Full Text HL-93-13L NON-IMMUNE DEFENSE AGAINST TUBERCULOSIS IN THE LUNG NIH GUIDE, Volume 22, Number 7, February 19, 1993 RFA: HL-93-13L P.T. 34 Keywords: Pulmonary Diseases Pathogenesis National Heart, Lung, and Blood Institute Letter of Intent Receipt Date: April 5, 1993 Application Receipt Date: June 10, 1993 PURPOSE The National Heart, Lung, and Blood Institute (NHLBI) invites grant applications for support of research on non-immune mechanisms of defense against tuberculosis (TB) in the lung. The primary objectives of this special grant program are to identify and delineate non-immune mechanisms that may be involved in the early stages of defense against infection and active disease by Mycobacterium tuberculosis (Mtb) in the lung. 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), Non-Immune Defense against Tuberculosis in the Lung, is related to the priority areas of HIV infection, and immunization and infectious diseases. Potential applicants may obtain a copy of "Healthy People 2000" (Full Report: Stock No. 017-001-00474-0) or "Healthy People 2000" (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 Among the disciplines and expertise that may be appropriate for this research program are biochemistry, cell biology, infectious diseases, microbiology, molecular biology, pharmacology, pathology, molecular genetics, and pulmonary medicine. Applications may be submitted by for-profit or non-profit organizations, public and private, such as universities, colleges, hospitals, laboratories, units of State or local governments, and eligible agencies of the Federal government. Foreign institutions are not eligible for the First Independent Research Support and Transition (FIRST) (R29) award. Applications from minority individuals and women are encouraged. All current policies and requirements that govern the research grant programs of the National Institutes of Health (NIH) will apply to grants awarded under this RFA. R01 Awards under this announcement to foreign institutions will be made only for research of very unusual merit, need, and promise, and in accordance with PHS policy governing such awards. MECHANISM OF SUPPORT The support mechanism for this program will be the individual research grant (R01) or the First Independent Research Support and Transition (FIRST) award (R29). While multidisciplinary approaches are encouraged, it is not the intent of this announcement to solicit applications for large studies encompassing a variety of individual subprojects, i.e., program projects. If collaborative arrangements through subcontracts with other institutions are planned, consult the program staff listed below. Applicants from institutions that have a General Clinic 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. In such a case, a letter of agreement from either the GCRC program director or principal investigator could be included with the application. Upon initiation of the program, the NHLBI will sponsor periodic meetings to encourage exchange of information among investigators who participate in this program. In the budget for the grant application, applicants should request travel funds for a one-day meeting each year, most likely to be held in Bethesda, Maryland. Applicants should also include a statement in their applications indicating their willingness to participate in these meetings. Applicants (who will plan and execute their own research programs) are expected to furnish their own estimates of time required to achieve the objectives of the proposed research project. Up to five years of support may be requested for R01s; five years are required for FIRST awards. Requested budgets for FIRST awards may not exceed those specified in the FIRST award guidelines. At the end of the initial award period, renewal applications may be submitted for peer review and competition for support through the regular grant program of the NIH. It is anticipated that support for this program will begin in September 1993. Administrative adjustments in project period and/or amount may be required at the time of the award. Since a variety of approaches would represent valid responses to this announcement, it is anticipated that there will be a range of costs among individual grants awarded. This RFA is a one-time solicitation. Future unsolicited competing continuation applications will compete with all investigator-initiated applications and will be reviewed according to the customary NIH peer review procedures. FUNDS AVAILABLE Although approximately $1,500,000 for this program is included in the financial plans for fiscal year 1993, award of grants pursuant to this RFA is contingent upon receipt of funds for this purpose. It is anticipated that six to eight new grants will be awarded under this program. The specific number to be funded will, however, depend on the merit and scope of the applications received and the availability of funds. RESEARCH OBJECTIVES Background The lung is the major portal of entry for Mtb and as a result the cells of the lung are usually the body's first contact with this pathogen. It is well established that the immunologic response to Mtb involves macrophages and lymphocytes is a complex series of events which are not yet completely understood; this is currently under vigorous renewed investigation. While the participation of components of the immune system is recognized as the major aspect of defense against mycobacterial infection, there does exist a substantial lag between the first encounter with the organisms in the lung and the occurrence of an immune response. It is of interest to examine whether a number of mechanisms are operational during the early stages of infection and are mediated by factors outside the immune system. It is likely that microorganisms first interact with lung tissue via adherence molecules or specific receptors. Often this interaction is facilitated by coating the organisms with opsonic agents or is inhibited because the organism does not have access to specific adherence molecules or receptors. Little is known about adherence mechanisms of Mtb in the lung. Although there is a relatively good understanding of the general principles governing pathogenesis of TB and host defense against Mtb, there is only rudimentary understanding of the molecular basis of pathogenesis and host defense. Virtually nothing is known about the identity of the molecules that may mediate phagocytosis of Mtb, or about the identity of the molecules that govern selection of the intracellular pathway of Mtb following phagocytosis. Similarly, information is lacking about molecules that mediate the organism's capacity to inhibit phagosome- lysosome fusion or the molecular mechanisms that allow Mtb to escape microbicidal activity of macrophages and survive intracellularly. It has become clear in the past decade that a number of lung cell products or processes, not usually associated with immune defenses, have the potential for protecting the lung against foreign substances by mechanisms that are still incompletely defined and understood. These include the oxidant/antioxidant system, surfactant and its components, and molecules such as nitric oxide. Whether or not these or other yet unrecognized mechanisms operate in the lung during infection with Mtb and the degree to which they participate in defense against Mtb needs to be examined. This initiative is intended to encourage such studies. Objectives and Scope The overall objective of this initiative is to stimulate research on non-immune defense mechanisms in the lung following infection with Mtb. Applications are invited for innovative multidisciplinary approaches to elucidate mechanisms which may be part of the lung's non-immune armamentarium against mycobacteria, especially Mtb. Several approaches relevant to the objectives of this RFA are described below to provide a perspective of the scope of the research that would meet the goals of the program. Studies in humans and animal models of disease are encouraged where possible. Investigators are also encouraged to consider other approaches that meet the goals of this program in addition to those cited below. Activated macrophages are key cells involved in the killing of microorganisms. Activation of these cells in the context of the immune response is achieved by lymphokines. However, under conditions that apparently are not directly associated with involvement of the immune system, alveolar macrophages incubated in a crude preparation of pulmonary surfactant demonstrate increased phagocytosis and killing of bacteria. This suggests a non-immune interaction between surfactant and alveolar macrophages that may have a role in the clearance of microbes from alveoli. Recent studies also suggest that surfactant protein A (SP-A) can modulate macrophage function. It is further suggested that this interaction between SP-A and macrophages is specific and possibly receptor-mediated. The macrophage functions thought to be involved in defense mechanisms modulated by SP-A are phagocytosis, intracellular killing, and chemotaxis. It would be important to determine whether SP-A plays a role in processing mycobacteria, especially Mtb, in the lung, and what mechanisms related to surfactant and its components contribute to lung defenses during infection. Evidence in the past several years has established a role for nitric oxide as a messenger molecule in white blood cells where it mediates tumoricidal and bactericidal effects. Activation of macrophages has been shown to result in enhanced expression of an inducible nitric oxide synthase, resulting in the sustained production of large amounts of nitric oxide. These activated macrophages then acquire the ability to kill or injure certain tumor cells, intracellular parasites, bacteria, and even normal cells. The enhanced nitric oxide production appears to play a key role in the cytotoxic and cytostatic ability of macrophages because inhibition of nitric oxide synthesis eliminates these effects. Many other cells, including pulmonary endothelial cells, also contain an inducible form of nitric oxide synthase and thus are potential candidates for participation in defense mechanisms in the lung involving this pathway. Until very recently, researchers have been unsuccessful in inducing high-output nitric oxide synthesis from human cells in vitro using a variety of inducers known to work well with rodent cells. However, a recent report has described the induction of high-output nitric oxide synthesis by human blood monocyte-derived macrophages infected with Mycobacterium avium. Investigation of how or if nitric oxide affects infectivity of Mtb in the lung and which lung cells are involved would meet the objectives of this program. Reactive oxygen species are now recognized for their antimicrobial activity in vitro and have been shown to be capable of participating in the direct killing of infectious agents. The balance between reactive oxygen molecules and their inhibitors is an important factor to be considered in pathogenetic mechanisms in the lung. Information which elucidates the role of oxidant/antioxidant mechanisms in the lung in response to infection by mycobacteria is also of interest to this program. Being underweight has been identified as a risk factor for TB. Almost nothing is known about the role of the nutritional status of the host and the underlying metabolic mechanisms which may be important to natural defense in the lung against Mtb. Studies identifying non-immune mechanisms in this area of research would also be appropriate for inclusion in this program. SPECIAL REQUIREMENTS Studies involving mycobacterial species other than Mtb may be used to meet the goals of this program, but these studies must be related to mechanisms that operate during infection and disease processes associated with Mtb. Applications that propose descriptive studies in humans only and do not contain studies directed at uncovering mechanisms of disease or supporting hypotheses related to mechanisms of disease will not be acceptable. This program will not support studies directed at development of animal models alone. Models must be applied to the study of non-immune disease mechanisms associated with infection of the lung by mycobacteria and wherever possible, the testing of hypotheses in the animal model should carry over to human studies. Applications that focus on molecular biology and molecular mechanisms related to the lung's defense against Mtb are of particular interest. STUDY POPULATIONS SPECIAL INSTRUCTIONS TO APPLICANTS REGARDING IMPLEMENTATION OF NIH POLICIES CONCERNING INCLUSION OF WOMEN AND MINORITIES IN CLINICAL RESEARCH STUDY POPULATIONS NIH policy is that applicants for NIH clinical research grants and cooperative agreements will be required to include minorities and women in study populations so that research findings can be of benefit to all persons at risk of the disease, disorder or condition under study; special emphasis should be placed on the need for inclusion of minorities and women in studies of diseases, disorders and conditions which disproportionately affect them. This policy is intended to apply to males and females of all ages. If women or minorities are excluded or inadequately represented in clinical research, particularly in proposed population-based studies, a clear compelling rationale should be provided. The composition of the proposed study population must be described in terms of gender and racial/ethnic group. In addition, gender and racial/ethnic issues should be addressed in developing a research design and sample size appropriate for the scientific objectives of the study. This information should be included in the form PHS-398 in Section 1-4 of the Research Plan AND summarized in Section 5, Human Subjects. Applicants are urged to assess carefully the feasibility of including the broadest possible representation of minority groups. However, NIH recognizes that it may not be feasible or appropriate in all research projects to include representation of the full array of United States racial/ethnic minority populations (i.e., Native Americans [including American Indians or Alaskan Natives], Asian/Pacific Islanders, Blacks, Hispanics). The rationale for studies on single minority population groups should be provided. For the purpose of this policy, clinical research includes human biomedical and behavioral studies of etiology, epidemiology, prevention (and preventive strategies), diagnosis, or treatment of diseases, disorders or conditions, including but not limited to clinical trials. The usual NIH policies concerning research on human subjects also apply. Basic research or clinical studies in which human tissues cannot be identified or linked to individuals are not subject to these policies. However, every effort should be made to include human tissues from women and racial/ethnic minorities when it is important to apply the results of the study broadly, and this should be addressed by applicants. For foreign awards, the policy on inclusion of women applies fully; since the definition of minority differs in other countries, the applicant must discuss the relevance of research involving foreign population groups to the United States' populations, including minorities. If the required information is not contained within the application, the application will be returned. Peer reviewers will address specifically whether the research plan in the application conforms to these policies. If the representation of women or minorities in a study design is inadequate to answer the scientific question(s) addressed AND the justification for the selected study population is inadequate, it will be considered a scientific weakness or deficiency in the study design and will be reflected in assigning the priority score to the application. NIH funding components will not award grants or cooperative agreements that do not comply with these policies. LETTER OF INTENT Prospective applicants are asked to submit by April 5, 1993, a letter of intent that includes a descriptive title of the proposed research, the name, address, and telephone number of the Principal Investigator, the names of any other participating institutions or investigators, and the number and title of the RFA in response to which the application may be submitted. A letter of intent is not binding, and it will not enter into the review of any application subsequently submitted, and is not a requirement for application. Such letters are requested for the purpose of obtaining an indication of the number of applications to be received. The NHLBI will not provide a response to a letter of intent. The letter of intent is to be received no later than April 5, 1993 and sent to: Chief, Centers and Special Projects Review Section National Heart, Lung, and Blood Institute Westwood Building, Room 553 Bethesda, MD 20892 Telephone: (301) 496-7351 FAX: (301) 402-1660 APPLICATION PROCEDURES The research grant application form PHS 398 (rev. 9/91) is to be used in applying for these grants. These forms are available at most institutional offices of sponsored research; from the Office of Grants Inquiries, Division of Research Grants, National Institutes of Health, 5333 Westbard Avenue, Room 449, Bethesda, MD 20892, telephone 301-496-7441; and from the NIH program administrator named below. Use the conventional format for research project grant applications and ensure the points identified in the section of "Review Procedures and Criteria" are fulfilled. To identify the application as a response to this RFA, check "yes" on item 2a of page 1 of the application and enter the title "NON-IMMUNE DEFENSE AGAINST TUBERCULOSIS IN THE LUNG," HL-93-13L. The RFA label available in the application kit must be affixed to the bottom of the face page of the original completed 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. Send or deliver the completed application and three signed and completed photocopies to: Division of Research Grants National Institutes of Health Westwood Building, Room 240 Bethesda, MD 20892** Send two additional copies of the application to the Chief, Centers and Special Projects Review section, 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. Otherwise the NHLBI cannot guarantee that the application will be reviewed in competition for the RFA. Applications must be received by June 10, 1993. If an application is received after this date, it will be returned to the applicant without review. The DRG will not accept any application in response to this announcement that is essentially the same as one currently pending initial review, unless the applicant withdraws the pending application. The DRG will not accept any application that is essentially the same as one already reviewed. This does not preclude the submission of substantial revisions of applications already reviewed, but such applications must include an introduction addressing the previous critique. REVIEW CONSIDERATIONS Upon receipt, applications will be reviewed for completeness by the DRG and responsiveness to the objectives of this RFA by the NHLBI. Incomplete applications will be returned without further consideration. If an application is judged unresponsive, the applicant will be contacted and given an opportunity to withdraw the application or to have it considered for the regular, investigator-initiated grant program of the NIH. Applications judged to be responsive will be reviewed for scientific and technical merit by an initial review group, convened by the Division of Extramural Affairs, NHLBI, solely to review these applications. This initial review will include a preliminary evaluation to determine scientific merit relative to the other applications received in response to this RFA (triage); the NIH will withdraw from further consideration applications judged to be noncompetitive and promptly notify the Principal Investigator and the official signing for the applicant organization. Those applications judged to be competitive will be further evaluated for scientific/technical merit by the usual peer review procedures. Review Criteria. The factors to be considered in the evaluation of scientific merit of each application will be those used in the review of traditional research project grant applications including, originality, and feasibility of the approach; the training, experience, and research competence of the investigator(s); the adequacy of the experimental design; the suitability of the facilities; and the appropriateness of the requested budget to the work proposed. AWARD CRITERIA The anticipated date of award is September 30, 1993. In addition to the scientific merit of the applications, awards will be based on responsiveness to the RFA and the availability of resources. INQUIRIES Direct inquiries regarding programmatic issues to: Anthony R. Kalica, Ph.D. Division of Lung Diseases National Heart, Lung, and Blood Institute Westwood Building, Room 6A09 Bethesda, MD 20892 Telephone: (301) 496-7034 FAX: (301) 496-9886 Direct inquiries regarding review matters to: Chief, Centers and Special Projects Review Section Division of Extramural Affairs National Heart, Lung, and Blood Institute Westwood Building, Room 553 Bethesda, MD 20892 Telephone: (301) 496-7351 FAX: (301) 402-1660 Direct inquiries regarding fiscal matters to: Raymond L. Zimmerman Division of Extramural Affairs National Heart, Lung, and Blood Institute Westwood Building, Room 4A17 Bethesda, MD 20892 Telephone: (301) 496-4970 FAX: (301) 402-1200 AUTHORITY AND REGULATIONS This program is described in the Catalog of Federal Domestic Assistance, No. 93.838. Grants will be awarded under the authority of the Public Health Service Act, Title III, Section 301 (Public Law 78-410, as amended: 42 USC 241) and administered under PHS grant policies and Federal Regulations 42 CFR Part 52 and 45 CFR Part 74. This program is not subject to the intergovernmental review requirements of Executive Order 12372 or to review by a Health Systems Agency. .
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