalveolar fluid for relevant cytokines and cells with genomic arrays for molecular networks or pathways; transbronchial lung biopsy tissue can be used as possible for similar genomic mapping studies o assess alveolar macrophages and dendritic cells for innate immune activity and cellular receptors o from mediastinal lymph node biopsy tissue and use of laser capture microdisection, isolate immune cells for genomic and proteomic studies MECHANISM OF SUPPORT This RFA will use the National Institutes of Health (NIH) Research Project Grants (R21) award mechanism(s). The R21 is intended to encourage exploratory and developmental research projects by providing support for the early and conceptual stages of these projects. The characteristics, requirements, preparation, and review criteria for the R21 application are described. Information on the R21 award mechanism can be found at http://grants.nih.gov/grants/funding/r21.htm. This mechanism does not require preliminary data but emphasizes creative and innovative approaches. The total project period for an application submitted in response to this RFA may not exceed 2 years. The maximum funds (direct costs) available over a 2 year period of support is $275,000. 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 should be submitted as regular research (R01) grants that will compete with all investigator- initiated applications and will be reviewed according to the customary peer review procedures. The anticipated award date is July 1, 2004. Applications that are not funded in the competition described in this RFA may be resubmitted as NEW investigator-initiated R01 applications using the standard receipt dates for NEW applications described in the instructions to the PHS 398 application. This RFA uses just-in-time concepts. It also uses the modular budgeting format. (see http://grants.nih.gov/grants/funding/modular/modular.htm). Specifically, if you are submitting an application with direct costs in each year of $250,000 or less, use the modular format. This program does not require cost sharing as defined in the current NIH Grants Policy Statement at http://grants.nih.gov/grants/policy/nihgps_2001/part_i_1.htm. FUNDS AVAILABLE The NHLBI intends to commit approximately $4,500,000 in FY 2004 to fund up to 10 new 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 $275,000 for the 2 year period (but no more than $200,000 in any one year). Although the financial plans of the NHLBI 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. 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. SPECIAL REQUIREMENTS Applications must propose research projects that focus on sarcoidosis and/or on lung granulomatous inflammation that is relevant to sarcoidosis. Basic immunologic studies not related to granulomatous lung inflammation are not responsive to this RFA. Also, projects related to hypersensitivity pneumonitis from organic antigens, beryllium exposure or eosinophilic granuloma are not considered responsive to this RFA, nor are projects involving Mycobacterium tuberculosis. Grantee's Meetings Upon initiation of the program, the NHLBI will sponsor annual meetings to encourage exchange of information among investigators who participate in this program. In their budgets, applicants should include funds for annual one-day grantees' meetings, most likely in Bethesda, Maryland. Applicants should also include a statement in their applications indicating their willingness to participate in these meetings. The first such meeting likely will take place in about 6 months after the award is issued. Cooperation Among Grantees Because of the possible difficulty of obtaining sufficient human tissue with which to conduct the studies, the awardees must include in their application, how many sarcoidosis patients from whom they expect to be able to obtain tissue, how the tissue is obtained and subsequently processed, and a willingness to participate in a meeting to determine how to standardize tissue collection so that it is usable by all awardees. Applicants must indicate in their application their willingness to share human tissue and data with other awardees and address how this information will be included as part of the patient consent process. Such sharing of tissue will also facilitate identification and evaluation of different potential targets in the same tissue from the same patient. 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: Herbert Y. Reynolds, M.D. Medical Officer, Lung Biology and Disease Program Division of Lung Diseases National Heart, Lung, and Blood Institute 6701 Rockledge Drive, Suite 10018, MSC 7952 Bethesda, MD 20892-7952 Telephone: (301) 435-0222 FAX: (301)480-3557 Email: reynoldh@nhlbi.nih.gov o Direct your questions about peer review issues to: Anne P. Clark, Ph.D. Chief, Review Branch Division of Extramural Affairs National Heart, Lung, and Blood Institute 6701 Rockledge Drive, Room 7214, MSC 7924 Bethesda, MD 20892-7924 (20817 for express/courier service) Telephone: (301) 435-0270 FAX: (301) 480-0730 Email: clarka@nhlbi.nih.gov o Direct your questions about financial or grants management matters to: Robert Pike Grants Management Officer Division of Extramural Affairs National Heart, Lung, and Blood Institute 6701 Rockledge Drive, Room 7144, MSC 7926 Bethesda, MD 20892-7926 Telephone: (301) 435-0171 FAX: (301) 480-3310 Email: piker@nhlbi.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, 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 Dr. Anne Clark at the address listed under WHERE TO SEND INQUIRIES. 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 http://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: All instructions for the PHS 398 (rev. 5/2001) must be followed, with these exceptions: o Research Plan Items a-d of the Research Plan (Specific Aims, Background and Significance, Preliminary Studies, and Research Design and Methods) may not exceed a total of 15 pages. No preliminary data are required but may be included if available. Please note that a Progress Report is not needed; competing continuation applications for an exploratory/developmental grant will not be accepted. Appendix. Use the instructions for the appendix detailed in the PHS 398 except that no more than 5 manuscripts, previously accepted for publication, may be included. 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: http://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 copies of the application, plus all collated sets of appendix material must be sent to Dr. Anne Clark at the address listed under where to send inquires. APPLICATION PROCESSING: Applications must be received on or before 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. Although there is no immediate acknowledgement of the receipt of an application, applicants are generally notified of the review and funding assignment within 8 weeks. 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. However, when a previously unfunded application, originally submitted as an investigator-initiated application, is to be submitted in response to an RFA, it is to be prepared as a NEW application. That is the application for the RFA must not include an Introduction describing the changes and improvements made, and the text must not be marked to indicate the changes. While the investigator may still benefit from the previous review, the RFA application is not to state explicitly how. PEER REVIEW PROCESS Upon receipt, applications will be reviewed for completeness by the CSR and responsiveness to special requirements of the RFA by the 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, all applications will: o Receive a written critique o 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 and assigned a priority score o Receive a second level review by the National Heart, Lung, and Blood Advisory 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: o Significance o Approach o Innovation o Investigator o Environment The scientific review group will address and consider each of these criteria in assigning the application's overall score, weighting them as appropriate for each application. The application does not need to be strong in all categories to be judged likely to have major scientific impact and thus deserve a high priority score. For example, an investigator may propose to carry out important work that by its nature is not innovative but is essential to move a field forward. SIGNIFICANCE: Does this study address an important problem? If the aims of the application are achieved, how will scientific knowledge be advanced? What will be the effect of these studies on the concepts or methods that drive this field? APPROACH: Are the conceptual framework, design, methods, and analyses adequately developed, well-integrated, and appropriate to the aims of the project? Does the applicant acknowledge potential problem areas and consider alternative tactics? INNOVATION: Does the project employ novel concepts, approaches or methods? Are the aims original and innovative? Does the project challenge existing paradigms or develop new methodologies or technologies? INVESTIGATOR: Is the investigator appropriately trained and well suited to carry out this work? Is the work proposed appropriate to the experience level of the principal investigator and other researchers (if any)? ENVIRONMENT: Does the scientific environment in which the work will be done contribute to the probability of success? Do the proposed experiments take advantage of unique features of the scientific environment or employ useful collaborative arrangements? Is there evidence of institutional support? ADDITIONAL REVIEW CRITERIA: In addition to the above criteria, the following items will be considered in the determination of scientific merit and the priority score: PROTECTION OF HUMAN SUBJECTS FROM RESEARCH RISK: The involvement of human subjects and protections from research risk relating to their participation in the proposed research will be assessed. (See criteria included in the section on Federal Citations, below). INCLUSION OF WOMEN, MINORITIES AND CHILDREN IN RESEARCH: The adequacy of plans to include subjects from both genders, all racial and ethnic groups (and subgroups), and children as appropriate for the scientific goals of the research. Plans for the recruitment and retention of subjects will also be evaluated. (See Inclusion Criteria in the sections on Federal Citations, below). CARE AND USE OF VERTEBRATE ANIMALS IN RESEARCH: If vertebrate animals are to be used in the project, the five items described under Section f of the PHS 398 research grant application instructions (rev. 5/2001) will be assessed. ADDITIONAL CONSIDERATIONS DATA SHARING: The adequacy of the proposed plan to share data. 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: September 22, 2003 Application Receipt Date: October 20, 2003 Peer Review Date: February - March 2004 Council Review: May 13, 2004 Earliest Anticipated Start Date: July 1, 2004 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 HUMAN SUBJECTS PROTECTION: Federal regulations (45CFR46) require that applications and proposals involving human subjects must be evaluated with reference to the risks to the subjects, the adequacy of protection against these risks, the potential benefits of the research to the subjects and others, and the importance of the knowledge gained or to be gained. http://www.hhs.gov/ohrp/humansubjects/guidance/45cfr46.htm MONITORING PLAN AND DATA AND SAFETY 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 and Safety Monitoring, NIH Guide for Grants and Contracts, June 12, 1998: http://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 "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 (http://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-001.html); a complete copy of the updated Guidelines are available at http://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 http://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 http://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 http://stemcells.nih.gov/index.asp and at http://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 http://grants.nih.gov/grants/policy/a110/a110_guidance_dec1999.htm. Applicants may wish to place data collected under this PA 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. STANDARDS FOR PRIVACY OF INDIVIDUALLY IDENTIFIABLE HEALTH INFORMATION: The Department of Health and Human Services (DHHS) issued final modification to the "Standards for Privacy of Individually Identifiable Health Information", the "Privacy Rule," on August 14, 2002. The Privacy Rule is a federal regulation under the Health Insurance Portability and Accountability Act (HIPAA) of 1996 that governs the protection of individually identifiable health information, and is administered and enforced by the DHHS Office for Civil Rights (OCR). Those who must comply with the Privacy Rule (classified under the Rule as "covered entities") must do so by April 14, 2003 (with the exception of small health plans which have an extra year to comply). Decisions about applicability and implementation of the Privacy Rule reside with the researcher and his/her institution. The OCR website (http://www.hhs.gov/ocr/) provides information on the Privacy Rule, including a complete Regulation Text and a set of decision tools on "Am I a covered entity?" Information on the impact of the HIPAA Privacy Rule on NIH processes involving the review, funding, and progress monitoring of grants, cooperative agreements, and research contracts can be found at http://grants.nih.gov/grants/guide/notice-files/NOT-OD-03-025.html. 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 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 Catalog of Federal Domestic Assistance at http://www.cfda.gov/ and is not subject to the intergovernmental review requirements of Executive Order 12372 or Health Systems Agency review. Awards are made under the authorization of Sections 301 and 405 of the Public Health Service Act as amended (42 USC 241 and 284 and under Federal Regulations 42 CFR 52 and 45 CFR Parts 74 and 92. All awards are subject to the terms and conditions, cost principles, and other considerations described in the NIH Grants Policy Statement. The NIH Grants Policy Statement can be found at http://grants.nih.gov/grants/policy/policy.htm The PHS strongly encourages all grant recipients to provide a smoke-free workplace and discourage the use of all tobacco products. In addition, Public Law 103-227, the Pro-Children Act of 1994, prohibits smoking in certain facilities (or in some cases, any portion of a facility) in which regular or routine education, library, day care, health care, or early childhood development services are provided to children. This is consistent with the PHS mission to protect and advance the physical and mental health of the American people.

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