IMMUNOPATHOGENESIS OF CHRONIC GRAFT REJECTION Release Date: May 30, 2000 RFA: AI-00-013 National Institute of Allergy and Infectious Diseases (http://www.niaid.nih.gov) National Heart, Lung, and Blood Institute (http://www.nhlbi.nih.gov) Letter of Intent Receipt Date: September 1, 2000 Application Receipt Date: October 23, 2000 APPLICATIONS IN RESPONSE TO THIS REQUEST FOR APPLCATIONS (RFA) MUST BE PREPARED USING A MULTI-PROJECT GRANT APPLICATION FORMAT; SPECIFIC INSTRUCTIONS FOR COMPLETING THE APPLICATIONS ARE IN AN NIAID BROCHURE ENTITLED INSTRUCTIONS FOR APPLICATIONS FOR MULTI-PROJECT AWARDS. PURPOSE The Division of Allergy, Immunology and Transplantation (DAIT) of the National Institute of Allergy and Infectious Diseases (NIAID), and the Divisions of Heart and Vascular Diseases (DHVD) and Lung Diseases (DLD) of the National Heart, Lung, and Blood Institute (NHBLI) invite applications for program projects in the immunopathogenesis of chronic graft rejection. Programs should be designed to: elucidate the cellular and molecular mechanisms involved in chronic allograft rejection; implement new, or improve upon existing therapeutic approaches to enhance graft survival; or, develop new prognostic tools which will aid in diagnosing the outcome of allograft transplant. 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), Immunopathogenesis of Chronic Graft Rejection , is related to: Heart Disease and Stroke, Respiratory Diseases, Diabetes and Chronic Disabling Diseases. Potential applicants may obtain a copy of "Healthy People 2010" at http://www.health.gov/healthypeople/ ELIGIBILITY REQUIREMENTS Applications may be submitted by domestic, 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. Multi-institutional applications are acceptable and encouraged. Foreign institutions are not eligible to apply. Racial/ethnic minority individuals, women, and persons with disabilities are encouraged to apply as Principal Investigators. MECHANISM OF SUPPORT The mechanism of support will be the program project (P01) grant. This type of award supports broadly based multidisciplinary research programs that have a well-defined central research focus or objective. An important feature of the program project is that the interrelationships of the individual scientifically meritorious projects will result in a greater contribution to the overall program goals than if each project were pursued individually. Standard NIH policy requires P01 applications to consist of a minimum of three interrelated individual research projects that contribute to the program objective. This type of award also can provide support for certain common resources termed cores. Such resources should be utilized by two or more projects within the award. Responsibility for the planning, direction, and execution of the proposed project will be solely that of the applicant. The total project period may not exceed 5 years. The anticipated award date is July 1, 2001. FUNDS AVAILABLE The estimated total funds [direct & facilities + administration (F&A)] available for the first year of support for this RFA will be $5 million. In fiscal year 2001, the NIAID and the NHLBI plan to make approximately 4 awards related to this RFA. This level of support is dependent on the receipt of a sufficient number of applications of high scientific merit. Applications in excess of $1,250,000 in total (direct and F&A) costs in the first year will be returned as non-responsive. Because the nature and scope of the research proposed may vary, it is anticipated that the size of each award will also vary. The usual NIH policies governing grants administration and management will apply. Although this program is provided for in the financial plans of the NIAID and the NHBLI, awards pursuant to this RFA are contingent upon the availability of funds for this purpose. Funding beyond the first and subsequent years of the grant will be contingent upon satisfactory progress during the preceding years and availability of funds. At this time, the NIAID and NHLBI have not determined whether or how this solicitation will be continued beyond the present RFA. RESEARCH OBJECTIVES Background With the advent of modern immunosuppressive therapies, one-year post- engraftment survival approaches 90% for some organs. However, long-term graft survival still remains poor, with 25% to 65% of all grafts failing within five years post-transplantation. While many of the pathological mechanisms which cause acute rejection have been defined and are effectively treated or prevented with standard immunosuppressive therapies and modern HLA typing techniques, these therapies have not significantly improved long-term clinical outcomes for many transplant patients. The complex, multistage processes that result in chronic rejection of vascularized allografts are poorly understood. While the determination of organ failure often relies on measurable physiological parameters, the early stages of chronic rejection are difficult to diagnose. Detection requires invasive procedures to obtain graft biopsies for histological evaluation. Organs undergoing chronic rejection manifest some common pathologic criteria such as: progressive vascular obliteration; infiltration of immunocytes; interstitial and tubular atrophy; graft arteriosclerosis; and a marked fibrotic response. The cellular and molecular mechanisms underlying these histopathological hallmarks remain obscure. Research Objectives and Scope Organ transplantation is the definitive therapy for most forms of end- stage organ disease; however, chronic graft rejection, the deleterious effects of global, life-long immunosuppressive therapy, and the shortage of donor organs continue to limit its success. Chronic graft rejection is the primary obstacle to long-term successful organ transplantation. While the armamentarium of immunosuppressive agents is impressive and the future prospect of tolerance induction to alleviate allograft rejection holds considerable promise, little is known about the pathologic mechanisms that effect chronic rejection. To better integrate basic science and clinical medicine, this RFA seeks to focus these disciplines on the pathogenesis of chronic graft rejection, the processes which foreshadow rejection of allografts long-term, and the development of diagnostic procedures which will aid in predicting the prognosis of allograft transplants. To this end, this RFA will fund research to: 1) elucidate the cellular and molecular events during the induction and effector phases of chronic solid organ graft rejection; 2) develop improved therapeutic approaches to enhance long-term graft survival; and 3) develop better prognostic tests to define and predict outcomes of allograft transplants. Many cell-cell, cell-matrix, and intracellular pathways have been implicated in the complex pathogenesis of chronic rejection. Recent studies have focused on chemokine/growth factor-receptor intracellular signaling pathways and on genes induced during the early onset of rejection. These pathways and genes lend themselves as targets for pharmacological and therapeutic intervention for both early diagnosis and possible prevention of graft rejection. In addition, cell-cell interaction between T cells, macrophages, and endothelial cells and interactions of cells with the extracellular matrix have been implicated in the onset and progression of chronic rejection. Thus, studies focused on these and other relevant cellular and molecular pathways that can serve as potential targets for intervention are of major interest. Applications that capitalize on the strengths of collaboration between physicians and scientists to maximize the potential for discovering novel approaches relevant to transplantation for human diseases are strongly encouraged. To foster the teamwork between basic scientists and transplant clinicians, NIH is especially interested in program projects that define the pathogenesis of chronic graft rejection in humans. Areas of particular interest are: identification of the targets recognized by the immune response in chronic rejection; definition of the relative contributions of immunocytes to the process of chronic rejection; studies of the response of targets cells (e.g. endothelial cells, smooth muscle cells) to lymphocytes, cytokines and growth factors; delineation of the molecular process(es) of chronic rejection, including studies of cytokines, infiltrating cell types, and methods to attenuate the actions of these cells and their products; development of new therapeutic approaches and improvement of existing therapeutic approaches for the treatment and/or prevention of chronic rejection. Examples of relevant studies include, but are not limited to, the following: o Recent scientific findings have highlighted the involvement of T cells, macrophages and their respective gene-products as causal for chronic rejection. The interaction of these cells and their factors with endothelial cells of the allograft may, in part, determine the success of the match. Studies which further analyze the infiltrating cellular components and their soluble mediators in in vivo human models are encouraged. o Cytokines are expressed in heart, kidney, lung, liver and skin allografts following engraftment and during acute and chronic rejection. While the majority of information concerning cytokine biology in transplantation has come from animal models, little is known about the role of cyokines in human allograft rejection. Cytokines and growth factors may play important mechanistic roles in transplant rejection. For example, IL-2, IL-6, IL-10, IL-1beta and TNF-alpha have been implicated in the pathogenesis of arteriosclerosis, and IL-4, TGF-beta may be involved in chronic allograft nephropathy. Alternatively, the mediators might serve as diagnostic indicators for the analysis of allograft rejection or graft dysfunction. A better understanding of the role these factors play in chronic rejection may provide justification for their use as interventional targets. o Certain solid organ allografts display alterations in adhesion molecules and extracellular matrix (ECM) components upon rejection. However, it has yet to be determined whether these alterations are a consequence or a cause of the pathogenesis of allograft rejection. If causal in nature, could these molecules be used as targets or markers to prevent chronic rejection? For example, in several organs, upregulation of endothelial adhesion molecules in the vascularized allograft is hypothesized to function in T cell recruitment to the graft site. Analysis of T cell:endothelial cell interactions in vivo and new information concerning the potential inhibition of such associations by anti-ICAM-1, -VCAM, or E-selectin may lead to strategies to decrease the risk of graft failure. o Although the long-term rejection of allografts is sometimes accompanied by the presence of infectious agents, the role of infections in chronic rejection is poorly understood. Recent studies have demonstrated a correlation between the presence of certain pathogens (e.g., cytomegalovirus, Mycobacterium tuberculosis, and Microsporidia) and a poor prognosis for long-term graft survival. Do these pathogens ignite an immune response which is detrimental to the allograft? Is the pathogenesis by which infectious agents induce chronic rejection similar/identical to naturally occurring chronic rejection in the absence of infection? Studies which aim to analyze the basic science behind the pathogenesis, with the goal of clinical intervention, are encouraged. o With the aim of developing new approaches, or improving existing approaches for the early detection of chronic organ rejection, applicants are encouraged to create and test novel, non-invasive diagnostic techniques for the early detection of chronic rejection. Technical applications are sought which partner basic science principles with clinical approaches. These techniques are particularly needed in the post-transplantation period during which the early stages of chronic rejection should be defined, characterized and potentially eliminated. SPECIAL AREAS OF INTEREST Heart A number of cardiac diseases result in heart failure, for which cardiac transplantation is the only successful treatment. The primary indications for heart transplantation are coronary artery disease and cardiomyopathy in adults, and congenital heart disease and cardiomyopathy in children. Nearly 5 million people in the United States have some form of heart failure and 20,000 to 40,000 of these could benefit from a heart transplant. In patients who survive the first year after transplant, chronic rejection is the major cause of death, arising in 50-60 percent of patients surviving five years post- transplant. Chronic rejection is manifested in the coronary arteries of the transplanted heart as a concentric and diffuse intimal hyperplasia such that distal portions of the coronary vessels occlude. There are multiple theories as to the etiology of this disease, but few confirmed risk factors have been defined. There are no proven therapies to prevent or treat chronic rejection, and the only cure is re-transplantation. Current methods of diagnosis include intravascular ultrasound and/or coronary angioscopy. Chronic rejection in heart transplantation is recognized by a variety of names: cardiac allograft vasculopathy (CAV), cardiac transplant atherosclerosis, and accelerated graft arteriosclerosis. The disease is believed to be caused by the immune response of the recipient to the donor organ and such responses have been shown to involve humoral and cellular immune components, as well as, complement, cytokines and growth factors. More studies are needed to: 1) define the risk factor(s) that contribute to CAV and their mechanism(s) of action; 2) develop new or improved methods to predict and diagnose early onset of CAV; and 3) identify viable targets for prevention and/or treatment of chronic rejection in the heart; and 4) determine the role, if any, of non- antigen specific responses, such as ischemia/reperfusion injury or brain death, in the development of chronic rejection. Kidney Kidney disease is a severe and costly public health problem that is increasing in the U.S. An estimated 10.9 million Americans suffer from kidney disease, including more than 360,000 who depend on dialysis or a kidney transplant to survive. Kidney transplantation accounts for 57 percent of all transplant procedures. This statistic reflects the fact that many common diseases, including diabetes and glomerulonephritis (a heterogeneous group of immunological diseases), result in end-stage renal disease (ESRD), for which transplantation is the preferred treatment. Unfortunately, chronic allograft dysfunction is the most common cause of ESRD beyond the post-transplantation periods, accounting for 25-30 percent of patients awaiting re-transplantation. While the exact mechanism(s) responsible for chronic renal allograft failure remain obscure, it is generally agreed that both alloantigen-dependent and alloantigen-independent factors influence chronic allograft nephropathy. These immune-mediated attacks often result in chronic allograft nephropathy (CAN) and are characterized by obliterative vasculopathy, glomerulosclerosis, and interstitial fibrosis. One of the major hypotheses for the etiology of CAN argues that destruction of the donor tissue arises due to a response from the recipient's allo-immune response to nonself antigens. Numerous immune cell types, immunoregulatory molecules, and cytokines have been implicated in the pathologic processes associated with CAN. Advanced studies are needed to define the: relative contributions of the humoral and cellular based immune systems in CAN; mechanisms responsible of the pathogenesis of chronic dysfunction in solid renal grafts; and, approaches to better diagnosis, management and treatment of CAN. Lung Lung transplantation is a viable therapeutic option and its use has increased since the first successful operations in the early 1980s. Most lung transplantations are performed for four major disease processes: chronic obstructive lung disease (COPD), cystic fibrosis (CF), idiopathic pulmonary fibrosis (IPF) and pulmonary hypertension (PH). As a result of improvements in surgical techniques, immunosuppression and postoperative management, the one-year survival rate is approximately 80 percent. In 50 percent of long-term lung transplant recipients, chronic lung allograft rejection manifests as bonchiolitis obliterans (OB), a complication involving scar formation and fibrosis in small airways accompanied by intimal thickening and sclerosis of vessels (chronic vascular rejection). Studies are necessary to identify and characterize the events that initiate and maintain repetitive injury to endothelium or epithelium that is followed by repair and proliferation of smooth muscle cells or fibroblasts, leading to development of fibrotic obstructive lesions. Further, studies focused on antigen-dependent processes, influenced by early immunologic events such as acute rejection and continuing host allo- responsiveness, or alloantigen-independent processes, such as prolonged ischemia, reperfusion injury or recurrent infection, are necessary to understand the progressive changes that occur in chronic rejection and the pathogenesis of OB. SPECIAL REQUIREMENTS Applications should emphasize: collaborative research between basic scientists and clinical investigators; the use of new and innovative approaches to enhance understanding of the immunopathogenesis of chronic graft rejection and the clinical application and relevance of such approaches; and the use of the most up-to-date concepts and techniques. Applications from multi-institutional consortia are encouraged in order to unsure the appropriate mix of scientific and clinical interests of transplantation in humans within the RFA. For applications in heart transplantation, clinical research must be included in one of two ways: 1) a clinical project involving human patients or material from human patients; or 2) one or more clinical aims in each project. The clinical project may be a clinical study or a mechanistic study attached to an ongoing trial. Projects that are descriptive only will not be acceptable. Projects may include animal models but only when the animal model can be definitely shown to be relevant to the human disease; and not in lieu of the requirement for either or both 1) or 2) above. For studies of lung transplantation, animal models are acceptable. However, evidence must be provided that it is a valid model of chronic rejection/bronchiolitis obliterans following lung transplantation. In addition, the proposed applications must have at least one clinical project involving human patients or utilizing human cells and/or tissue. A single application may contain projects related to chronic rejection in the heart, lung and/or kidney. Basic research and preclinical studies using laboratory animals is not encompassed under this solicitation for other transplantation systems. It is imperative that all applications focus on the immunopathogenesis of chronic rejection in humans. Clinical trials evaluating the safety and efficacy of therapeutic regimens in humans will not be supported under this RFA; however, the analysis of data obtained from ongoing or completed clinical trials related to chronic rejection that are supported by public or private organization is highly encouraged. Please note, in order to assure a strong level of commitment on the part of the principal investigator of each project, a minimum of 15% effort on the application is required. Projects not meeting this requirement will be returned as non-responsive. STUDY POPULATIONS 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 are 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 read the "NIH Guidelines for Inclusion of Women and Minorities as Subjects in Clinical Research," published in the Federal Register of March 28, 1994 (FR 59 14508-14513) and in the NIH Guide for Grants and Contracts, Vol. 23, No. 11, March 18, 1994, and is available on the web at: http://grants.nih.gov/grants/guide/notice-files/not94-100.html 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 Lawrence Kerr, Ph.D. listed under INQUIRIES. Program staff may also provide additional relevant information concerning the policy. 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. LETTER OF INTENT Prospective applicants are asked to submit by September 1, 2000 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, does not commit the sender to submit an application, and does not enter into the review of a subsequent application, the information that it contains allows NIAID staff to estimate the potential review workload and plan the review. The letter of intent is to be sent to Dr. Meherotra listed under INQUIRIES. APPLICATION PROCEDURES Applicants for P01 grants must follow special application guidelines in the NIAID Brochure entitled INSTRUCTIONS FOR APPLICATIONS FOR MULTI- PROJECT AWARDS (April 1999); this brochure is available via the WWW at: http://www.niaid.nih.gov/ncn/grants/multibron.htm The research grant application form PHS 398 (rev. 4/98) is to be used in applying for these grants. Application kits are available at most institutional offices of sponsored research and 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: GrantsInfo@nih.gov. Applications are also available on the World Wide Web at http://grants.nih.gov/grants/forms.htm. For purposes of identification and processing, item 2a on the face page of the application must be marked "YES" and the RFA number AI-00-013 and the words "IMMUNOPATHOGENESIS OF CHRONIC REJECTION" must be typed in. The RFA label and line 2 of the application should both indicate the RFA number. The RFA label must be affixed to the bottom of the face page. 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. The sample RFA label available at: http://grants.nih.gov/grants/funding/phs398/label-bk.pdf has been modified to allow for this change. Please note this is in pdf format. Applications must be received by October 23, 2000. Applications that are not received as a single package on the receipt date or that do not conform to the instructions contained in PHS 398 (rev. 4/98) Application Kit (as modified in, and superseded by, the NIAID BROCHURE ENTITLED "INSTRUCTIONS FOR APPLICATIONS FOR MULTI-PROJECT AWARDS"), will be judged non-responsive and will be returned to the applicant. It is highly recommended that the appropriate NIAID or NHBLI program contact be consulted before submitting the letter of intent and during the early stages of preparation of the application. (See program contact under INQUIRIES). Submit a signed, typewritten original of the application, including the Checklist, and three signed, exact, single-sided 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 mail or courier service) At the time of submission, two additional exact copies of the grant application and all five sets of any appendix material must be sent to Dr. Meherotra listed under INQUIRIES. Concurrent submission of an R01 and a Component Project of a Multi- project Application: Current NIH policy permits a component research project of a multi-project grant application to be concurrently submitted as a traditional individual research project (R01) application. If, following review, both the multi-project application and the R01 application are found to be in the fundable range, the investigator must relinquish the R01 and will not have the option to withdraw from the multi-project grant. This is an NIH policy intended to preserve the scientific integrity of a multi-project grant, which may be seriously compromised if a strong component project(s) is removed from the program. Investigators wishing to participate in a multi- project grant must be aware of this policy before making a commitment to the Principal Investigator and awarding institution. 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 could be included with the application. SPECIAL INSTRUCTIONS FOR COMPLETION OF APPLICATIONS IN RESPONSE TO THIS RFA Applicants for P01 grants must follow special application guidelines in the NIAID Brochure entitled INSTRUCTIONS FOR APPLICATIONS FOR MULTI- PROJECT AWARDS (April 1999); this brochure is available via the WWW at: http://www.niaid.nih.gov/ncn/grants/multibron.htm The brochure presents specific instructions for sections of the PHS 398 (rev. 4/98) application form that should be completed differently than usual. For all other items in the application, follow the usual instructions in the PHS 398. REVIEW CONSIDERATIONS Review Procedures Upon receipt, applications will be reviewed for completeness by the NIH Center for Scientific Review and for responsiveness by NIAID staff. 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 Division of Extramural Activities, NIAID 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 Advisory Allergy and Infectious Diseases Council. Review Criteria The general criteria for P01 grant applications are presented in the NIAID brochure entitled INSTRUCTIONS FOR APPLICATIONS FOR MULTI-PROJECT AWARDS (April 1999). Additional review criteria specific to this RFA are: Schedule Letter of Intent Receipt Date: September 1, 2000 Application Receipt Date: October 23, 2000 Scientific Review Date: February, 2001 Advisory Council Date: June, 2001 Earliest Date of Award: July, 2001 AWARD CRITERIA Funding decisions will be made on the basis of scientific and technical merit as determined by peer review, program balance, and the availability of funds. INQUIRIES Written and telephone inquiries concerning this RFA are encouraged. The opportunity to clarify any issues or questions from potential applicants is welcome. Requests for the NIAID brochure "INSTRUCTIONS FOR APPLICATIONS FOR MULTI-PROJECT AWARDS" as well as inquiries regarding programmatic (eligibility and research scope) issues, may be directed to: Lawrence D. Kerr, Ph.D. Division of Allergy, Immunology and Transplantation (DAIT) National Institute of Allergy & Infectious Diseases (NIAID) National Institutes of Health 6700-B Rockledge Rd., Rm. 5129 Bethesda, Maryland 20892-7640 Telephone: (301) 496-5598 Fax: (301) 402-2571 Email: LKerr@niaid.nih.gov National Heart, Lung, and Blood Institute (NHBLI) For chronic rejection in the heart: Judith Massicot-Fisher, Ph. D. National Heart, Lung and Blood Institute Division of Heart and Vascular Diseases 6701 Rockledge Drive MSC 7940 Bethesda, MD 20892-7940 Telephone: (301) 435-0528 Fax: (301) 480-1454 E-mail : massicoj@nhlbi.nih.gov For chronic rejection in the lung(s): Susan Garfinkel, Ph.D. NHLBI, Division of Lung Diseases 2 Rockledge Center 6701 Rockledge Drive Bethesda, MD 20892-7952 Telephone: (301)435-0222 FAX: (301)480-3557 E-mail: GarfinkS@NHLBI.NIH.GOV Direct inquiries regarding preparation of the application and review issues, and address the letter of intent to, and mail two copies of the application and all five sets of appendices to: Dr. Priti Meherotra Division of Extramural Activities National Institute of Allergy and Infectious Diseases Room (insert), MSC-7616 6700-B Rockledge Drive Bethesda, MD 20892-7616 Telephone: (301)(435-9369) FAX: (301)(402-2638) Email: PM158@nih.gov Direct inquiries regarding fiscal matters to: Ms. Pamela Fleming Division of Extramural Activities National Institute of Allergy and Infectious Diseases Room 2119, MSC-7614 6700-B Rockledge Drive Bethesda, MD 20892-7614 Telephone: (301) 402-6580 FAX: (301) 480-3780 E-mail: PFlemming@niaid.nih.gov AUTHORITY AND REGULATIONS This program is described in the Catalogue of Federal Domestic Assistance No. 93.855, (DAIT) and 93.837 (DHVD) and 93.838 (DLD). 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 Public Health Service 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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