Full Text HL-95-013 HIV-ASSOCIATED PATHOGENS OF THE LUNG: LIFE CYCLE REGULATION NIH GUIDE, Volume 24, Number 1, January 13, 1995 RFA: HL-95-013 P.T. 34 Keywords: AIDS Pulmonary Diseases Microbiology National Heart, Lung, and Blood Institute Letter of Intent Receipt Date: March 3, 1995 Application Receipt Date: April 28, 1995 PURPOSE The purpose of this solicitation is to encourage research on the molecular basis of cell/life cycle regulation of pathogens and opportunistic microorganisms that cause lung disease in HIV-infected hosts. The request for applications (RFA) focuses on ways in which the environment in the host lung, including signals from host lung cells may affect the microbial mechanisms that determine growth and replication of the microbial agents. Examples of microorganisms that would be appropriate for study under this program are Mycobacterium tuberculosis, Pneumocystis carinii, Histoplasma capsulatum, and Coccidioides immitis. 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, HIV-Associated Pathogens of the Lung: Life Cycle Regulation, is related to the priority area of 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 Applications may be submitted by domestic and foreign for-profit and non-profit institutions, public and private, such as universities, colleges, hospitals, laboratories, units of state and local governments and eligible agencies of the Federal government. Foreign institutions are not eligible for the First Independent Research Support and Transition (FIRST) award (R29). Applications from minority individuals women and new investigators are encouraged. All current policies and requirements that govern the research grant programs of the NIH will apply to grants awarded under this RFA. Awards under this RFA 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. Among the disciplines and expertise that may be appropriate for this research program are cell biology, microbiology, genetics, immunology, molecular immunology, molecular biology, infectious diseases, pathology, and pulmonary medicine. MECHANISM OF SUPPORT The support mechanism for this program will be the National Institutes of Health (NIH) individual research project grant (R01) and the FIRST award (R29). While multidisciplinary approaches are encouraged, it is not the intent of this RFA 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 under INQUIRIES. 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. Because a variety of approaches would represent valid responses to this RFA, 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 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 1995. Administrative adjustments in project period and/or amount may be required at the time of the award. The National Institute of Allergy and Infectious Diseases (NIAID) also supports research aimed at a better understanding of the interactions between the HIV-infected host and a variety of pathogenic and opportunistic infectious agents. Therefore, applications that are of mutual interest are likely to be given a secondary assignment to NIAID in accordance with the NIH referral guidelines. FUNDS AVAILABLE Although financial plans for fiscal year 1995 include approximately $2,000,000 for the total cost of the program for the first year, award of grants pursuant to this RFA is contingent upon receipt of funds for this purpose. It is anticipated that no more than eight awards will be issued 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 portal of entry for a variety of microorganisms many of which produce disease associated with the HIV epidemic. Furthermore, the lung is the site of the initial host response to these invading agents and as such is involved in both specific and non-specific mechanisms of defense against infection. In HIV- infected individuals and other immunocompromised hosts the ability of invading agents to disseminate systemically appears to be enhanced due to suppressed cellular immunity. Many of the organisms that threaten immunocompromised individuals have complex life/cell cycles that along with host factors may regulate pathogenic processes in the lung. Little is known about the mechanisms by which pathogenic and opportunistic microorganisms, some of which may have been dormant for years, become harmful to the host. For some of these organisms lack of progress in understanding aspects of their life/cell cycle that influence pathogenesis can be ascribed to difficulty of in vitro culture. For example, the pathogenic Mycobacteria grow very slowly and methods to maintain sustained growth of Pneumocystis carinii in vitro are still being sought. Rapid advances are occurring in understanding the molecular regulation of the order and timing of eukaryotic cell growth and division, including signals that limit growth and cause or prevent cell division. For example, cyclins acting through cyclic-AMP dependent protein kinase appear to be an important feature of the mechanism that integrates cell growth with cell division. A more detailed knowledge of the cell cycle indicates that cell replication appears to depend not just on cell size, but also on the rate of growth and it has become apparent that it is possible for one regulatory mechanism to override another, under certain environmental conditions. Although investigators have begun to define the homeostatic mechanisms that integrate cell growth and division in molecular terms, little is yet known about the enzymatic machinery that might control the rate and timing of life/cell cycling in many pulmonary pathogens and opportunistic agents that cause disease in humans. The mechanisms whereby host cells and specific forms of these microorganisms interact in the lung and the extent to which the intracellular environment of lung cells influence the life/cell cycle of these microbes are also poorly understood. Tuberculosis (TB) has reemerged as an urgent health problem in the United States in the 1980s in conjunction with the HIV epidemic as well as with other factors such as increased homelessness and immigration of people from areas where the incidence of TB is high. An estimated 15 million people in the United States are currently infected with Mycobacterium tuberculosis (Mtb). It is expected that in many of these individuals Mtb will remain dormant, yet a number of them will develop active disease at some point, most likely through reactivation of the organisms they harbor. This is particularly important because of the ease with which Mtb is communicated and because of the many individuals who have medical conditions, especially HIV infection, that increase their risk of developing active TB. A variety of host factors, in addition to HIV infection, put patients at increased risk of TB, presumably by compromising their immune responses. However, little is known about the actual mechanisms that control interactions between the host and Mtb and how such factors may alter the life cycle of the organism. Such knowledge might provide the basis for developing new strategies to prevent and treat TB. Pneumoncystis carinii pneumonia (PCP) continues to be an important complication in individuals infected with HIV. While the use of a number of drugs has had an overall suppressive effect on the incidence of PCP, there remain a number of problems associated with therapy for this infection. It is anticipated that a better understanding of the mechanisms involved in the interaction between host lung cells and the infectious forms of P. carinii might provide alternative approaches for treating this opportunistic infection. Objectives and Scope The objective of this program is to elucidate the role of life/cell cycle regulation of a variety of microorganisms that are associated with the pathogenesis of lung disease, particularly but not exclusively, in the setting of HIV infection. These could include various bacteria, fungi, and protozoa which act as opportunists or as well-recognized microbial pathogens either alone or in combination with HIV infection. Areas of interest under this program include the identification of markers of microbial replication and the interaction of host and microbial factors that allow organisms to continue to remain viable in cells or tissues for many months or years without replicating. Of particular interest are the cellular mechanisms responsible for a change in the relationship between the host cells and the microorganism that lead to active disease processes in the lung. Mycobacteria and P. carinii are likely candidates, but studies that propose to investigate other organisms are also encouraged. For example a variety of fungal organisms such as Histoplasma, Candida, Coccidioides and Aspergillus are also of particular interest. A better understanding of the enzymes controlling life/cell cycle processes might provide insight into the phenomena of microbial latency and activation/reactivation as well as provide novel targets for antimicrobial chemotherapy. The cell division machinery of Mycobacteria, especially Mtb, and the regulation of microbial division, especially in lung tissue, offer potential targets for study with respect to pulmonary tuberculosis. It is thought that the DNA synthetic mechanisms and cell division apparatus of Mtb are unique. The genome of Mtb is 70 percent guanine and cytosine, suggesting that its DNA polymerase has adapted to handle its more highly stable form of DNA. The cell division of Mtb is exceptionally slow for a pathogenic bacterium. It is unknown whether this is due to pauses in DNA synthesis, a low constant rate of DNA synthesis, gaps between DNA synthesis and cell division, or factors unrelated to DNA replication. The DNA replication process of Mtb is thought to be highly error prone which would help explain why the spontaneous occurrence of resistance to chemotherapeutic agents is much higher for Mtb than for other microorganisms. This also suggests that the DNA polymerase of Mtb may proofread inefficiently during replication. The signals that regulate DNA synthesis and the growth of Mtb, especially in the lung remain to be uncovered. The extent to which reactivation may be regulated by DNA replication processes and whether host cell factors influence these processes are completely unknown. While the tubercle bacilli can remain "dormant" for decades in host cells little is known about the signals that regulate the transition between active growth and the "dormant" state. Projects that are directed toward gaining mechanistic insights into the processes of reactivation of Mtb, particularly in the immunocompromised host are of interest. Projects dealing with fungal infections associated with immunocompromised hosts would also be responsive. For example these might focus on Coccidioides immitis which is characterized by a sequence which involves inhalation of infectious conidia into the respiratory tract where they undergo conversion to spherules. It has been suggested that leukocytes and carbon dioxide in the lung play a role in regulating this morphologic change. Once formed the spherules undergo a complex series of processes which give rise to endospores before being distributed locally in the lung or being disseminated to other organs of the body. In addition to the morphologic considerations, a number of other factors are thought to contribute to the virulence of these organisms. These include the antiphagocytic properties of the organism's cell wall, the thickness and large size of the spherule form of the organism and the large number of endospores released from each spherule. The way in which such processes are signalled and regulated are appropriate topics for study under this RFA. In vitro experiments, animal studies and innovative studies using human cells or tissues, are encouraged. Research involving humans should be formulated in the context of mechanistic studies and should address specific hypotheses. Large scale clinical studies are beyond the scope of this RFA. SPECIAL REQUIREMENTS Applications that propose descriptive studies and do not contain hypothesis driven research directed at understanding the mechanisms underlying cell/life cycles of microorganisms and how these contribute to the pathogenesis of lung disease will not be acceptable. Studies focused exclusively on microorganisms will not be acceptable; applications must address microbial-host interactions. Studies directed at understanding how lung cell signals from an immunocompromised host interact with microbial signals to direct microbial growth, replication, dormancy and reactivation are of special interest. Applications that focus on issues relevant to the HIV-immunocompromised host and that use molecular approaches are of particular interest. 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 28, 1994 (FR 59 14508-14513), and reprinted in the NIH GUIDE FOR GRANTS AND CONTRACTS of March 18, 1994, Volume 23, Number 11. Investigators also may obtain copies of the policy 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 March 3, 1995, 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, the information that it contains allows NIH 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 Dr. C. James Scheirer, at the address listed under INQUIRIES. 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 and from the Office of Grants Information, Division of Research Grants, National Institutes of Health, Westwood Building, Room 449, Bethesda, MD 20892, telephone (301) 710-0267. Use the conventional format for research project grant applications and ensure the points identified in the section REVIEW CONSIDERATIONS 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 "HIV-Associated Pathogens of the Lung: Life Cycle Regulation" HL-95-013. The RFA label found in form PHS 398 application kit must be affixed to the bottom of the face page of the original completed application form PHS 398. 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 photocopies in one package 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, Review Branch, DEA at the address listed under INQUIRIES. 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 this RFA. Applications must be received by April 28, 1995. 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 RFA 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 this RFA by the NHLBI. Incomplete applications will be returned without further consideration. If the application is not responsive to the RFA, DRG staff may contact the applicant to determine whether to return the application to the applicant or submit it for review in competition with unsolicited applications at the next review cycle. Applications that are complete and responsive to the RFA will be evaluated for scientific and technical merit by an appropriate peer review group convened by the Division of Extramural Affairs, NHLBI in accordance with the review criteria stated below. As part of the initial merit review, a process (triage) 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. 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. Review Criteria. The factors to be considered in the evaluation of scientific merit of each application will be similar to those used in the review of traditional research project grant applications including the novelty, 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; the appropriateness of the requested budget to the work proposed; and the adequacy of plans to include both genders and minorities and their subgroups as appropriate for the scientific goals of the research. Plans for the recruitment and retention of subjects will also be evaluated. The initial review group will also examine the provisions for the protection of human and animal subjects and the safety of the research environment. AWARD CRITERIA The anticipated date of award is September 29, 1995. In addition to the scientific merit of the applications, awards will be based on significance to the subject of the RFA and the availability of resources. INQUIRIES Inquiries concerning this RFA are encouraged. The opportunity to clarify any issues or questions from potential applicants is welcome. Direct inquiries regarding programmatic issues to: Hannah H. Peavy, M.D. Division of Lung Diseases National Heart, Lung, and Blood Institute Westwood Building, Room 6A09 Bethesda, MD 20892 Telephone: (301) 594-7425 FAX: (301) 594-7487 Email: hpv%nihhwb1.bitnet@cu.nih.gov Direct inquiries regarding review matters and mail the letter of intent to: C. James Scheirer, Ph.D. Division of Extramural Activities National Heart, Lung, and Blood Institute Westwood Building, Room 557 Bethesda, MD 20892 Telephone: (301) 594-7478 FAX: (301) 594-7407 Email: james_scheirer%nihhwb1.bitnet@cu.nih.gov 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) 594-7420 FAX: (301) 594-7492 Email: raymond_zimmerman%nihhwb1.bitnet@cu.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, amended by Public Law 99-158, 42 USC 241 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 to review by a Health Systems Agency. The Public Health Service (PHS) strongly encourages all grant recipients to provide a smoke-free workplace and promote the non-use of all tobacco products. This is consistent with the PHS mission to protect and advance the physical and mental health of American people. .
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