COORDINATION OF VASCULARIZATION AND LUNG DEVELOPMENT RELEASE DATE: September 24, 2002 RFA: HL-03-006 National Heart, Lung, and Blood Institute (NHLBI) (http://www.nhlbi.nih.gov) LETTER OF INTENT RECEIPT DATE: February 19, 2003 APPLICATION RECEIPT DATE: March 19, 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 National Heart, Lung, and Blood Institute (NHLBI) invites applications to address the interactive relationships between vasculogenesis, including angiogenic/angiostatic modulation, and the developing lung. The purpose of this RFA is to stimulate research that will increase our knowledge of these interactive processes by supporting fundamental studies focusing on the cellular and molecular mechanisms that coordinate the formation of the lung and its vasculature during the process of normal lung development or that contribute to arrested or aberrant lung development. It is expected that these studies will involve a systems biology approach to lung development and will gather information on the temporo-spatial expression of regulatory genes, growth factors and receptors involved in the process of vasculogenesis and angiogenesis during lung development. Such new information would provide the basis for intervention to reverse arrested alveolization, which is a feature of the chronic lung disease observed in very-low- birth-weight premature infants. Such new information might also clarify some of the apparent associations between early developmental events and the pathobiology of adult lung disease. RESEARCH OBJECTIVES Background The development of the lung vasculature is a highly orchestrated process, involving the formation of new vessels, followed by cessation of further vascular proliferation. During development, there are two distinct and separate processes, vasculogenesis and angiogenesis, which are considered responsible for organ vascularization. Vasculogenesis is the organization of undifferentiated endothelial cells into vascular structures. It is followed by angiogenesis, whereby previously formed vessels extend into under-vascularized regions. In this process, endothelial cells proliferate and sprout from the previously formed vessels, forming new vascular structures. The precise alignment of lung structural components and vasculature is required for normal pulmonary function. Infants born with congenital alveolar-capillary dysplasia die of respiratory failure because of failure to oxygenate effectively. However, little is understood about the mechanisms that regulate and coordinate growth and differentiation of normal lung and its vasculature or about the factors that lead to disrupted alignment of the vasculature and the arrested growth of alveolar structure observed in the presentation of bronchopulmonary dysplasia (BPD) in the post-surfactant era. There is great potential for treating a variety of neonatal diseases by employing various factors to stimulate normal vascular development or to interfere with pathological processes, but realizing that potential depends on clarification of the many complex relationships that are operative during normal lung development. Growth factors such as basic fibroblast growth factor (FGF) and vascular endothelial growth factor (VEGF) are known to enhance migration, proliferation and dedifferentiation of endothelial cells, leading to the appearance of vascular structures in tissue undergoing repair. Other findings suggest that the unique temporal and spatial expression of specific VEG-F isoforms during lung development promotes the vascular patterning of the lung as it develops. Likewise, an important balance between angiogenic modulators like interleukin 8 (IL8) and angiostatic modulators like interleukin 10 (IL10) may be modulated by a biochemical cascade of cytokine signals which may serve to regulate normal development, but which may also be elaborated excessively as a consequence of conditions which result in injury. For instance, intermittent hypoxia is a relatively common condition, which occurs during maternal sleep disordered beathing and during apnea of prematurity, producing deleterious fluctuations in the levels of free radicals, cytokines, and growth factors leading to lung injury. The control of vascularization in the developing lung via paracrine mechanisms represents an important area of scientific overlap between organ development and the repair of injured tissue. Problems and opportunities in studying the process of lung development arise from the fact that different lung components e.g. the vasculature, the extracellular matrix and the parenchyma of the lung, are interacting with one another while they are developing concurrently. For instance, reduction in the level of the transcription factor Fox f1 causes neonatal pulmonary hemorrhage and abnormalities in the process of alveologenesis, implicating it in the regulation of mesenchyme- epithelial interaction critical for lung morphogenesis. Little is known about the composite of early, complex interactions of this type, which ultimately determine the structure and function of the adult pulmonary vasculature. An operational understanding of how to foster precise alignment of lung structural components and vasculature is required for successful function of lung transplants, tissue implants and/or revitalization and construction of operative artificial organs. BPD, which is now primarily seen in very low birth weight premature infants who are surviving in increased numbers in the post-surfactant era, is believed to be a clinical example of developmental mis-alignment. The prevailing view of this disorder is that arrested development of the vasculature may be the factor that limits formation of alveolar structure. Knowledge gained through studies on the developing vasculature could potentially yield an appropriate clinical approach to this problem. Likewise, understanding these interactions is fundamental in estimating the potential utility of any approach to therapeutic intervention in the area of adult lung injury and vascular proliferative disease. Understanding the influence of parallel development of the lung and its vasculature could uncover information useful in preventing the development of co-morbid conditions later in life. For example, in the neonatal rat, the number of alveoli increases logarithmically during the first week of life. Dexamethasone treatment during this critical period of lung development in rats resulted in sustained lung hypoplasia and increased the severity of subsequent, hyperoxia-induced, pulmonary hypertension. In other studies, vitamin A, which appears to stimulate the generation of alveoli in adult mice, has been shown to effect the localization of VEGF at axonal points in the vasculature of neonatal rats, and may, thereby, stimulate the development of alveolar capillaries. Objectives and Scope This RFA is intended to stimulate investigations of the molecular mechanisms that coordinate the development of lung vasculature and parenchyma. Multidisciplinary studies that bring together investigators with expertise in developmental biology of the lung and vasculature are encouraged. New approaches that address basic areas that have the potential to lead to development of novel treatments for developmental and congenital abnormalities are also encouraged. In addition to those discussed above, some research topics that will be responsive to this program are listed below. These are only examples, applicants are encouraged to propose other topics that address the overall goals of this initiative, consistent with the SPECIAL REQUIREMENTS section below. o assess the temporo-spatial relationships between the expression of genes governing the regulation of lung structural development and genes involved in pulmonary vascularization o develop methods to explore whether vascularization initiates structural organization, or whether signals liberated by the developing lung activate recruitment of vascular primordia into the developing lung and participate in their structural differentiation o address the positive and negative roles of inflammation during the coordinated development of the lung and the pulmonary vasculature. o track the simultaneous progression of vascular and parenchymal stem cells during lung development. o develop vascularized lung tissue for eventual clinical replacement of damaged tissue. o Characterize the effects of intermittent hypoxia on the coordination between vasculogenesis and the developing lung, and elucidate the underlying pathological mechanisms. MECHANISM OF SUPPORT This RFA will use the NIH R01 (investigator-initiated research project grant) 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 September 30, 2003. This RFA uses just-in-time concepts. It also uses the modular budgeting format. (see https://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. FUNDS AVAILABLE The NHLBI intends to commit approximately $4,000,000 in FY 2003 to fund 8 to 10 new and/or competitive continuation grants in response to this RFA. An applicant may request a project period of up to four years and a budget for direct costs of up to $250,000 per year. Because the nature and scope of the proposed research will vary from application to application, it is anticipated that the size and duration of each award will also vary. Although the financial plans of the NHLBI to 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. Since the total costs for a subcontract or consortium are included in the direct cost request, one additional module of $25,000 above the cap may be requested for the facilities and administrative costs associated with third party agreements. A module requested for this purpose must be clearly identified in the budget justification section of the application, and will be restricted for this purpose only at the time of award. 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 o Faith-based or community based organizations 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 The NHLBI will sponsor meetings to encourage the exchange of information among investigators who participate in this program. In the preparation of the budget for the grant application, applicants should factor in travel funds for an annual program meeting to be held in Bethesda, Maryland. Applicants should also include a statement in their application, indicating their willingness to participate in such meetings. General Clinical Research Centers Applicants from institutions that have a General Clinical Research Center (GCRC) funded by the NIH National Center for Research Resources may wish to identify the GCRC as a resource for conducting the proposed research. If so, a letter of agreement from either the GCRC program director or principal investigator should be included with the application. Restrictions and Exclusions Studies are limited to a systems biology approach to lung development. Therefore, applications focused exclusively on lung vascular development will not be considered responsive. Likewise, applications focused exclusively on lung structural development, or primarily on growth factors and growth factor receptors, will not be considered responsive. 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: Dr. Mary Anne Berberich Division of Lung Diseases National Heart, Lung, and Blood Institute 6701 Rockledge Drive, Room 10102, MSC 7952 Bethesda, MD 20892-7952 Telephone: (301) 435-0222 FAX: (301) 480-3557 Email: berberim@nhlbi.nih.gov o Direct your questions about peer review issues to: Dr. Anne P. Clark 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: Mr. Owen O. Bobbitt Grants Operations Branch Division of Extramural Affairs National Heart, Lung, and Blood Institute 6701 Rockledge Drive, MSC 7926 Bethesda, MD 20892-7926 Telephone: (301) 435-0177 FAX: (301) 480-0422 Email: bobbitto@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 should be sent, on or before the date listed at the beginning of this document, to Dr. Anne Clark at the address listed under WHERE TO SEND INQUIRES. 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 https://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. SPECIFIC INSTRUCTIONS FOR MODULAR GRANT APPLICATIONS: All applications submitted to this RFA must use the modular budget format. Applications requesting up to $250,000 per year in direct costs must be submitted in a modular grant format. Applications requesting one module ($25,000) above the cap due to subcontract or consortium facilities and administrative costs associated with third party agreements must also be submitted in modular format and may request up to $275,000 per year in direct costs. 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 https://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 https://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: https://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 and all five collated sets of Appendix material must be sent to Dr. Anne Clark at the address listed under WHERE TO SEND INQUIRIES. 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 WHERE TO SEND 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 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 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? 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: February 19, 2003 Application Receipt Date: March 19, 2003 Peer Review Date: June/July 2003 Council Review: September 4-5, 2003 Earliest Anticipated Start Date: September 30, 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 (https://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-001.html), a complete copy of the updated Guidelines are available at https://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 https://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 https://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-039.html. 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 https://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. 93.837, 93.838, and 93.839 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 https://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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