FUNCTIONAL HETEROGENEITY OF THE PERIPHERAL, PULMONARY AND LYMPHATIC VESSELS RELEASE DATE: September 24, 2002 RFA: HL-03-004 National Heart, Lung, and Blood Institute (NHLBI) (http://www.nhlbi.nih.gov) LETTER OF INTENT RECEIPT DATE: January 14, 2003 APPLICATION RECEIPT DATE: February 14, 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 functional heterogeneity of the arterial and venous sides of the peripheral and pulmonary vessels as well as the lymphatics. The purpose of this RFA is to support fundamental studies focusing on the cellular and molecular mechanisms that contribute to the functional differences which account for the heterogeneous nature of the adult peripheral, pulmonary and lymphatic vessels. These studies are to be limited to non-coronary arteries, pulmonary vessels, and the venous and lymphatic circulations. RESEARCH OBJECTIVES Background The economic and public health burdens of peripheral and pulmonary vascular diseases and diseases of the lymphatics are immense, contributing to increased morbidity and mortality especially as people age. An important observation is that arteries, veins and lymphatics are structurally and functionally heterogeneous, at the regional, tissue, cellular and molecular levels. Examples are the blood-brain barrier, the unique pulmonary circulation, blood flow regulation in the various vascular beds, and localized vascular lesions. It is likely that these structural and functional similarities and differences contribute to the etiology of peripheral vascular, pulmonary and lymphatic diseases. It is here that functional heterogeneity becomes important physiologically, and especially in the treatment of the large numbers of vascular diseases. Functional heterogeneity refers to the phenotype (from the tissue, cellular and to the molecular levels) that is unique to different vessels. These characteristics may be related to the diverseness of the endothelial cells, myocytes and other components of a particular vessel or even vascular bed, or may be regionally specific within the same vessel or vascular bed. Understanding how all the vascular components interact and contribute to the functional heterogeneic nature of the vasculature is a neglected area in vascular biology. New opportunities abound in unraveling this field with the tools and approaches that are currently available to the investigator. Therefore, a better understanding of the cellular and molecular factors that contribute to this heterogeneity should provide insight into the pathogenesis of peripheral vascular, pulmonary and lymphatic diseases, and would lead to new and more effective treatments. The derivation of vascular heterogeneity is multifaceted, beginning when the nascent vasculature is laid down in the embryo. Structural and functional changes occur during organogenesis, driven by genetic, environmental, hormonal, hematologic and tissue specific factors, as well as by intralumenal hemodynamic forces, eventually resulting in the formation of the mature vessel. Although the mechanisms that drive early vascular development are being actively pursued, very little is known about the mechanisms contributing to structural and functional remodeling of the nascent vessels that ultimately define the properties of the adult vascular tree. Furthermore, most vascular studies focus primarily on the arterial side of the circulation with few addressing the venous and, fewer still, the lymphatic circulations. The heterogeneity of the vasculature is further exemplified in the interaction of blood proteins and cells with the vessel wall, where these interactions may be modified by different shear forces and inflammatory mediators of the disparate vascular beds. On the arterial side, hemostatic balance is believed to be regulated by vascular bed- specific endothelial cell signaling pathways, involving specific endothelial gene expression unique to the vessel and regulated by surrounding tissue. While some progress has been made with coronary vessels, the peripheral arteries have been essentially neglected. On the venous side, the etiology and risk factors for venous thrombosis are different from those contributing to arterial thrombosis. Venous thrombosis is most common in the lower extremities and is favored in slow flow and low oxygen environments. The distinctive properties of the venous endothelium, its response to shear forces, and its interaction with blood proteins and cells leading to thrombus formation need to be better understood. Even within a specific vascular system, such as the pulmonary circulation where there are phenotypic and functional differences in vascular cells, the functional significance of these differences remains to be resolved. Further still, the lymphatic circulation has a unique position in its relationship to the arterial and venous circulations in terms of vascular permeability, fluid transfer, macromolecular homeostasis and immunity in that there is no heart to provide hemodynamic pressure and propulsion, flow is obstructed easily, and collaterals may not form. In congenital cases, lymphedema may be asymmetric, even though a mutation is present throughout the body. With respect to the vessel itself, the majority of studies continue to focus on the inner and medial layers of the vessel rather than on the outer wall. The outer wall, which includes the adventitial layer and in certain vessels the vasa vasorum, has historically been assigned a passive role of simply providing nutrients to the medial and inner layers. Now, these layers are felt to play a significant role in maintaining vessel integrity, and may contribute to the initiation and progression of certain types of vascular disease. Little is known about the phenotypic differences in these outer layers and how they contribute to vascular functional heterogeneity. The outcome of these studies ultimately should lead to better treatment of peripheral vascular, pulmonary and lymphatic diseases, and may also lead to the development of highly specific and dynamic imaging probes that will provide for more accurate diagnoses and assessments of treatment. Objectives and Scope This RFA will support studies on the cellular and molecular mechanisms that contribute to the differences and functional heterogeneity of the adult peripheral, pulmonary and lymphatic vessels. Although studies that compare functional differences between dissimilar vascular systems, such as pulmonary versus non-pulmonary vessels are encouraged, they are not required. It is strongly encouraged that applicants propose studies that will relate findings to the functional differences unique to a particular vessel or vascular bed. Since there is little current research explicitly designed to study vascular heterogeneity, these studies may require interdisciplinary collaborations between vascular cellular and molecular biologists, hematologists, clinicians and vascular surgeons. Research aims that would be considered responsive include, but are not limited to: o studies on the factors involved with vessel maturation and remodeling in different organs o development and utilization of genetically engineered animal models to study hemodynamic forces and vascular heterogeneity and function o studies to differentiate the functional and genetic differences between arterial, venous and lymphatic endothelial and smooth muscle cells o studies to address the metabolic and immunologic differences of the arterial, venous and lymphatic circulations o studies on the mechanisms controlling the homing behavior of endothelial precursor cells and how this relates to vascular heterogeneity o mechanistic studies that focus on the role of the adventitia and vasa vasorum in maintaining vessel integrity and in the initiation and progression of disease o studies on the factors which cause lymphatic and vascular malformations o studies that focus on the molecular characteristics of the leg veins and their interaction with blood o studies that investigate the properties of the peripheral and pulmonary vascular signaling pathways and how perturbations lead to a prothrombic state o studies that address how specific differences in, for example, endothelial cell surface receptors and adhesion molecules, permeability and fluid transport properties, response to hypoxia or hyperoxia, or interactions with other vascular cells influence development and susceptibility to lung injury o studies using hypoxia, including intermittent hypoxia, to elucidate the basis of heterogeneity of different vascular beds 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 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. 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 Upon initiation of the program, the NHLBI will sponsor annual 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 the one meeting each year to be held in Bethesda, Maryland. Applicants should also include a statement in the applications indicating their willingness to participate in such meetings. The first such meeting likely will take place within 3 months of award. Restrictions and Exclusions Although studies that compare functional differences between dissimilar vascular systems, such as pulmonary versus non-pulmonary vessels are encouraged, they are not required. However, it is strongly encouraged that applicants must propose studies that will relate findings to the functional differences unique to a particular vessel or vascular bed. In this regard, studies addressing the coronary arterial vessels will not be considered responsive unless they focus on the adventitial layer or the vasa vasorum. Studies using human tissue will be considered responsive. General Clinical Research Center 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. 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. Stephen S. Goldman Division of Heart and Vascular Diseases National Heart, Lung, and Blood Institute Rockledge 2 6701 Rockledge Drive, MSC 7956 Bethesda, MD 20892-7956 Telephone: (301)435-0560 FAX: (301) 480-2858 Email: goldmans@nhlbi.nih.gov Dr. Dorothy B. Gail Division of Lung Diseases National Heart, Lung, and Blood Institute Rockledge 2 6701 Rockledge Drive, MSC 7952 Bethesda, MD 20892-7952 Telephone: (301)435-0222 FAX: (301) 480-3557 Email: gaild@nhlbi.nih.gov Dr. Pankaj Ganguly Division of Blood Diseases and Resources National Heart, Lung, and Blood Institute Rockledge 2 6701 Rockledge Drive, MSC 7950 Bethesda, MD 20892-7950 Telephone: (301)435-0070 FAX: (301) 480-1046 Email: gangulyp@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/carrier 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 Operation Branch Division of Extramural Affairs National Heart, Lung, and Blood Institute Rockledge 2 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 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 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 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: 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 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 and five 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 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 sent 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 INQUIRES. 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 or 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 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 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: January 14, 2003 Application Receipt Date: February 14, 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 (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. 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 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 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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