Full Text PA-97-085 THE LATENT STATE IN TUBERCULOSIS INFECTION NIH GUIDE, Volume 26, Number 24, July 25, 1997 PA NUMBER: PA-97-085 P.T. Keywords: National Institute of Allergy and Infectious Diseases National Heart, Lung, and Blood Institute PURPOSE The National Institute of Allergy and Infectious Diseases (NIAID)and National Heart, Lung, and Blood Institute (NHLBI) National Institutes of Health (NIH), invite applications that propose to investigate the "latent" phase of infection by Mycobacterium tuberculosis (M.tb) and the mechanism(s) by which M.tb is reactivated in some hosts. For the purposes of this initiative, "the latent state" refers to that state of infection during which clinical disease is inapparent, yet infection of the host has been established. The mechanisms by which this phase terminates in some hosts and persistent bacilli are re-activated, leading to development of active disease, are also of interest. 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 PA," THE LATENT STATE IN TUBERCULOSIS INFECTION" is related to the priority area(s) of Immunization and Infectious Diseases, and HIV Infection. 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 202-512-1800). ELIGIBILITY Applications may be submitted by domestic and foreign, for-profit and non-profit organizations, public and private, such as universities, colleges, hospitals, laboratories, units of State and local governments, and eligible agencies of the Federal government. Foreign institutions are not eligible for FIRST awards (R29). Racial/ethnic minority individuals, women, and persons with disabilities are encouraged to apply as Principal Investigators. MECHANISM OF SUPPORT Traditional research project grant (R01) and FIRST award (R29) applications may be submitted in response to this program announcement). Applications for R01 grants may request up to five years of support; applications for R29 grants must request five years of support. Responsibility for the planning, direction, and execution of the proposed research for all applicable mechanisms of support will be solely that of the applicant. RESEARCH OBJECTIVES Background Tuberculosis remains the most prevalent cause of death due to a single infectious pathogen in the world today. Not only do an estimated 3 million persons die annually of tuberculosis, but one- third of the world's population is believed to be currently infected with the causative agent, M.tb. This apparently healthy population, although not currently infectious, represents a vast reservoir of potential future transmitters. It has been estimated that ten percent of immunocompetent, infected persons will develop active disease during their lifetime, and 8-9% of those who are immunocompromised by concurrent HIV infection will develop active tuberculosis per year, thereby becoming capable of transmitting M.tb to others. The extended course of therapy required for adequate treatment of even drug-susceptible strains of M.tb is necessitated by the difficulty of eradicating persistent bacilli. Current drugs kill actively growing M.tb within days, but months of therapy are needed to fully eliminate the persistent organisms. Despite the enormous impact on public health of the latent phase of M.tb infection, little is known about the biology of the bacterium during this stage of infection, the bacillus-host interaction, the immunologic parameters that are involved in establishing persistent infection, or the mechanisms of pathogen and host that lead to reactivation of M.tb and development of active disease. This lack of understanding is reflected in a dearth of effective immunologic and chemotherapeutic tools to treat latent M.tb infection or prevent reactivation. Research Objectives and Scope NOTE: Three complementary Program Announcements are being issued: "The Latent State in Tuberculosis Infection"; "Tuberculosis - Basic Biology, Immunology and Pathogenesis"; and "Innovative Approaches to Investigating Human Tuberculosis". Applications which focus on understanding the latent state in tuberculosis infection and/or reactivation of tuberculosis should be submitted in response the PA "The Latent State in Tuberculosis Infection". Applications which focus on the use of model systems and or mycobacterial species other than M.tb to further understanding of any other aspect of tuberculosis should be submitted in response to the PA "Tuberculosis - Basic Biology, Immunology and Pathogenesis"; and applications which primarily focus on use of M.tb and/or human cells, tissues or study populations to study any aspect of human tuberculosis, per se, other than latency/reactivation should be submitted in response to the PA "Innovative Approaches to Investigating Human Tuberculosis". The subject of latency is currently a key gap in tuberculosis research programs funded by NIAID and NHLBI. We aim to remedy this situation by encouraging applications that focus on the molecular basis of latency and development of effective tools for diagnosing, treating and intervening against the latent state. These include, but are not limited to, applications addressing: o host and/or bacterial mechanisms and processes that cause or are involved in entry into the latent state, including definition of the regulatory genes and factors responsible; o biology, biochemistry and physiology of the bacterium during latency, including identification of genes and their products responsible for or important to the maintenance of latency; o microbial regulatory factors that repress latency and lead to establishment of active disease; o possible role(s) of immunologic factors/mechanisms in establishing, maintaining and repressing latency; o development/improvement of animal models reflective of latency in human tuberculosis; o development of skin test(s) or other diagnostic tool(s) that can distinguish latent infection from BCG vaccination from active disease; o development of therapeutic agents effective against latent bacteria; o development of anti-TB vaccine candidates capable of conferring protective efficacy against latent organisms by, for example, blocking reactivation and/or subsequent transmission; development of "post-exposure" animal models suitable for evaluating such vaccine candidates. Whole genome approaches, capitalizing on the availability of M.tb genomic sequence, are encouraged where appropriate. INCLUSION OF WOMEN AND MINORITIES IN RESEARCH INVOLVING HUMAN SUBJECTS It is the policy of the NIH that women and members of minority groups and their subpopulations must be included in all NIH supported biomedical and behavioral research projects involving human subjects, unless a clear and compelling rationale and justification are provided that inclusion is inappropriate with respect to the health of the subjects of 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 28, 1994 (FR 59 14508-14513) and the NIH Guide for Grants and Contracts, Vol. 23, No. 11, March 18, 1994. Investigators may obtain copies from these sources or from the program staff listed under INQUIRIES. Program staff may also provide additional relevant information concerning the policy. APPLICATION PROCEDURES Applications are to be submitted on the grant application for PHS 398 (rev. 5/95) and will be accepted on the standard application deadlines as indicated in the application kit. Application kits are available at most institutional offices of sponsored research and may be obtained from the Office of Extramural Outreach and Information, National Institutes of Health, 6701 Rockledge Drive, MSC 7910, Bethesda, MD 20892-7910, telephone (301) 710-0267, email: asknih@odrockm1.nih.gov. For purposes of identification and processing, item 2 on the face page of the application must be marked "YES". The PA number and the PA title must also be typed in section 2. The completed, signed original and five legible, single-sided copies of the application and any appendices must be sent or delivered to: DIVISION OF RESEARCH GRANTS NATIONAL INSTITUTES OF HEALTH 6701 ROCKLEDGE DRIVE, ROOM 1040, MSC 7710 BETHESDA, MD 20892-7710 BETHESDA, MD 20817-7710 (for express/courier service) R29 APPLICANTS ONLY. R29 applications must include at least three (3) sealed letters of reference attached to the face page of the original application. FIRST applications submitted without the required number of reference letters will be considered incomplete and will be returned without review. ALL APPLICANTS REQUESTING $500,000 OR MORE IN ANNUAL DIRECT COSTS. The NIH Policy Update on Acceptance for Review of Unsolicited Applications that Request More Than $500,000 Direct Cost for Any One Year applies to applications in response to this PA. The Policy Update was published in the NIH Guide for Grants and Contracts, Volume 25, No. 14, May 3, 1996, and became effective June 1, 1996. Potential applicants must contact the appropriate program staff listed in INQUIRIES below to initiate clearance processes for acceptance of their applications. GCRC INSTITUTIONS Applicants from institutions that have a General Clinical Research Center (GCRC) funded by the NIH National Center for Research Resources may wish to identify the Center as a resource for conducting the proposed research. If so, a letter of agreement from the GCRC Program Director must be included in the application material. REVIEW CONSIDERATIONS Review Procedures Applications will be assigned on the basis of established PHS referral guidelines. Upon receipt, applications will be reviewed for completeness by the NIH Division of Research Grants. Incomplete applications will be returned to the applicant without further consideration. Applications will be reviewed for scientific and technical merit by study sections of the Division of Research Grants, NIH, in accordance with the standard NIH peer review procedures. As part of the initial merit review, all applications will receive a written critique and undergo a process in which only those applications deemed to have the highest scientific merit, generally the top half of the applications under review, will be discussed, assigned a priority score, and receive a second level review by the appropriate national advisory council. Review Criteria The five criteria to be used in the evaluation of grant applications are listed below. The goals of NIH-supported research are to advance our understanding of biological systems, improve the control of disease, and enhance health. The reviewers will comment on the following aspects of the application in their written critiques in order to judge the likelihood that the proposed research will have a substantial impact on the pursuit of these goals. Each of these criteria will be addressed and considered by the reviewers in assigning the overall score weighting them as appropriate for each application. Note that the application does not need to be strong in all categories to be judged likely to have a major scientific impact and thus deserve a high priority score. For example, an investigator may propose to carry out important work that by its nature is not innovative but is essential to move a field forward. 1. Significance. Does this study address an important problem? If the aims of the application are achieved, how will scientific knowledge be advanced? What will be the effect of these studies on the concepts or methods that drive this field? 2. Approach. Are the conceptual framework, design, methods, and analyses adequately developed, well-integrated, and appropriate to the aims of the project? Does the applicant acknowledge potential problem areas and consider alternative tactics? 3. Innovation. Does the project employ novel concepts, approaches or method? Are the aims original and innovative? Does the project challenge existing paradigms or develop new methodologies or technologies? 4. Investigator. Is the investigator appropriately trained and well suited to carry out this work? Is the work proposed appropriate to the experience level of the principal investigator and other researchers (if any)? 5. Environment. Does the scientific environment in which the work will be done contribute to the probability of success? Do the proposed experiments take advantage of unique features of the scientific environment or employ useful collaborative arrangements? Is there evidence of institutional support? The initial review group will also examine: the appropriateness of proposed project budget and duration; the adequacy of plans to include both genders and minorities and their subgroups as appropriate for the scientific goals of the research and plans for the recruitment and retention of subjects; the provisions for the protection of human and animal subjects; and the safety of the research environment. AWARD CRITERIA Applications will compete for available funds with all other favorably recommended applications. The following will be considered when making funding decisions: quality of the proposed project as determined by peer review, program balance among research areas of the announcement, and availability of funds. INQUIRIES Written and telephone inquiries are encouraged. The opportunity to clarify any issues or questions from potential applicants is welcome. Inquiries regarding programmatic issues may be directed to Dr. Ann M. Ginsberg at NIAID and Dr. Hannah H. Peavy at NHLBI: Ann M. Ginsberg, MD, Ph.D. Division of Microbiology and Infectious Diseases National Institute of Allergy and Infectious Diseases Solar Building, Room 3B06 6003 Executive Blvd. Bethesda, MD 20892-7630 Telephone: (301) 496-5305 Fax: (301) 496-8030 EMAIL: ag73i@nih.gov Hannah H. Peavy, M.D. Division of Lung Diseases National Heart, Lung, and Blood Institute Two Rockledge Centre, Suite 10018, MSC 7952 6701 Rockledge Drive Bethesda, Maryland 20892-7952 Telephone: (301) 435-0222 FAX: (301) 480-3557 E-mail: hannah_peavy@nih.gov Direct inquiries regarding fiscal matters to Ms. Catherine Walker, NIAID and Mr. Raymond L. Zimmerman, NHLBI: Ms. Catherine Walker Division of Extramural Activities National Institute of Allergy and Infectious Diseases Solar Building, Room 4B32 6003 Executive Blvd. Bethesda, MD 20892-7610 Telephone: (301)402-7146 Fax: (301)480-3780 Email: cwalker@mercury.niaid.nih.gov Raymond L. Zimmerman Grants Operations Branch Division of Extramural Affairs National Heart, Lung, and Blood Institute Two Rockledge Centre, Suite 7154, MSC 7926 6701 Rockledge Drive Bethesda, MD 20892-79?? Telephone: (301) 435-0171 FAX: (301) 480-3310 E-mail: raymond_zimmerman@nih.gov AUTHORITY AND REGULATIONS This program is supported under authorization of the Public Health Service Act, Sec. 301(c), Public Law 78-410, as amended. The Catalogue of Federal Domestic Assistance Citations are No. 93.838. and No. 93.856. Awards will be administered under PHS grants 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 Health Systems review. The Public Health Service 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 the American people. .
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