MOLECULAR TARGETS AND INTERVENTIONS IN PULMONARY FIBROSIS RELEASE DATE: March 14, 2002 RFA: HL-02-020 National Heart, Lung, and Blood Institute (NHLBI) (http://www.nhlbi.nih.gov/) LETTER OF INTENT RECEIPT DATE: August 23, 2002 APPLICATION RECEIPT DATE: September 20, 2002 THIS RFA CONTAINS THE FOLLOWING INFORMATION o Purpose of this RFA o Research Objectives o Mechanism 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 support a broad research effort to develop new therapeutic approaches for pulmonary fibrosis (PF). The primary objective is to support applications to discover and validate molecular targets for interfering with fibrogenesis in PF in humans and identify agonists or antagonists that interact with the previously or newly identified targets to attenuate, halt, or reverse the fibrotic process. Applicants must plan to utilize human PF patients or tissue to identify targets and agents that interact with them. RESEARCH OBJECTIVES PF is a chronic diffuse interstitial lung disease of unknown cause, characterized pathologically by inflammation and fibrosis of the lung parenchyma. Prognosis is poor with a fifty per cent mortality at five years after diagnosis and considerable morbidity during those years. Previous investigations have documented the role for inflammation in the pathogenesis of PF and current therapeutic strategies are aimed at suppressing the inflammation. Data generated over the past decade also have established the concept that the molecular processes underlying the fibrogenesis component may represent a new opportunity for therapeutic intervention. Attempts to treat PF have for the most part consisted of anti- inflammatory drugs, almost exclusively steroids. The effectiveness of steroids is variable and can be associated with significant side effects. Although recent findings suggest interferon-gamma may prove to have beneficial effects, alternative approaches to treatment are needed that have the advantages of reduced cost, increased specificity, and reduced side effects. One approach to new treatments would be to identify new agents that interact with previously identified molecules or pathways (e.g., TGF- Beta, growth factors, proteinases, apoptosis, myofibroblast differentiation and proliferation, signaling pathways, collagen synthesis) that are known to be involved in the development of fibrosis. Such agents could range from small molecules to vaccines. One recent example of this approach has been to focus on 5-lipoxygenase as a target for intervention in PF. This RFA is meant to support applications designed to identify agents that interact with such previously identified molecular targets to inhibit progression or reverse fibrosis in PF patients. There are also potentially new molecular targets to be discovered, which if agonists or antagonists existed, could provide new approaches to treatment of PF. There are many new powerful technologies and resources that are available to look for differences between normal and fibrotic lung tissue (e.g., levels of specific proteins or signaling patterns) and thus could identify potential targets for intervention. Such technologies include laser capture microdissection, microarrays, and mass spectroscopy analysis of proteins, which could be used to identify molecular targets in the pathways leading fibrotic lung disease. This RFA is meant to support applications designed to identify new targets for intervention in PF, using new technologies. Although there may be considerable data on a cellular or molecular pathway"s involvement in the pathogenesis of PF, the point of greatest vulnerability in the pathway and therefore, perhaps the optimal point of drug attack, may not be clear. This RFA is intended to support identification of a target(s) and validation of its role in the development of pulmonary fibrosis. Applicants may address targets related to cellular or molecular pathways known to be involved in the pathogenesis of PF, or identify targets in pathways previously unknown to be related to PF. Investigators may use their own creativity in defining an approach. For example, some may prefer to use a genetic, structural biology or molecular biology approach to target identification/validation employing information from genetic studies or studies of pathways, whereas others may prefer to identify the function of a cellular target after first finding the target as a result of exploring binding patterns of natural products or other ligands to normal and fibrotic tissue. MECHANISM OF SUPPORT This RFA will use National Institutes of Health (NIH) Individual Research Project Grant (R01) award mechanism. 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. The anticipated award date is July 1, 2003. This RFA uses "Just-In-Time" (JUST) concepts. It also uses the modular budgeting formats (see http://grants.nih.gov/grants/funding/modular/modular.htm). FUNDS AVAILABLE The NHLBI intends to commit approximately $3,000,000 in FY 2003 to fund 4 to 6 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 up to $500,000 per year. 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 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 Grantees" 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 within 3 months of award. 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 PF 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. Such sharing of tissue will also facilitate identification and evaluation of different potential targets in the same tissue from the same patient. Applicants should include sufficient funds to cover the cost of shipping tissues. Exclusions In order to be responsive to this RFA, applications must propose studies involving the use of human PF patients or patient tissue. Applications whose primary focus is development of an animal model of PF will not be considered responsive. In addition, in order to be responsive, applications must contain each of the following items: o a statement of willingness to participate in an initial meeting to standardize collection, processing, and shipping of human PF tissue o a statement of willingness to share human PF tissue and data with other awardees o a strategy for identifying agonists or antagonists for a target molecule in the fibrotic pathway o a strategy for testing the impact of the interaction of an agent with the target on PF 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: Dorothy B. Gail, Ph.D. Director, Lung Biology and Diseases 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: gaild@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 7178, MSC 7924 Bethesda, Maryland 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: Teneshia G. Alston Grants Operations Branch Division of Extramural Affairs National Heart, Lung, and Blood Institute 2 Rockledge Centre, Room 7154 Bethesda, Maryland 20892-7926 Telephone: (301) 435-0150 FAX: (301) 480-3310 E-mail: alston@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, 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: Anne P. Clark, Ph.D. Chief, Review Branch Division of Extramural Affairs National Heart, Lung, and Blood Institute 6701 Rockledge Drive, Room 7178, MSC 7924 Bethesda, Maryland 20892-7924 (20817 for express/courier service) Telephone: (301) 435-0270 Fax: (301) 480-0730 Email: clarka@nhlbi.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 http://grants.nih.gov/grants/funding/phs398/phs398.html in an interactive format. For further assistance contact GrantsInfo, Telephone (301) 435-0714, Email: GrantsInfo@nih.gov. SPECIFIC INSTRUCTIONS FOR MODULAR GRANT APPLICATIONS: Applications 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 http://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 http://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: 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 as well as all five collated sets of Appendix material must be sent to: Anne Clark, Ph.D. Chief, Review Branch Division of Extramural Affairs National Heart, Lung, and Blood Institute 6701 Rockledge Drive Room 7178, MSC 7924 Bethesda, MD 20892-7924 (20817 for express/courier service) Telephone: (301) 435-0270 FAX: (301) 480-0730 Email: ClarkA@nhlbi.nih.gov 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. Principal investigators should not send supplementary material without first contacting the Scientific Review Administrator (SRA). The SRA will be identified in the letter sent to you indicating that your application has been received. If you have not received such a letter within three weeks after submitting the application, contact Dr. Anne Clark at the address listed under Inquiries. PEER REVIEW PROCESS Upon receipt, applications will be reviewed for completeness by the CSR and responsiveness by the NHLBI. 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 (IC) 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 Institute National 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 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. For example, you 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 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. (6) ACCESS TO PF PATIENTS: Access to adequate human PF patients or tissue to conduct the studies proposed. 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: August 23, 2002 Application Receipt Date: September 20, 2002 Peer Review Date: February 2003 Council Review: May 2003 Earliest Anticipated Start Date: July 1, 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 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 (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_2 001.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://grants.nih.gov/grants/stem_cells.htm 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. 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 No. 93.838 and is not subject to the intergovernmental review requirements of Executive Order 12372 or Health Systems Agency review. 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 described at http://grants.nih.gov/grants/policy/policy.htm and under Federal Regulations 42 CFR 52 and 45 CFR Parts 74 and 92. 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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