STRATEGIES TO AUGMENT ALVEOLIZATION Release Date: April 17, 1998 RFA: HL-98-011 P.T. National Heart, Lung, and Blood Institute Letter of Intent Receipt Date: June 15, 1998 Application Receipt Date: September 4, 1998 THIS REQUEST FOR APPLICATIONS (RFA) USES "MODULAR GRANT" AND "JUST-IN-TIME" CONCEPTS AND INCLUDES DETAILED MODIFICATIONS TO STANDARD APPLICATION INSTRUCTIONS AND MUST BE USED WHEN PREPARING APPLICATIONS IN RESPONSE TO THIS RFA. PURPOSE This solicitation invites research grant applications focused on regulation of alveolar formation in the lung. The goal of the program is to generate genetic, cellular and molecular information about alveolar formation that will ultimately lead to the development of rational clinical interventions in aberrant lung development, injury, or disease processes. 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 RFA, Strategies to Augment Alveolization, is related to the priority areas of maternal and infant health, chronic disabling diseases, and tobacco. 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 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 for research of very unusual merit, need, and promise, and in accordance with PHS policy governing such awards. Among the disciplines and expertise that may be appropriate for this program are developmental biology, molecular biology, physiology, molecular genetics, biochemistry, pharmacology, morphometry, pathology, pediatrics and pulmonary medicine. MECHANISM OF SUPPORT This RFA will use the NIH individual research project grant (R01) mechanism of support. Investigators without prior R01 support are encouraged to apply for this RFA and to identify their status as a new investigator 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. Although multi-disciplinary approaches are encouraged, it is not the intent of this RFA 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 eight modules ($200,000 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 staff following the initial review. The APPLICATION PROCEDURES section of this RFA provides specific details of modifications to standard PHS 398 application kit instructions. FUNDS AVAILABLE It is anticipated that for fiscal year 1999, approximately $2,500,000 total costs will be available for the first year of support for this initiative. Award of grants pursuant to this RFA is contingent upon receipt 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. Facilities and Administrative costs will be awarded based on the negotiated rates. RESEARCH OBJECTIVES Background Three major lung diseases are characterized by the presence of too few alveoli for normal gas exchange: emphysema, diffuse interstitial fibrosis, and bronchopulmonary dysplasia (BPD). Alveolar destruction is the main recognized cause of alveolar insufficiency in emphysema and in interstitial fibrosis. In BPD, there is impaired septation that, along with alveolar destruction, results in too few alveoli for adequate gas exchange. Other less common causes of alveolar destruction that result in inadequate gas exchange include pulmonary tuberculosis, sarcoidosis, other granulomatous diseases, and several occupational lung. Unlike the liver, which can regenerate in response to destruction, there has been no indication that the lung can regenerate destroyed alveoli, either spontaneously or by means of pharmacologic induction. Thus, the only remediation for individuals with too few alveoli for life-sustaining gas exchange is lung transplantation. However, recent investigations have, for the first time, suggested that pharmacologic-induced generation of alveoli is indeed possible. Treatment with all-trans retinoic acid induces formation of increased numbers of alveoli in lungs of neonatal rats where it also prevents the inhibition of alveolus formation by corticosteroid hormones. The ability of retinoic acid to induce alveolar septation has also been demonstrated with fetal murine lungs in culture. In adult rats, retinoic acid abrogates key features of emphysema (i.e., larger but fewer alveoli and increased lung volume) in an elastase-generated model of the disease. Whether retinoic acid treatment results in improved lung function and gas exchange is not yet known, nor is the cellular and molecular basis of the effects of retinoic acid on lung alveoli understood. Yet these results provide a first glimpse at the possibility of regenerating lost alveoli by pharmacologic means. The cellular and molecular events regulating septation and alveolar formation in the developing and postnatal lung are not well characterized. The role of potential suppressive signals and the responding genes that may exist to terminate the process of septation and alveolar formation are virtually unknown. Identifying genes that play a role in suppressing alveolar formation is important for understanding conditions in which unregulated growth of alveoli might be directed toward repair of lung injury in the adult. It is clear from studies of liver regeneration that signals originating in extrahepatic organs play a key role in hepatic regeneration. It is especially instructive in this regard that liver size is tightly tied to body size, a liver from a small animal transplanted into a large animal grows to become proportionate to the body size of the recipient, the reverse occurs when a liver from a large animal is transplanted into a small animal. Thus, extrahepatic signals have a critical role in liver regeneration and in establishing liver size. Similarly, extra-pulmonary factors regulate the formation of pulmonary alveoli as corticosteroid impair and thyroid hormones accelerate the formation of alveoli in newborn rats. Likewise, thyroid hormone-induced increases in metabolic rate in adult animals are associated with increased alveolar surface area and probably increased alveolar number. It is clear from these observations that regulation of genetic transcription is complex and involves a hierarchy of other factors as well. However, the cascade of signal molecules and receptors which govern this hierarchy provides many opportunities for interaction, both spatial and temporal, between regulatory genes and signals with both positive and negative effects. It is within this hierarchical context that new opportunities for clinical intervention like that observed for trans-retinoic acid are likely to emerge. Whether retinoic acid treatment results in improved lung function and gas exchange remains to be determined by further morphogenic, pharmacologic and physiologic studies. It is likely that other pharmacologic agents could elicit similar responses and/or ensure functional status for the newly formed structures, perhaps by stimulating their vascularization. However, as the science of retinoic acid action in the regulation of alveolar formation is explored, gaps in our knowledge of the process of alveolization will be uncovered and important signal molecules will likely be identified. From studies of the genes induced by retinoic acid we should be able to gain insight into whether remodeling and development utilize the same pathways. Studies designed to clarify the reversibility of the retinoic acid effect and the activity of other retinoid analogues, agonists, and antagonists in the process of alveolarization will likely uncover other, non-pulmonary systemic agents which induce formation of alveoli. There is reasonably clear evidence that agents expected to alter the lung matrix, e.g., collagenase, growth factors and other transcription factors affect the formation of alveoli. Environmental conditions also influence the formation of alveoli. Oxygen tension is involved in the formation of alveoli and hypoxia exerts a developmentally dependent influence which may be important for alveolization and lung function in individuals born at high altitude. Emphysema-like lesions can be readily induced in rodents by protein-reduced diets, in the absence of any evidence of inflammatory cell accumulations. However, the molecular signals and responsive genes involved in all these observable effects are, as yet, unknown. Fundamental studies of lung alveolar formation also have the potential to re-direct effort to prevention as well as repair should a genetic pre-disposition or biochemical predictor of alveolar destruction be uncovered. Objectives and Scope The objective of this initiative is to encourage studies to define the principles which determine the possibilities for regeneration of lung alveoli. However, since opportunities for repair of damaged tissue in the lung are still poorly understood, research could be directed at understanding the normal mechanisms underlying the formation and functional differentiation of alveoli during development as a framework for understanding the potential to improve the abnormal condition. For example, projects are encouraged that aim to define the molecular events regulating septation and alveolar formation in the developing and postnatal lung. Likewise, the role of suppressive signals and the responding genes that may exist to terminate the process of septation and alveolar formation would be of interest as would identification of extra-pulmonary factors involved in the regulation of alveolar formation and regeneration. Examples of areas of research that might be included under this RFA are as follows: * identification of genes induced by retinoic acid, * identification of stem cells and markers for septal formation during alveolization, * identification of genes involved in regulating septation, * identification and characterization of the retinoic acid receptors involved in alveolization, * regeneration of alveoli in animal models of emphysema, * assessment of the activity of retinoid analogues, agonists, and antagonists on alveolization, * retinoic acid storage and secretion by lung fibroblasts during alveolization, * assessment of functional status of newly formed alveoli, * assessment of the reversibility of the retinoic acid effect on increased septation, * relevance of tissue levels of retinoic acid for alveolization in premature and normal infants and in adults, * comparison of the efficacy of retinoic acid with other morphogenic agents which may effect the formation of alveoli, * toxicity assessment of concentrations of retinoic acid which effect alveolization. These are examples only. Investigators should not feel limited to the subjects mentioned above and are encouraged to submit other topics pertinent to the objectives of the RFA. It is anticipated that human, animal, and in vitro studies would be appropriate. SPECIAL REQUIREMENTS Upon initiation of the program, the NHLBI will 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 concerned with global processes involved in normal lung development are not acceptable. The intent of this program is to focus on the specific generation of alveoli and, therefore, studies of normal alveolar development and its regulation may be included. Applications that propose descriptive studies and do not contain hypothesis driven studies directed at understanding the mechanisms that influence alveolization and its regulation will not be acceptable. Applications that focus on positive effectors of alveolization 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, 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. Investigators also may obtain copies of the policy 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, by June 15, 1998, 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 sent to Dr. C. James Scheirer, at the address listed under INQUIRIES. APPLICATION PROCEDURES The research grant application form PHS 398 (rev. 5/95) is to be used for applying for these grants. These forms 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@od.nih.gov. 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: o FACE PAGE - As a reminder, Item 7 should be completed to indicate Modular Direct Costs requested and Item 8 should reflect Total Costs (Modular Direct plus F&A costs). o 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. o 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 EIGHT modules ($200,000 direct costs) per year may be requested and each applicant may request up to four 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. o 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. Under the justification for the principal investigator, indicate if you are a new investigator (i.e., an investigator without prior R29 or R01 support). - 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. o 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 F&A) 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. o 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. o 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 staff if there is a possibility for an award. o CHECKLIST - No "Checklist" page is required as part of the initial application. A completed Checklist will be requested by NHLBI staff if there is a possibility for an award. 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. APPLICATIONS NOT CONFORMING TO THESE GUIDELINES WILL BE CONSIDERED UNRESPONSIVE TO THIS RFA AND WILL BE RETURNED WITHOUT FURTHER REVIEW. The RFA label available 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. Submit a signed, typewritten original of the application 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 September 4, 1998. 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 Applications will be reviewed for completeness by the CSR and for responsiveness by NHLBI. Incomplete and/or nonresponsive applications will be returned to the applicant without further review. 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 NIH peer review procedures. 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. 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. 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 review, comments on the following aspects of the application will be made 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 assignment of the overall score. (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, the adequacy of plans to include both genders and minorities and their subgroups as appropriate for the scientific goals of the research will be reviewed. Plans for the recruitment and retention of subjects will also be evaluated. The initial review group will also examine the provisions for the protection of human and animal subjects, the safety of the research environment, and conformance with the NIH Guidelines for the Inclusion of Women and Minorities as Subjects in Clinical Research. The roster of the initial review group will be available via the NHLBI homepage. 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. Applications from new investigators will be strongly considered. The anticipated date of award is April 1,1999. INQUIRIES Inquiries concerning this RFA are encouraged. The application is available on the NHLBI home page at the following address: http://www.nhlbi.nih.gov/nhlbi/nhlbi.htm. Potential applicants may request a copy of sample budget and justification pages, as previously stated. The opportunity to clarify any issues or questions from potential applicants is welcome. Direct inquiries regarding programmatic issues to: Mary Anne Berberich, Ph.D. Division of Lung Diseases National Heart, Lung, and Blood Institute 6701 Rockledge Drive Room 10102 Bethesda, MD 10892 Telephone: (301) 435-0222 FAX: (301) 480-3557 Email: Direct inquiries regarding fiscal matters (e.g. sample budget pages) to: Raymond L. Zimmerman Division of Extramural Affairs National Heart, Lung, and Blood Institute 6701 Rockledge Drive, Suite 7154, MSC 7926 Bethesda, MD 20892-7926 Telephone: (301) 435-0171 FAX: (301) 480-3310 Email: zimmermr@gwgate.nhlbi.nih.gov Direct inquires regarding review issues, address the letter of intent to, and mail two copies of the application to: C. James Scheirer, Ph.D. Division of Extramural Affairs National Heart, Lung, and Blood Institute 6701 Rockledge Drive, Room 7220, MSC 7924 Bethesda, MD 20892-7924 Telephone: (301) 435-0266 FAX: (301) 480-3541 Email: james_scheirer@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 U.S.C. 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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