SPECIALIZED CENTERS OF RESEARCH--PATHOBIOLOGY OF FIBROTIC LUNG DISEASE PATHOBIOLOGY OF LUNG DEVELOPMENT CELLULAR AND MOLECULAR MECHANISMS OF ASTHMA Release Date: September 27, 1999 RFA: HL-00-001 National Heart, Lung, and Blood Institute Letter of Intent Receipt Date: January 7, 2000 Application Receipt Date: August 30, 2000 PURPOSE The primary objective of the Specialized Center of Research (SCOR) programs supported by the Division of Lung Diseases is to foster multidisciplinary basic and clinical research enabling basic science findings to be more rapidly applied to clinical problems. The basic and clinical research to be supported through this Request for Applications (RFA) will be related to one of the above three categories. It is expected that results from these SCOR grants will have an impact on the prevention, diagnosis, and treatment of fibrotic lung disease, pulmonary diseases in infants and children, and asthma. HEALTHY PEOPLE 2000 The Public Health Service (PHS) is committed to achieving the health promotion and disease prevention objectives of "Healthy People 2000," a PHS-led national activity for setting priority areas. This RFA, SCORs in Pathobiology of Fibrotic Lung Disease, Pathobiology of Lung Development, and Cellular and Molecular Mechanisms of Asthma, is related to the priority areas of Occupational Safety and Health, Environmental Health, Maternal and Infant Health, Diabetes and Chronic Disabling Diseases and Immunization and Infectious Diseases. Potential applicants may obtain a copy of "Healthy People 2000" (Full Report: Stock No. 017-001-00474-0 or Summary Report: Stock No. 017-001-00473-1) through the Superintendent of Documents, Government Printing Office, Washington, DC 20402-9325 (telephone 202-783-3238) or at http://odphp.osophs.dhhs.gov/pubs/hp2000. ELIGIBILITY REQUIREMENTS Applications may be submitted by for-profit or nonprofit domestic institutions, public or private, such as universities, colleges, hospitals, and laboratories. Awards will not be made to foreign institutions. However, under exceptional circumstances, a foreign component critical to a project may be included as a part of that project. Racial/ethnic minority individuals, women and persons with disabilities are encouraged to apply as Principal Investigators and as project leaders. This RFA is intended to support SCOR grants for basic and clinical investigations. Therefore, applications that include only basic or only clinical research will not be responsive to this RFA. In addition, clinical research projects focused on large epidemiologic studies or large clinical trials will be considered unresponsive to this RFA. The Principal Investigator should be an established research scientist with the ability to ensure quality control and the experience to administer effectively and integrate all components of the program. A minimum time commitment of 25 percent is expected for this individual. The Principal Investigator must also be the project leader of one of the component research projects. If, through peer review, this project is not recommended for further consideration, the overall SCOR application will not be considered further. If this project is judged by peer review to be of low scientific merit, it will markedly reduce the overall scientific merit ranking assigned to the entire application by the review committee. Project leaders must agree to commit at least 20 percent effort to each project for which they are responsible. MECHANISM OF SUPPORT This RFA will use the National Heart, Lung, and Blood Institute (NHLBI) SCOR (P50) grant to support this research program. New and renewal applications will be responsive to this RFA. Responsibility for the planning, direction, and execution of the proposed research will be solely that of the applicant. All current policies and requirements that govern the research grant programs of the NIH will apply to grants awarded under the RFA. Basic and Clinical Research The overall concept of a SCOR program focuses on scientific issues related to diseases relevant to the mission of the NHLBI. It is essential, therefore, that all applications include both basic and clinical research projects. Interactions between basic and clinical scientists are expected to strengthen the research, enhance transfer of fundamental research findings to the clinical setting, and identify new research directions. Plans for transfer of findings from basic to clinical studies should be described. Each SCOR grant application and award must include research involving human patients/subjects. Support may be provided for human biomedical and behavioral studies of etiology, pathogenesis, prevention and prevention strategies, diagnostic approaches, and treatment of diseases, disorders or conditions. Small population-based studies, where the research can be completed within 5 years, may also be proposed. In addition, basic research projects must be included that relate to the clinical focus. A SCOR may also contain one or more core units that support the research projects. Length of SCOR Programs Each NHLBI SCOR program is limited to 10 years of support. Exceptions to this policy will be made only if a thorough evaluation of needs and opportunities, conducted by a committee composed of non-federal experts, determines that there are extraordinarily important reasons to continue a specific SCOR program. Under this policy, a given SCOR grant is awarded for a 5-year project period following an open competition. Only one 5-year competing renewal is permitted, for a total of 10 years of support, unless the SCOR program is recommended for extension. This is the second competition for these three SCOR programs and, therefore, will undergo a comprehensive evaluation during the second year of the upcoming project period. The evaluation will be conducted according to the following timetable: Program Announced: FY 1994 Project Period (First Competition): FY 1997 through FY 2001 Program Reannounced: FY 2000 Project Period (Second Competition): FY 2002 through FY 2006 Letter to SCOR Directors Regarding SCOR Evaluation Plans: FY 2003 (mid-way through year 02 of 2nd project period) SCOR Evaluation Meeting: FY 2003 (late in year 02 of 2nd project period) Notification of SCOR Directors of NHLBI Decision: FY 2004 (mid-way through year 03 of 2nd project period) The NHLBI does not limit the number of SCOR applications in a given SCOR program from one institution nor does it limit the number of applications in the three SCOR programs described in this announcement from one institution. However, there must be a different SCOR principal investigator for each application and each application must be self-contained and independent of the other(s). This does not preclude cooperation planned or possible among participants of SCORs after awards are made. Scientific overlap among applications will not be accepted. If more than one application in a given program is envisioned from an institution, the institution is encouraged to discuss its plans with the NHLBI SCOR program administrator. FUNDS AVAILABLE Applicants may request up to $1,350,000 direct costs, not including facilities and administrative costs (F&A) for collaborating institutions, in the first year with a maximum increase of no more than 3 percent in each additional year requested in the application. Award of grants pursuant to this RFA is contingent upon receipt of funds for this purpose. It is estimated that a total of $26,000,000 will be available for the first year of support for the 3 programs and it is anticipated that up to 15 awards will be made. Equipment is included in the budget limitation. However, requests for expensive special equipment that cause an application to exceed this limit may be permitted on a case-by-case basis following staff consultation. Such equipment requires in-depth justification. Final decisions will depend on the nature of the justification and the Institute's fiscal situation. Consortium Arrangements If a grant application includes research activities that involve institutions other than the grantee institution, the program is considered a consortium effort. Such activities may be included in a SCOR grant application, but it is imperative that a consortium application be prepared so that the programmatic, fiscal, and administrative considerations are explained fully. The published policy governing consortia is available in the business offices of institutions that are eligible to receive Federal grants-in-aid. Consult the latest published policy governing consortia before developing the application. If clarification of the policy is needed, contact Mr. Ray Zimmerman, Grants Operations Branch, NHLBI, 301 435-0171. Applicants of SCOR grants should exercise great diligence in preserving the interactions of the participants and the integration of the consortium project(s) with those of the parent institution, because synergism and cohesiveness can be diminished when projects are located outside the group at the parent institution. F&A costs paid as part of a consortium agreement are excluded from the limit on the amount of direct costs that can be requested. RESEARCH OBJECTIVES Background These SCOR programs focus on three disease areas: fibrosis associated with chronic interstitial lung disease; diseases in the newborn related to abnormal lung development and premature birth; and asthma. All of these diseases remain major public health problems with associated high morbidity and mortality. Emphasis will be placed on understanding these disease processes at the cellular and molecular levels taking advantage of such state of the art approaches as genomic technologies and informatics that are now available. In addition, these SCORs will enable investigators to readily translate their basic research findings to clinical application in well characterized patient populations. The first SCOR program initiated within the Division of Lung Diseases was in 1971 and was entitled Pulmonary SCOR. Since then, several modifications and changes in program direction and focus have been made. In the 1975 and 1980 competitions, SCOR programs were announced in four disease categories: Chronic Airways Diseases, Fibrotic and Immunologic Interstitial Lung Diseases, Pediatric Pulmonary Diseases, and Pulmonary Vascular Diseases; in the 1985 competition the disease categories were: Chronic Diseases of the Airways, Occupational and Immunologic Lung Diseases, Respiratory Disorders of Neonates and Children, and Pulmonary Vascular Diseases. The SCOR program expanded in 1977 with the solicitation for applications in Adult Respiratory Failure. This program was reannounced in 1982 and 1987, resulting in five and four awards, respectively. In response to a congressional mandate, two new SCOR programs, Cardiopulmonary Disorders of Sleep and Cystic Fibrosis, were announced in 1988, resulting in three awards in each program. Following an evaluation, a SCOR competition was announced in 1989 in three programs: Chronic Diseases of the Airways, Occupational and Immunologic Lung Diseases, and Lung Biology and Disease in Infants and Children, with three, four and seven awards being made, respectively. Upon the recommendation of an ad hoc advisory group, the Adult Respiratory Failure and Pulmonary Vascular Diseases programs were combined and a new program in Acute Lung Injury was announced in 1991, with six awards being made. Also in 1991, Cardiopulmonary Disorders of Sleep and Cystic Fibrosis were reannounced, resulting in three awards in Cardiopulmonary Disorders of Sleep and four awards in Cystic Fibrosis. Following a SCOR evaluation, new SCOR programs were announced in 1996 in Neurobiology of Sleep and Sleep Apnea and in Airway Biology and Pathogenesis of Cystic Fibrosis, with four awards being made in each program. The Acute Lung Injury program was also reannounced in 1996, resulting in seven awards. The National Heart, Lung, and Blood Institute implemented a new policy in 1992 that a SCOR program can be supported for a maximum of 10 years, unless the outcome of a programmatic evaluation indicates that further support is warranted. To address this policy, the Division convened a committee, composed of Pulmonary Diseases Advisory Committee members and ad hoc consultants, to evaluate the SCOR programs in Occupational and Immunologic Lung Diseases, Lung Biology and Disease in Infants and Children, and Chronic Diseases of the Airways. As a part of the evaluation process, written and oral comments were received from the SCOR directors of these three programs. As a result of this evaluation, new SCOR programs were recommended in Pathobiology of Fibrotic Lung Disease, Pathobiology of Lung Development, and Cellular and Molecular Mechanisms of Asthma. It is the reannouncement of these three programs for the second 5-years of funding that is the subject of this RFA. Proposed Research Applications must be addressed to only one of the three disease categories identified below to be acceptable for this competition. A SCOR grant is a 5 year program, therefore, an applicant should submit a 5 year plan for all the projects. If a project can be completed in less than 5 years, it should not be included in the application. Examples of research topics of interest for each SCOR program under competition are listed below. These research topics are intended to provide a perspective of the scope of research that would meet the objectives of this program. It is not required that all or any of these topics be included; investigators are encouraged to consider other topics that are relevant to the goals of these programs. Pathobiology of Fibrotic Lung Disease Pulmonary fibrosis is a disease of unknown etiology and has a devastating course. Initiating events are unknown and patients are diagnosed at a stage where little can be done to reduce the morbidity they suffer or prevent their death due to the disease. For example, the mortality from idiopathic pulmonary fibrosis is approximately 50 percent within 5 years of diagnosis. Investigations of this disease are still at a very early and basic stage. The goal of this SCOR program is to increase our knowledge of the disease through laboratory and clinical investigations, with a focus on identifying initiating events, early clinical symptoms, underlying pathogenic mechanisms, and interventions which can slow or reverse the progressive replacement of normal lung tissue with fibrotic tissue. Since fibrosis can appear in a number of chronic interstitial diseases, this program offers the opportunity for in vitro, animal, and human studies on diseases such as idiopathic pulmonary fibrosis, sarcoidosis, and autoimmune-, occupational- and environmentally-induced lung disease. Although the underlying pathogenic mechanisms involved in disease development and progression have benefitted from considerable attention, additional work is required in order to understand the events involved. Pulmonary fibrosis is characterized by replacement of normal lung architecture by fibrotic tissue. The events that lead to an exaggerated accumulation of fibroblasts, collagen, and extracellular matrix involve a number of complex cellular and molecular processes. The nature of both the inflammatory responses and the triggering mechanism that induce the fibrotic response in the lung remain poorly understood. More information is needed about how the normal regulation of fibroblast proliferation and activation and collagen synthesis has been subverted. Metalloproteinases are involved in altering connective tissue matrix and remodeling. Their role in pulmonary fibrosis pathogenesis needs to be further defined. A role for apoptosis and the Fas-Fas ligand pathway in fibrosis also deserve additional investigation. How fibroblasts act as "sentinel" cells and initiators of events leading to fibrosis, and the existence and participation of fibroblasts with unique phenotypes in fibrotic lesions are also areas of interest. The potential role for an autoimmune response and infectious agents in the etiology of pulmonary fibrosis and other interstitial lung diseases are also areas that are relevant to this program. Prime objectives of this program include: further exploration of molecular and cellular interactions between immune and inflammatory responses, fibroblasts, macrophages, and lymphocytes, growth factors, and intracellular signaling pathways in pulmonary fibrosis. Cytokines and other molecular factors act on cells via specific receptors and result in the expression of new genes and gene products that contribute to a fibrotic response. Investigation of the nature of such cell-surface receptors, subsequent intracellular signaling, regulation of gene expression at the translation and transcription level, and identification of transcription factors are areas that are relevant to this SCOR program. Investigation of changes in the expression of specific genes that result in aberrant healing of injury and development of fibrotic lesions are important areas of interest within this program. Identification of biomarkers in blood or bronchoalveolar lavage fluid that would assist in an earlier diagnosis and disease status or progression would be very useful. Although there are animal models that are used in fibrosis research, many suffer from "contamination" with characteristics more similar to acute lung injury. Fibrosis research would benefit from the availability of an animal model of pulmonary fibrosis that more closely resembles the human disease. Steroids have been used as the standard treatment of pulmonary fibrosis. They are inadequate by many parameters - they do little to affect the disease course and have very serious adverse side-effects that can add to the morbidity caused by the disease. Pilot clinical studies to identify and test new interventions are an important part of this SCOR program. The ability to specifically target strategic points in the fibrotic process suggests that new interventions may be successful by interfering with fibroproliferation and collagen deposition. The wide range of other compounds that may be beneficial therapeutically include: suramin, relaxin, prostaglandin-E2, leukotriene antagonists and inhibitors of leukotriene synthesis, captopril and other angiotensin converting enzyme inhibitors, and angiotensin II receptor antagonists. The SCOR program, through the clinical component, provides the opportunity to conduct pilot trials. This SCOR program also provides an opportunity to conduct small scale pilot population-based studies. Pilot studies to determine how to systematically collect, in a standardized way, such information as medical and family history for use in identifying risk factors, the earliest events in the disease course, or the cause(s) of the disease would make a significant contribution to understanding the disease. Similarly, coordinated standardized collection of biological specimens (e.g., blood, bronchoalveolar lavage fluid and cells, biopsy tissue and slides) in association with clinical data could be a valuable resource for testing hypotheses. Although systematic large-scale investigations of the role for environmental exposures, infectious agents, or genetic susceptibility contributions to the disease are beyond the scope of this SCOR program, pilot studies could provide a basis for larger scale case-control studies of the etiology of pulmonary fibrosis, similar to the NHLBI-supported study in sarcoidosis (ACCESS). Pilot studies could also provide the basis for future studies of the possible interaction of environmental and genetic factors and the natural history of pulmonary fibrosis. Pathobiology of Lung Development Bronchopulmonary dysplasia (BPD) is a disease of disordered lung growth characterized by abnormal size and shape of alveoli. The increased incidence of this chronic lung disease, which has accompanied the increased survival of very low birth weight infants and which develops over time ex utero, has identified it as a developmental disease. Likewise, persistent pulmonary hypertension of the newborn (PPHN) represents a failure to achieve the maturational transition in vascular resistance, while lung hypoplasia is a manifestation of arrested lung growth. The mechanisms underlying the development of these diseases are complex but, now, technologically approachable. The objective of this SCOR program continues to be the acquisition and application of new knowledge essential for improving clinical care of infants and children with developmental respiratory disorders. An important goal of this program will be to discern how the process of lung development is altered in lung diseases of infants and children such as BPD, PPHN, lung hypoplasia and chronic bronchiolitis. In recent years, molecular tools have been developed which permit lung biologists and research neonatologists to re-visit the embryology of the lung in molecular terms. We should now be able to delineate the sequence of events that occurs during normal development of the lung organ system so that an instance of pathologic lung development may be identified as a consequence of an altered determinant that results in a specific negative event or cascade of negative events. Therefore, characterization of abnormal lung development is dependent upon the profile of the normal lung, its vasculature, and its immune system. Identification of genetic determinants of structure and of growth factors and tissue cytokines which are involved in regulating growth and structural/functional differentiation of the lung would be an important part of the profile. Other pharmacologic agents which could augment structure, stimulate lung growth or enhance function might be identified or developed on the basis of this information. Delay of maturation of both cellular and local mucosal immune function can initiate inflammatory processes in the course of lung development which, in turn, negatively impact on the process of lung development. Studies concerned with the effect of pre- and post-natal infection and reactive inflammation on the subsequent course of lung development and during the fragile stages of lung maturation in infancy and early childhood would provide information concerning the development of immunity in the lung as a factor in both immediate lung development and long-term lung function. Information on the ontogeny of pulmonary defense mechanisms would be expected to translate into the prevention and more effective management of childhood pulmonary infections and chronic bronchiolitis. The mechanisms involved in the systematic orchestration of the formation of new vessels in the developing embryo, followed by cessation of further vascular proliferation, represent an important area of overlap between organ development (vasculogenesis) and the repair of injured tissue (angiogenesis). Control of vascularization is a cross-cutting area of science with implications for organ development, tissue repair and disease processes. The fundamental relationship between angiogenic/angiostatic modulation in the developing vasculature and in organ development should be examined in the lung. Molecular embryology approaches may also be applied to the ontogeny of the pulmonary vasculature and the etiology, prevention and management of clinical conditions such as PPHN. Studies to elucidate the relationship of early insults to lung development and subsequent lung disease in childhood, adolescence and adulthood are encouraged. Follow-up studies as well as the development of relevant models of aberrant lung development are also encouraged. Rational therapeutic intervention should be explored, if possible, in situations where some aspect of abnormal growth and differentiation can be identified as a significant feature of the clinical disease. The development of profiles and screens for reliable prognostic assessment of disease is also encouraged. Cellular and Molecular Mechanisms of Asthma Asthma is a chronic, often life-long disease with increasing prevalence, morbidity and mortality. The complexities of human asthma are only now becoming fully appreciated. The focus of this SCOR reannounncement continues to be the delineation of the cellular and molecular mechanisms underlying acute and chronic asthma through multidisciplinary basic and clinical investigations. Inflammation, hyperresponsiveness, and airflow obstruction are the hallmarks of asthma and thought to result from multiple, independent, or interacting pathways involving genetic, environmental and inflammatory phenomena. The molecular mechanisms leading to asthma heterogeneity require investigation as well as the parameters that differentiate atopic patients with and without asthma. Elucidating the cellular and molecular mechanisms leading to and relationship between chronic inflammation, airway remodeling and repair, airways hyperresponsiveness, persistence of asthma, and the fixed and reversible airway obstruction associated with asthma, are important goals of this program. Of specific interest are studies on the potential sources of long-term airway "memory" cells; events regulating the function of recruited and resident airway cells; the role of cytokines, adhesion molecules, growth factors and proteases in mediating the physiologic or anatomic changes seen in chronically inflamed airways; cell-cell and cell matrix interactions; the role of innate immunity in the initiation/perpetuation of airway inflammation; mechanisms leading to mucous cell and goblet cell hyperplasia and mucus hypersecretion; how all of the these changes influence the natural history of asthma; and how they can be therapeutically arrested or prevented. Identification of biomarkers of inflammation that reflect disease activity are needed to help monitor the progression of asthma and the effectiveness of therapy. If the aberrant cellular activities leading to asthma are due to dysfunction of cell receptor signaling mechanisms, it will be important to establish the cellular, molecular, and physiologic basis of receptor/signal transduction dysfunction in asthma. Maternal, fetal, immune, infectious and other factors involved in the onset and development of asthma early in life and its persistence or reemergence in later life are incompletely understood. Childhood infections have been postulated to play a role, either causative or protective, in the development of childhood asthma. It is important to establish how some respiratory pathogens contribute to development and exacerbation of, or the protection from childhood asthma, including the effects of the timing, duration, and frequency of exposure to infections, their interaction with allergens, influence on the immune system, and the potential impact of early treatment with antibiotics on the development of the disease and its sequelae. Progress is being made in establishing the chromosomal location for some of the asthma associated genes. However, identification of asthma associated gene(s), either contributing to predisposition to asthma, the development and regulation of airway inflammation and remodeling, modifying the course of the disease, or patient's response to therapy remains to be established. The availability of existing longitudinal and clinical databases provides an essential component to base studies of gene-gene and gene-environment interactions. Molecular genetic techniques and high throughput gene expression technologies with sophisticated informatics need to be brought into asthma research to help advance the goal of identifying asthma associated genes, reasons for their altered expression, and the nature and function of the proteins for which they code. Studies in human subjects and with human materials, especially children and young adults, are strongly encouraged. Large epidemiologic studies or clinical studies requiring longer than 5 years will not be supported under this announcement. Appropriately designed in vitro and in vivo studies with animal models are encouraged, but must be relevant to asthma and suitable for addressing the mechanistic information sought in this solicitation. Use of state of the art genomic technologies and informatics is especially encouraged where appropriate, to accelerate research on asthma pathogenesis and treatment. SPECIAL REQUIREMENTS Special features of SCOR grants are: o They provide opportunities for investigators with mutual or complementary interests to engage in multidisciplinary research focusing on a specific respiratory disorder. o Inherent in the SCOR program is a special interaction between the SCOR director, the grantee institution and the Division of Lung Diseases. Funds are specifically allocated in a SCOR grant for investigators from different SCORs to meet and discuss problems of mutual interest and to participate in workshops addressing common research areas. o The Division's overall SCOR program and each SCOR grant undergo periodic evaluation. The progress reports are prepared for the information of the National Heart, Lung, and Blood Advisory Council, the Division of Lung Diseases staff, and ad hoc members of SCOR evaluation groups. Requirements of SCOR grants: o Research conducted at the individual centers must include both basic science and clinical research, to assure that advances in the basic sciences are translated rapidly into clinical applications and that clinical needs will provide a direction for the basic sciences. Therefore, each SCOR grant application and award must include one or more research projects involving human subjects/patients. The basic research projects should clearly relate to the disease focus and contribute to elucidation of mechanisms underlying the disease, or to improved diagnosis or management of the disease. o Each component project requires a well-described hypothesis, preliminary data and a time-table for conducting the proposed investigations. o If core facilities are included, the relationship of each component project to each core should be described. o The principal investigator should be an established scientist with the ability to ensure quality control and the experience to administer effectively and integrate all components of the program. A minimum time commitment of 25 percent is expected for this individual. The principal investigator must also be the project leader of one of the component research projects. If, through peer review, this project is not recommended for further consideration, the overall SCOR application will not be considered further. If this project is judged by peer review to be of low scientific merit, it will markedly reduce the overall scientific merit ranking assigned to the entire application by the review committee. o Project leaders must agree to commit at least 20 percent effort to each project for which they are responsible. Investigators with minimal research experience but promising credentials may participate; however, it is expected that most of the project directors will be investigators with significant research experience. o Each SCOR must have a well-delineated organizational structure and administrative mechanism that foster interactions between investigators, accelerate the pace of research, and ensure a productive research effort. o If a project director transfers to another institution, support for the project will normally not be continued as a consortium. Because of the size and complexity of a SCOR, prospective applicants are urged to consult with the staff of the Division of Lung Diseases early in the preparation of the application (see INQUIRIES Section). To provide opportunity for such interactions, the time frame for implementation of this program includes an ample interval between the release of this announcement and the receipt date for applications. All applications must be prepared according to the Special Instructions that are available from the Director, Division of Lung Diseases (see INQUIRIES Section). INCLUSION OF WOMEN AND MINORITIES IN RESEARCH INVOLVING HUMAN SUBJECTS It is the policy of the NIH that women and members of minority groups and their subpopulations must be included in all NIH supported biomedical and behavioral research projects involving human subjects, unless a clear and compelling rationale and justification is provided that inclusion is inappropriate with respect to the health of the subjects or the purpose of the research. This policy results from the NIH Revitalization Act of 1993 (Section 492B of Public Law 103-43). All investigators proposing research involving human subjects should read the "NIH Guidelines For Inclusion of Women and Minorities as Subjects in Clinical Research", which have been published in the Federal Register of March 9, 1994 (F 59 11146-11151), and reprinted in the NIH GUIDE FOR GRANTS AND CONTRACTS of March 18, 1994, Volume 23, Number 11, available on the web at: https://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 the NIH that children (i.e., individuals under the age of 21 years) 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: https://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. LETTER OF INTENT Prospective applicants are asked to submit, by January 7, 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, and does not enter into the review of subsequent applications, it assists the NHLBI staff to estimate the potential review workload and to avoid conflict of interest in the review. The letter of intent is to be sent to: C. James Schreirer, Ph.D. Division of Extramural Affairs National Heart, Lung, and Blood Institute 6701 Rockledge Drive, Room 7220, MSC 7924 Bethesda, Maryland 20892-7924 Telephone: 301 435-0266 FAX: 301 480-3541 E-mail: SchreireJ@nih.gov APPLICATION PROCEDURES The research grant application form PHS 398, rev. (4/98), is to be used in applying for these grants. These forms are available at most institutional offices of sponsored research or may be obtained from the Division of Extramural Outreach and Information Resources, National Institutes of Health, 6701 Rockledge Drive, MSC 7910, Bethesda, Maryland 20892-7910, telephone (301) 710-0267, E-mail: GrantsInfo@nih.gov. Special instructions for preparing a SCOR application are available by contacting Director, Division of Lung Diseases, as indicated under "INQUIRIES." The RFA label included in grant application form PHS 398 (rev. 4/98) must be affixed to the bottom of the face page of the application. Failure to use this label could result in delayed processing of the application such that it may not reach the review committee in time for review. In addition, the RFA title and number must be typed on line 2 of the face page of the application form and the "YES" box must be marked. The sample RFA label available at: https://grants.nih.gov/grants/funding/phs398/label-bk.pdf has been modified to allow for this change. Please note this is in pdf format. Send or deliver 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 Two Rockledge Centre 6701 Rockledge Drive, Room 1040 Bethesda, Maryland 20892 Bethesda, Maryland 20817 (for express/courier service) Send two additional copies of the application to C. James Schreirer, Ph.D. at the address listed under LETTER OF INTENT. It is important to send these two copies at the same time as the original and three copies are sent to the Center for Scientific Review (CSR); otherwise, the NHLBI cannot guarantee that the application will be reviewed in competition for this RFA. Applications must be received by August 30, 2000. If an application is received after that date, it will be returned to the applicant without 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 CSR and responsiveness by the NHLBI staff. Incomplete applications or applications deemed not responsive to the RFA 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. Applicants should submit the highest quality applications possible to CSR as no site visits or reverse site visits will be held. As part of the initial merit review, a streamlined process may be used by the initial review group in which the scientific merit of applications relative to other applications received in response to the RFA will be determined. Applications judged to be of high scientific merit will be discussed and be assigned a priority score, and will also receive a second level of review by the National Heart, Lung, and Blood Advisory Council. Applications determined to be of low scientific merit will be withdrawn from further consideration and the principal investigator and the official signing for the applicant organization will be notified. Factors to be considered in the evaluation of each application will be similar to those used in review of traditional research grant applications and, in addition, will include overall proposed interactions among basic and clinical research projects. Major factors to be considered in the evaluation of applications include: o Scientific merit of the proposed basic and clinical research projects including significance, importance, and appropriateness of the theme; innovation, originality, and feasibility of the approach; and adequacy of the experimental design. o Leadership, scientific stature, and commitment of the program director; competence of the investigators to accomplish the proposed research goals and their time commitment to the program; and the feasibility and strength of consortium arrangements. o Collaborative interaction among basic and clinical research components, the balance between them, and plans for transfer of potential findings from basic to clinical studies. o Adequacy of the environment for performance of the proposed research including clinical populations and/or specimens; laboratory facilities; proposed instrumentation; quality controls; administrative structure; institutional commitment; and, when needed, data management systems. o Appropriateness of the budget for the proposed program. AWARD CRITERIA The anticipated date of award is December 1, 2001. Awards will be made according to priority score, availability of funds, and programmatic priorities. INQUIRIES Written and telephone inquiries concerning the RFA are encouraged. The opportunity to clarify any issues or questions from potential applicants is welcome. Special supplemental instructions for the preparation of grant applications for SCORs may be obtained by contacting Director, Division of Lung Diseases, as indicated below. Anyone submitting a grant application must follow the special supplemental instructions for preparing an application. Direct inquiries regarding programmatic issues to: Suzanne Hurd, Ph.D. Director, Division of Lung Diseases National Heart, Lung, and Blood Institute 6701 Rockledge Drive, Room 10018, MSC 7952 Bethesda, Maryland 20892 Telephone: 301 435-0233 FAX: 301 480-3547 E-mail: Hurds@nih.gov Direct inquiries regarding fiscal matters to: Raymond Zimmerman Grants Operations Branch Division of Extramural Affairs National Heart, Lung, and Blood Institute 6701 Rockledge Drive, Room 7154, MSC 7926 Bethesda, Maryland 20892-7926 Telephone: 301 435-0171 FAX: 301 480-3310 E-mail: ZimmermR@nih.gov AUTHORITY AND REGULATIONS This program is described in the Catalog of Federal Domestic Assistance No. 93.838. Awards are made under authorization of the Public Health Service Act, Title IV, Part A (Public Law 78-410, as amended by Public Law 99-158, 42 USC 2241 and 285) and administered under PHS grants policies and Federal Regulations 42 CFR 52 and 45 CFR Part 74. This program is not subject to the intergovernmental review requirements of Executive Order 12372 or Health Systems Agency review. The PHS strongly encourages all grant and contract recipients to provide a smoke-free workplace and promote the non-use of all tobacco products. In addition, Public Law 103-227, the Pro-Children Act of 1994, prohibits smoking in certain facilities (or in some cases, any portion of a facility) in which regular or routine education, library, day care, health care or early childhood development services are provided to children. This is consistent with the PHS mission to protect and advance the physical and mental health of the American people.
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