ROLE OF INFECTIOUS AGENTS IN VASCULAR DISEASES Release Date: September 10, 2001 RFA: RFA-HL-02-002 National Heart, Lung, and Blood Institute (http://www.nhlbi.nih.gov) Letter of Intent Receipt Date: January 7, 2002 Application Receipt Date: February 12, 2002 THIS RFA USES "MODULAR GRANT" AND "JUST-IN-TIME" CONCEPTS. MODULAR INSTRUCTIONS MUST BE USED FOR RESEARCH GRANT APPLICATIONS REQUESTING LESS THAN $250,000 PER YEAR IN ALL YEARS. MODULAR BUDGET INSTRUCTIONS ARE PROVIDED IN SECTION C OF THE PHS 398 (REVISION 5/2001) AVAILABLE AT http://grants.nih.gov/grants/funding/phs398/phs398.html. PURPOSE The National Heart, Lung, and Blood Institute (NHLBI) invites research grant applications to conduct studies on the role of infectious agents in the development of vascular disease. A potentially important role of infectious agents in the development of vascular disease is suggested by studies showing an association between vascular diseases and certain bacterial and viral infections. The objective of this program is to encourage in vitro and in vivo research on the specific cellular and molecular mechanisms by which infectious agents contribute to atherogenesis. The secondary objective is to encourage the development of the biological basis for therapeutic interventions that target these molecular mechanisms. 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 Request for Applications (RFA), "Role of Infectious Agents in Vascular Diseases" 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/. 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 and 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. MECHANISM OF SUPPORT This RFA will use the National Institutes of Health (NIH) investigator- initiated grant award (R01) mechanism. Responsibility for the planning, direction, and execution of the proposed project will be solely that of the applicant. The total project period for an application submitted in response to this RFA may not exceed four years. This RFA is a one-time solicitation. Future unsolicited competing continuation applications will compete with all investigator-initiated applications and be reviewed according to the customary peer review procedures. The anticipated award date is September 30, 2002. Specific application instructions have been modified to reflect "MODULAR GRANT" and "JUST-IN-TIME" streamlining efforts that have been adopted by the NIH. Complete and detailed instructions and information on Modular Grant applications have been incorporated into the PHS 398 (rev. 5/2001). Additional information on Modular Grants can be found at http://grants.nih.gov/grants/funding/modular/modular.htm FUNDS AVAILABLE The NHLBI intends to commit approximately $3 million in FY 2002 to fund up to eight new grants in response to this RFA. An applicant may request a project period of up to four years and a budget for direct costs not to exceed $250,000 per year, or ten modules of $25,000 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. RESEARCH OBJECTIVES Background Established cardiovascular risk factors such as hypercholesterolemia, smoking, diabetes, and hypertension do not fully explain the etiology or incidence of coronary heart disease. Such findings suggest that additional, less substantiated risk factors may contribute significantly to vascular pathogenesis. For a number of years, observational studies in humans have provided intriguing hints linking certain viral and bacterial infections to atherosclerosis, coronary events, or restenosis after arterial intervention. The in vivo documentation of the involvement of members of the herpes virus family in atherosclerotic processes ranges from solid evidence of causality in chickens to observational and associative studies in humans. More recently, a growing body of in vitro work has suggested possible pathophysiological mechanisms by which herpes viruses, most notably cytomegalovirus (CMV), might contribute to vascular disease. Regarding bacterial agents, the association of Chlamydia pneumoniae and atherosclerosis has been demonstrated indirectly by seroepidemiology, and this obligate intracellular prokaryote has been detected in atherosclerotic plaques. In studies performed in vitro, atherogenic changes in vascular cells following infection by Chlamydia have been described. Recent studies combining animal models of atherosclerosis with animal models of infectious disease have produced results consistent with a vasculopathic role for infectious agents in mammals. Both Chlamydia and CMV are ubiquitous pathogens found in 50 to 70% of most populations where they can reside intracellularly in a chronic, persistent or latent state. Whether periods of reactivation and productive infection are required for pathogenesis is unknown. Although Chlamydia and CMV have been found in vascular lesions, the primary cell types in which these agents act is still unclear. Macrophages are thought to be one of the primary sites of CMV latency, and macrophage infiltration of injured vascular wall endothelium may be the method by which CMV is deposited in plaques. However, the conditions and specific factors controlling macrophage permissiveness for CMV, establishment of CMV latency, and reactivation of productive infection are not well understood. Similarly, the local factors and conditions that mediate the ability of CMV to infect vascular endothelium or smooth muscle cells are largely unknown. It has been hypothesized that Chlamydia antigens found in plaques may have been deposited by circulating macrophages carrying phagocytized or parasitic Chlamydia from the lung. A number of in vitro studies in macrophages, endothelial cells, and smooth muscle cells have identified mechanisms by which Chlamydia, CMV or other herpes viruses might potentiate atherogenesis. Such mechanisms include increases in proliferation, procoagulant proteins, leukocyte adhesion, and cytokine production, as well as augmented cholesterol uptake and esterification. CMV immediate-early gene products inhibit the tumor suppressor p53, which may mediate the accumulation of smooth muscle cells seen in atherosclerotic plaques. DNA fragments from herpes simplex virus (HSV), and CMV have been shown to immortalize aortic smooth muscle cells. Chlamydia and herpes virus infection of endothelium each result in increased expression of growth factors, cytokines, and cell adhesion molecules, which promotes binding of inflammatory cells--a cascade that may be accompanied by endothelial dysfunction. Chlamydia, HSV or CMV infection of endothelial cells also increases acute phase reactants, and each of these pathogens alters cholesterol metabolism in infected cells. For many of these infection-related cellular changes, a cause-and-effect relationship remains to be proven definitively by the identification of the specific molecular interactions that trigger these events. Mechanistic studies suggest that gene products of infectious agents can act directly on vascular cells. Nevertheless, an important question is whether infectious agents--only sometimes found in atheroma--can exert vasculopathic effects without infecting vascular cells. For example, the atherogenic changes seen in infected endothelial and smooth muscle cells can be caused by systemic inflammation due to chronic infection and activation of circulating inflammatory cells. In addition, another important mechanism by which infectious agents might increase vascular disease without directly infecting vascular cells is through exacerbation or augmentation of well known risk factors such as hypercholesterolemia. Several animal models have been developed for vascular diseases, including atherosclerosis, in non-human primates, rabbits and mice. CMV infection has been studied in numerous animals including rats, mice and guinea pigs, and Chlamydia infection has been studied in rabbits and mice. More recent studies combining infectious-agent and atherosclerotic animal models have shown increases in various measures of vascular disease such as prevalence of arterial inflammatory cell infiltrates or accelerated arterial intimal thickening. While the development of these models is essential, it is critical that animal models be established that mimic the subclinical status of these pathogens in man. The establishment of infectious disease/vascular disease animal models opens the opportunity to test specific inhibitors of the disease process, which can provide solid evidence of causality. Also, these models allow rational development of antiviral and antibacterial therapies including drugs, vaccines, and other novel approaches that target specific pathogenic mechanisms. A preventive CMV vaccine has been available for a number of years but it has limited efficacy and is unlikely to affect latent CMV. A Chlamydia vaccine is not yet available. While traditional vaccines may be beneficial for uninfected individuals, they may be ineffective against existing intracellular latent and chronic pathogens. Therefore, the testing of a variety of therapeutic possibilities that target direct, indirect, or systemic atherogenic mechanisms of infectious agents seems warranted. It is possible that infectious agents currently showing weak associations with vascular disease, as well as infectious agents not previously associated with atherogenesis, may contribute to vascular pathogenesis. Indeed, the presence of such unrecognized agents could be a confounding factor in studies of infectious agents that are associated with increased vascular disease. Therefore, studies of new agents and those that have been shown to have marginal association to vascular disease will continue to be important. Research Areas Areas of research that would be considered responsive to the RFA are listed below. These areas are not inclusive, however, and investigators are strongly encouraged to discuss proposed submissions with the appropriate staff at the NHLBI. o Biology of Latency and Infection: Identification and study of in vivo sites of latency at the organ, tissue, and cellular levels, characterization of conditions/factors controlling permissiveness for infection, establishment of latency, and reactivation of productive infection in macrophages, endothelium, smooth muscle cells, and other relevant cell types. o Molecular Mechanisms of Pathogenesis: Characterization of direct, specific molecular interactions between genomes/gene products of infectious agents and infected cells, and the resulting atherogenic potential of altered cell characteristics and functions, study of indirect or systemic effects of infectious agents harbored in both vascular and non-vascular-wall cells, such as macrophages, and other cell types, studies of specific mechanisms by which infectious agents might augment or exacerbate traditional risk factor such as hypercholesterolemia, hypertension and others. o Animal Models: Development and characterization of models of atherosclerosis in which the infectious agent is the primary cause of atherosclerosis. Specific aims should include studies elucidating the underlying mechanisms. In addition, plans to disseminate the animal models and willingness to share these models and tissue from the models with the scientific community are expected to be part of these proposals. o Animal Studies: Studies in animal models of infection and atherosclerosis that define the status of the infectious agent including pathogen load, temporal and spatial distribution, and state of latency/activation with the aim of precisely determining and substantiating in vivo pathobiologic mechanisms of atherogenesis. These studies may be done either in existing models or in models developed specifically for this purpose. o Molecular Interventions: Development of specific interventions in both in vitro and in vivo systems that target the molecular mechanisms of atherogenesis induced by infectious agents in order to establish causality, and determine possible therapeutic approaches. o Other Pathogens: Study of vasculopathic effects of agents with potential association with atherogenesis. EXCLUSIONS Applications focusing on the following areas will be considered nonresponsive to the objectives of this initiative: o Applications that propose development of animal models without plans to study the underlying molecular mechanisms, and prevention or treatment modalities. o Applications that propose to study the biology of latency of infection not related to atherogenesis. o Applications that propose to study the role of HIV in atherogenesis. o Applications that propose large clinical or epidemiological studies. SPECIAL REQUIREMENTS Upon initiation of the program, NHLBI will sponsor periodic meetings to encourage exchange of information and collaborations among investigators who participate in this program. Applicants should request travel funds for the Principal Investigator and key personnel for two 2-day meetings, to be held the first and the third year of the program, most likely in Bethesda, Maryland. Applicants should include a statement in their applications indicating their willingness to participate in these meetings, and to interact openly and to share animal models, tissues and special reagents with other study participants to provide the greatest promise for scientific advances from the approved research scope of the awards. 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 sub-populations must be included in all NIH-supported biomedical and behavioral research projects involving human subjects, unless a clear and compelling rationale and justification are 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 research involving human subjects should read the UPDATED "NIH Guidelines for Inclusion of Women and Minorities as Subjects in Clinical Research," published in the NIH Guide for Grants and Contracts on August 2, 2000 (http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-048.html), a complete copy of the updated Guidelines are available at http://grants.nih.gov/grants/funding/women_min/guidelines_update.htm: The revisions relate to NIH defined Phase III clinical trials and require: a) all applications or proposals and/or protocols to 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) all investigators to report accrual, and to conduct and report analyses, as appropriate, by sex/gender and/or racial/ethnic group differences. INCLUSION OF CHILDREN AS PARTICIPANTS IN RESEARCH INVOLVING HUMAN SUBJECTS It is the policy of NIH 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 was published in the NIH Guide for Grants and Contracts, March 6, 1998, and is available at the following URL address: http://grants.nih.gov/grants/guide/notice-files/not98-024.html Investigators also may obtain copies of these policies from the program staff listed under INQUIRIES. Program staff may also provide additional relevant information concerning the policy. 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. This policy announcement is found in the NIH Guide for Grants and Contracts Announcement dated June 5, 2000, at the following website: http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-039.html. URLS IN NIH GRANT APPLICATIONS OR APPENDICES All applications and proposals for NIH funding must be self-contained within specified page limitations. Unless otherwise specified in an NIH solicitation, internet addresses (URLs) should not be used to provide information necessary to the review because reviewers are under no obligation to view the Internet sites. Reviewers are cautioned that their anonymity may be compromised when they directly access an Internet site. 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 RFA 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. LETTER OF INTENT Prospective applicants are asked to submit 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 a subsequent application, the information that it contains allows NHLBI staff to estimate the potential review workload and plan the review. The letter of intent is to be sent to Dr. Deborah Beebe at the address listed under INQUIRIES by January 7, 2002. APPLICATION PROCEDURES The PHS 398 research grant application instructions and forms (rev. 5/2001) at http://grants.nih.gov/grants/funding/phs398/phs398.html are to be used in applying for these grants. This version of the PHS 398 is available in an interactive, searchable PDF format. Beginning January 10, 2002, the NIH will return applications that are not submitted on the 5/2001 version. For further assistance contact GrantsInfo, Telephone 301/435-0714, Email: GrantsInfo@nih.gov. SPECIFIC INSTRUCTIONS FOR MODULAR GRANT APPLICATIONS 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, reviewers and NIH staff. The research grant application form PHS 398 (rev. 5/2001) at http://grants.nih.gov/grants/funding/phs398/phs398.html is to be used in applying for these grants, with modular budget instructions beginning on page 13 of the application instructions. 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. 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 Dr. Deborah Beebe at the address listed under Inquiries. 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. 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 yet received such a letter within three weeks after submitting the application, contact Dr. Deborah Beebe at the address listed under Inquiries. 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 Upon receipt, applications will be reviewed for completeness by the CSR and responsiveness by the NHLBI. Incomplete and/or non-responsive applications will be returned to the applicant without further consideration. Applications that are complete and responsive to the RFA will be evaluated for scientific and technical merit by an appropriate peer review group convened by the NHLBI in accordance with the review criteria stated below. As part of the initial merit review, all applications will receive a written critique and 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, assigned a priority score, and 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 the application 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 assigning the overall score, weighting them as appropriate for each application. Note that the application does not need to be strong in all categories to be judged likely to have major scientific impact and thus deserve a high priority score. For example, an investigator may propose to carry out important work that by its nature is not innovative but is essential to move a field forward. (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 to the above criteria, in accordance with NIH policy, all applications will also be reviewed with respect to the following: o The adequacy of plans to include both genders, minorities and their subgroups, and children as appropriate for the scientific goals of the research. Plans for the recruitment and retention of subjects will also be evaluated. o The reasonableness of the proposed budget and duration in relation to the proposed research. o 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 The adequacy of the proposed plan to share and disseminate data, animal models (newly developed and existing), tissues and special reagents. Schedule Letter of Intent Receipt Date: January 7, 2002 Application Receipt Date: February 12, 2002 Peer Review Date: May-June, 2002 Council Review: September 5-6, 2002 Earliest Anticipated Start Date: September 30, 2002 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. INQUIRIES Inquiries concerning this RFA are encouraged. The opportunity to clarify any issues or answer questions from potential applicants is welcome. Direct inquiries regarding programmatic issues to: Eser Tolunay, Ph.D. Division of Heart and Vascular Diseases National Heart, Lung, and Blood Institute 6701 Rockledge Dr., Room 10-186, MSC 7956 Bethesda, MD 20892 Telephone: (301) 435-0550 FAX: (301) 480-2858 Email: TolunayE@nhlbi.nih.gov Send letter of intent and 2 copies of the application, and direct inquiries regarding review matters to: Deborah P. Beebe, Ph. D. Chief, Review Branch Division of Extramural Affairs National Heart, Lung, and Blood Institute 6701 Rockledge Dr., Room 7178, MSC 7924 Bethesda, MD 20892-7924 Telephone: (301) 435-0270 Fax: (301) 480-3541 Email: BeebeD@nhlbi.nih.gov Direct inquiries regarding fiscal matters to: Owen Bobbitt Grants Operations Branch Division of Extramural Affairs National Heart, Lung, and Blood Institute 6701 Rockledge Dr., Room 7134, MSC 7926 Bethesda, MD 20892 Telephone: (301) 435-0177 FAX: (301) 480-0422 Email: BobbittO@nhlbi.nih.gov AUTHORITY AND REGULATIONS This program is described in the Catalog of Federal Domestic Assistance No. 93.837. 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 and Federal Regulations 42 CFR 52 and 45 CFR Parts 74 and 92. This program is not subject to the intergovernmental review requirements of Executive Order 12372 or Health Systems Agency review. The PHS strongly encourages all grant 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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