Full Text HL-96-014 SCOR IN NEUROBIOLOGY OF SLEEP AND SLEEP APNEA, AIRWAY BIOLOGY AND PATHOGENESIS OF CYSTIC FIBROSIS, AND ACUTE LUNG INJURY NIH GUIDE, Volume 25, Number 23, July 12, 1996 RFA: HL-96-014 P.T. 34 Keywords: Pulmonary Diseases Sleep Disorders Injury National Heart, Lung, and Blood Institute Letter of Intent Receipt Date: December 13, 1996 Application Receipt Date: July 22, 1997 PURPOSE The primary objective of the Specialized Centers of Research (SCORs) programs supported by the Division of Lung Diseases is to foster multi disciplinary 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 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 sleep apnea, cystic fibrosis and acute lung injury. 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 Request for Applications (RFA), SCORs in Neurobiology of Sleep and Sleep Apnea, Airway Biology and Pathogenesis of Cystic Fibrosis, and Acute Lung Injury, is related to the priority areas of diabetes and chronic disabling diseases, unintentional injury, 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). ELIGIBILITY REQUIREMENTS Applications may be submitted by for-profit and nonprofit domestic institutions, public and private, such as universities, colleges, hospitals, and laboratories. This RFA is intended to support SCOR grants for basic and clinical investigations. Applications that include only basic or only clinical research will not be responsive to this announcement. In addition, clinical research projects focused on large epidemiologic studies or large clinical trials will be considered unresponsive to this RFA. 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. Women and minority investigators are encouraged to apply. 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 determined non-competitive, 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 Institutes of Health (NIH) specialized centers (P50) mechanism to support this research program. All applications received in response to the Neurobiology of Sleep and Sleep Apnea and Airway Biology and Pathogenesis of Cystic Fibrosis programs will be considered as new applications. Applications submitted by current SCOR groups must be sufficiently changed to meet the objectives of one of these programs. Applications received in response to the Acute Lung Injury program may be either new or renewal applications. Responsibility for the planning, direction, and execution of the proposed project 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, which is defined as research conducted with human patients/subjects or on material of human origin such as tissue or other specimens for which an investigator directly interacts with 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 epidemiologic studies, where the research can be completed within five 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 five-year project period following an open competition. Only one five-year competing renewal is permitted, for a total of 10 years of support, unless the SCOR program is recommended for extension. The NHLBI comprehensive evaluation of the Neurobiology of Sleep and Sleep Apnea and Airway Biology and Pathogenesis of Cystic Fibrosis SCOR programs will be conducted during the second project period according to the following timetable: Program Announced: FY 1996 Project Period (First Competition): FY 1998 through FY 2003 Program Reannounced: FY 2001 Project Period (Second Competition): FY 2003 through FY 2008 Letter to SCOR Directors Regarding SCOR Evaluation Plans: FY 2005 (mid-way through year 02 of 2nd project period) SCOR Evaluation Meeting: FY 2005 (late in year 02 of 2nd project period) Notification of SCOR Directors of NHLBI Decision: FY 2006 (mid-way through year 03 of 2nd project period) This is the second competition for the Acute Lung Injury program 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 schedule: Program Announced: FY 1991 Project Period (First Competition): FY 1994 through FY 1998 Program Reannounced: FY 1996 Project Period (Second Competition): FY 1999 through FY 2003 Letter to SCOR Directors Regarding SCOR Evaluation Plans: FY 2000 (mid-way through year 02 of 2nd project period) SCOR Evaluation Meeting: FY 2000 (late in year 02 of 2nd project period) Notification of SCOR Directors of NHLBI Decision: FY 2001 (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 For new applications, the applicants may request up to $1,140,000 direct costs, not including indirect costs for collaborating institutions, in the first year, and for renewal applications, the applicants may request a 10 percent increase over the last year of the preceding project period or a total of $1,140,000, whichever is greater. An increase of no more than four percent may be requested in each additional year. Award of grants pursuant to this RFA is contingent upon availability of funds for this purpose. It is estimated that a total of $14,000,000 will be available for the first year of support for the three programs and it is anticipated that 13 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 requests require 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. Indirect 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 The SCOR program was initiated within the Division of Lung Diseases in 1971 as a "Pulmonary SCOR." Since then, several modifications and changes in program direction have been made. In the 1975 and 1980 competitions, the DLD SCOR program was announced in four disease categories: Chronic Airways Diseases, Fibrotic and Immunologic Lung Diseases, Pediatrics, 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, with the latter competition resulting in four awards. As a result of a congressional mandate, two new SCOR programs, Cardiopulmonary Disorders During Sleep and Cystic Fibrosis, were announced in 1988, resulting in a total of five awards. In 1989, the DLD announced a SCOR competition in Chronic Diseases of the Airways, Occupational and Immunologic Lung Diseases, and Lung Biology and Disease in Infants and Children, following an evaluation of these programs. The Division made a total of 14 awards in FY 1992 in these three SCOR categories. An evaluation of the Pulmonary Vascular Diseases and Adult Respiratory Failure SCOR programs resulted in the recommendation to combine the two programs into a single new SCOR program in Acute Lung Injury. This new program was announced in 1991 along with renewal programs in Cardiopulmonary Disorders of Sleep and Cystic Fibrosis. In FY 1993, a total of seven awards were made for centers in Cardiopulmonary Disorders of Sleep and Cystic Fibrosis and six awards were made in FY 1994 for centers in Acute Lung Injury. In response to the new Institute policy that each SCOR program is limited to 10 years of support, unless a programmatic evaluation indicates that further support is warranted, 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. The evaluation resulted in new SCOR programs being announced in 1994 for Pathobiology of Fibrotic Lung Disease, Pathobiology of Lung Development, and Cellular and Molecular Mechanisms of Asthma. Awards will be made in FY 97 for these three programs. An evaluation in 1995 by a group of consultants of the SCOR programs in Cardiopulmonary Disorders of Sleep and Cystic Fibrosis resulted in the recommendation that new SCOR programs be announced in Neurobiology of Sleep and Sleep Apnea and in Airway Biology and Pathogenesis of Cystic Fibrosis, two of the programs included in this RFA. The third program, Acute Lung Injury, is the renewal of a SCOR program begun in FY 1994. Justification for announcing a competition in the SCOR programs in Neurobiology of Sleep and Sleep Apnea, Airway Biology and Pathogenesis of Cystic Fibrosis, and Acute Lung Injury is based on the recommendations from the SCOR evaluation, on past accomplishments, which have been provided in reports from the Division and the Institute, and on opportunities for new research directions. Funding for the Cardiopulmonary Disorders of Sleep and Cystic Fibrosis centers expires on September 29, 1998 and for the Acute Lung Injury centers on November 30, 1998. 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. Neurobiology of Sleep and Sleep Apnea The objective of this SCOR program is to integrate the molecular, cellular and genetic approaches to sleep control with clinical investigations on the etiology and pathogenesis of sleep disorders, particularly sleep apnea. The research topics identified below are offered as examples that would be responsive to this announcement. Recent advances in the cellular and molecular neurobiology of sleep offer new opportunities to study the basic mechanisms of sleep and the consequences of disturbed sleep (e.g., sleepiness, hypoxia, and cardiovascular disease). Studies directed at understanding the fundamental neurophysiologic/pharmacologic, neuroanatomic, cellular and molecular nature of sleep regulation and homeostasis; interaction of CNS mechanisms involved in the regulation of sleep/wake states; and the relationship between putative sleep modulators and the pathogenesis of cardiopulmonary disturbances during sleep are areas that need further study. Genetic expression of neuromodulators and mediators during normal sleep and in sleep apnea is another area that requires more attention. For example, molecular approaches should be applied to determine what neurons express sleep promoting genes, whether sleep apnea causes changes in gene transcription, and to elucidate the regulatory signals involved in these genetic events. It is also important to determine how levels of sleep promoting compounds are genetically controlled in the sleep/wake cycle, and whether experimental alterations of specific genes alter sleep behavior. It is now known that homeostatic and circadian factors contribute to regulation of sleep and wakefulness. It is important to understand the interaction between biological clocks, chronobiology and sleep/wake behaviors at the cellular and molecular level, as well as determine how the neural circuits in the brain respond to input from the circadian pacemaker. Studies are also needed to investigate whether apoptosis and other neurodegenerative processes in sleep-related brain regions contribute to the respiratory disturbances. Pharmacologic agents, implants of genetically-engineered cells and gene transfer technologies need to be considered. Sleep disordered breathing and snoring have been implicated as risk factors for the development of hypertension, ischemic heart disease and cerebral infarction. It is important to examine the pathophysiology of sleep apnea in relation to cardiovascular diseases. There is also a need for more vigorous basic research directed towards understanding the autonomic nervous system, central cardiovascular control, and the neurophysiologic and neuropharmacologic mechanisms that regulate cardiovascular and circulatory adjustments during sleep. Epidemiologic studies have provided new insights into the prevalence of sleep apnea. Studies are needed to better define sleep apnea, identify possible sleep phenotypes and determine its predictors and antecedents, particularly in its early phases. One important question is what is the effect of sleep apnea in childhood on development of sleep disorders in later life? Evidence now suggests that the nature of sleep disturbances due to sleep apnea in children may be different than in adults. Attention should be given to the relationship between pathologic and physiologic abnormalities, gender specific factors and the impact of sleep apnea in children and the family. Better objective measures and standardized criteria for sleep apnea, including the associated morbidity and mortality should be investigated. Since excessive daytime sleepiness is a major clinical consequence of sleep apnea, it is important to focus on the basic neural mechanisms that produce sleepiness and design new approaches to evaluate daytime performance/alertness and sleepiness. Critical assessment of therapeutic approaches and development of new therapeutic strategies for sleep disorders, particularly pharmacologic approaches remain important goals of this SCOR program. Airway Biology and Pathogenesis of Cystic Fibrosis Despite dramatic advances in our understanding of the molecular and cellular basis of CF, our knowledge of the biology, structure and function of CFTR remains superficial. There is a critical need to begin to translate our current knowledge of CFTR into the broader aspects of airway biology, the pathogenesis of CF, and the development of new pharmacologic or gene therapies. The objective of the SCOR program is to utilize our current knowledge of CFTR as a focus of information, to promote advances in research on the pathogenesis of CF, the role of CFTR in airway biology, and the development of new treatment strategies. CF lung disease is characterized by chronic bacterial infections and inflammation that progressively destroy the lung. Yet it is not understood how a defect in CFTR leads to this bacterial colonization and inflammation. Information on how CF begins and progresses in the airway with respect to inflammation and/or infection is particularly important. Also critical is an understanding of the role of host defense mechanisms and inflammatory mediators in preventing or contributing to pathogenesis. How the loss of CFTR alters airway function is poorly understood. The airway surface fluid (ASF), believed to play a role both in fetal lung development and in adult pulmonary homeostasis and defense, may be critical in influencing lung function. Yet, our overall understanding of the mechanisms which generate and control ASF, and how CFTR affects it, is still lacking. ASF includes contributions from the submucosal glands; serous gland cells within the submucosal glands have been shown to contain large quantities of CFTR. Thus, an evaluation of the contribution of the submucosal glands versus the surface epithelium in normal fluid and electrolyte balance and in the pathogenesis of CF is needed. Developmental issues regarding fluid and electrolyte balance and information on stem or progenitor cells are also critical to our understanding of basic aspects of lung biology and would be helpful for therapeutic approaches. The role of CFTR plays in human airway epithelial function needs to be better defined. Critical to our understanding of how mutations in CFTR cause disease are structural biology studies both on mutant and wild-type CFTR. CFTR is known to function as a chloride channel and as a regulator of both sodium and chloride channels. Yet issues remain unresolved regarding the intramolecular and intermolecular interactions of different domains of CFTR, functional control of airway processes including ion transport, infection and inflammation, and consequences of mutations to the function of CFTR and the pathogenesis of CF. As potential sites of therapeutic targets designed to provide alternate pathways for fluid production in CF airways, it would be important to study alternate ion channels, uncover new receptors which control lung function and develop methods of overcoming aberrant processing of mutant CFTR. Despite the new information on the primary defect in CF, there are still no new therapies which correct the primary defect or activate alternative pathways to prevent airway disease. Thus, there is a critical need to translate the new knowledge regarding the pathogenesis of CF and the function of CFTR into new treatment strategies. Thus, the development of novel pharmacologic and gene therapies focusing on the primary consequences of CF (i.e., defective CFTR) would be important, such as the development of agents which correct defective CFTR or which interfere with bacterial colonization. Several barriers to persistent correction of defective CFTR function such as vector-induced inflammation and low efficiency of airway cell transduction, have been identified. Thus, new strategies to overcome these barriers and to prevent inflammation are needed. Identification of appropriate lung cell targets for gene transfer such as progenitor, surface and submucosal gland cells is needed. Development and use of animal models, tissues, and cells derived from the lung may be appropriate for certain studies, but, when feasible, human lung materials should be employed. When warranted, research involving human patients/subjects is preferable. Acute Lung Injury The pathogenesis of acute lung injury/acute respiratory distress syndrome (ALI/ARDS) is thought to be related to an over-reaction of the inflammatory/immune system. In sepsis, a frequent predecessor to ARDS, a sequence of mediator responses has been clearly documented, and agents have been created that block the activity of the mediators. Although these agents are protective in animal models, clinically useful and specific therapies have not been found. This is in part because the inflammatory response has turned out to be much more complex than originally thought. Particularly important, now that many mediator systems have been identified, is to determine the interactions between the various systems. Promising areas for new insights may be found from studies of the relationship between inflammatory cell activation, surface adhesion molecules, and signal transduction; the interaction of oxidants with nuclear transcription factors; the mechanisms by which endotoxin increase intracellular oxidants; and the molecular mechanisms through which surfactant proteins modify nitrosation reactions remain to be characterized. The barrier and metabolic functions of the endothelium are disturbed during ALI and the molecular determinants of these processes need to be delineated. Similarly, progress has been made in the description of ion channels in the alveolar epithelium; however, the exact structure and function are unknown. The determinants of cell death and recovery need to be examined as do the factors that promote fibrosis as opposed to healing after tissue injury. Studies with knockout animals have shown that absence of adhesion molecules from birth does not alter the inflammatory response. However, the inflammatory system is redundant and these experiments do not prove that alterations in adhesion molecules are not important in human disease. ALI/ARDS is an acute and acquired disease. Models using inducible promoters would allow for manipulation of mediator levels throughout the course of the disease. Animal models are needed that accurately reflect human disease. In this regard, multidisciplinary studies that are directed towards understanding the integrated response of the entire organism to lung tissue injury may be particularly useful. Multiple Organ Dysfunction Syndrome (MODS), a frequent cause of death during ARDS, is particularly suited to whole animal studies where the integrated response of the whole organism can be studied. For example, the lung is known to produce large amounts of glutamine, an important gut nutrient. In sepsis, release of glutamine from the lung increases, but as ARDS develops, the release of glutamine from the lung drops precipitously, possibly affecting intestinal metabolism and viability, and furthering progression of MODS. Other interactions between the lung and other organs and their contribution to ARDS pathogenesis need to be elucidated in both animals and humans. Many questions remains about the progression and natural history of ALI/ARDS. There is a need to evaluate the role of inflammatory mediators in humans while controlling for confounding variables such as comorbidities, duration of disease, and physiologic variables. Other aspects of pathophysiology, including tissue oxygenation and metabolism, need to be investigated in patients as well as in the laboratory. Recently, two gene products of tumor necrosis factor (TNF) have been identified in humans, and the presence of homozygous TNFB2 gene as opposed to TNFB1 predicted the outcome of patients with sepsis. More needs to be done to evaluate possible genetic control of the response to tissue injury in humans. A clinical core is required to provide the following functions: enroll and characterize all ALI/ARDS patients; provide access to patients and patient samples for the research projects; and facilitate coordination within a SCOR center and among the ALI SCOR centers. 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 and clinical research to ensure that advances in the basic sciences are translated rapidly into clinical applications and that clinical needs will provide a direction for the basic research. Therefore, each SCOR grant application and award must include one or more research projects involving human patients/subjects. 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 RFA, June 1996 and the receipt date for applications, July 22, 1997. 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 new policy results from the NIH Revitalization Act of 1993 (Section 492B of Public Law 103-43) and supersedes and strengthens the previous policies (Concerning the Inclusion of Women in Study Populations, and Concerning the Inclusion of Minorities in Study Populations) which have been in effect since 1990. The new policy contains some new provisions that are substantially different from the 1990 policies. 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 (F59 11146-11151), and reprinted in the NIH GUIDE FOR GRANTS AND CONTRACTS of March 18, 1994, Volume 23, Number 11. Investigators may obtain copies from these sources or from the program staff or contact person listed below. Program staff may also provide additional relevant information concerning the policy. LETTER OF INTENT Prospective applicants are asked to submit, by December 13, 1996, 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: Chief, Review Branch Division of Extramural Affairs National Heart, Lung, and Blood Institute Two Rockledge Centre, Suite 7093 6701 Rockledge Drive, MSC 7924 Bethesda, MD 20892-7924 APPLICATION PROCEDURES The research grant application form PHS 398 (rev. 5/95) 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 Office of Grants Information, Office of Extramural Outreach and Information Resources, National Institutes of Health, 6701 Rockledge Drive, MSC 7910 Bethesda, MD 20892-7910 Telephone: (301) 710-0267 Email asknih@odrockm1.od.nih.gov. and from the NIH program administrator listed under INQUIRIES. Specific instructions for preparing a SCOR application are also available from the program contact listed under INQUIRIES. The RFA label included in grant application form PHS 398 (rev. 5/95) 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. Send or deliver a signed, typewritten original of the application, including the Checklist, and three signed photocopies, in one package to: DIVISION OF RESEARCH GRANTS NATIONAL INSTITUTES OF HEALTH 6701 ROCKLEDGE DRIVE, ROOM 1040 - MSC 7710 BETHESDA, MD 20892-7710 BETHESDA, MD 20817 (for express/courier service) Send two additional copies of the application to Chief, Review Branch 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 Division of Research Grants (DRG); otherwise, the NHLBI cannot guarantee that the application will be reviewed in competition for this RFA. Applications must be received by July 22, 1997. If an application is received after that date, it will be returned to the applicant without review. DRG 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 Division of Research Grants 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 DRG 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 DRG as no site visits nor 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 applications will be determined to be competitive or non-competitive based on their scientific merit relative to other applications received in response to the RFA. Applications judged to be competitive 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 non-competitive 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 September 30, 1998 (FY 1998) for the Neurobiology of Sleep and Sleep Apnea and Airway Biology and Pathogenesis of Cystic Fibrosis programs and December 1, 1998 (FY 1999) for the Acute Lung Injury program. 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. Direct inquiries regarding programmatic issues and requests for supplemental instructions to: Suzanne Hurd, Ph.D. Division of Lung Diseases National Heart, Lung, and Blood Institute 6701 Rockledge Drive, Suite 10018, MSC 7952 Bethesda, MD 20892-7952 Telephone: (301) 435-0233 FAX: (301) 480-3547 Email: hurds@gwgate.nhlbi.nih.gov Direct inquiries regarding fiscal matters to: Raymond Zimmerman Division of Extramural Affairs National Heart, Lung, and Blood Institute 6701 Rockledge Drive, Room 7154, MSC 7926 Bethesda, MD 20892-7926 Telephone: (301) 435-0171 FAX: (301) 480-3310 Email: zimmermr@gwgate.nhlbi.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 U.S.C. 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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