Full Text PA-96-066 RESEARCH ON THE HEMATOLOGIC ABNORMALITIES IN AIDS NIH GUIDE, Volume 25, Number 24, July 19, 1996 PA NUMBER: PA-96-066 P.T. 34 Keywords: AIDS Blood Diseases Biology, Cellular Immunology National Institute of Diabetes and Digestive and Kidney Diseases National Heart, Lung, and Blood Institute PURPOSE The National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) and the National Heart, Lung, and Blood Institute (NHLBI) invite grant applications for support of research addressing fundamental questions of hematologic abnormalities exhibited by humans infected by Human Immunodeficiency Viruses (HIV), the infectious agents of Human Acquired Immunodeficiency Syndrome (AIDS). Hematologic abnormalities in patients with the HIV infection are common. These abnormalities can significantly impact on the course of treatment for thesepatients. Fundamental progress has been made in the understanding of the molecular biology and clinical aspects of retroviral infection. It has become clear that further studies of retroviral-induced neoplasms of immunodeficiency states will continue to provide useful new information about the cellular and humoral basis of the immune responses, including the mechanisms leading to hematologic abnormalities which are seen following HIV infection. This announcement is intended to solicit applications for support of studies on the cellular basis of these hematologic abnormalities. 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. 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 REQUIREMENTS 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 Independent Research Support and Transition (FIRST) (R29) awards. Racial/ethnic minority individuals, women, and persons with disabilities are encouraged to apply as principal investigators. MECHANISM OF SUPPORT This PA will use the National Institutes of Health (NIH) individual research project grant (R01) and FIRST (R29) award mechanisms. Responsibility for planning, direction, and execution of the proposed project will be solely that of the applicant. Because the nature and scope of the research proposed in response to this PA may vary, it is anticipated that the size of an award will vary also; however, the support of requests exceeding the NIDDK average grant size of $160,000 direct cost for R01 grants would be unusual and require ample justification. FIRST (R29) awards are limited to $350,000 direct cost over the five year period. RESEARCH OBJECTIVES The objective of this program announcement is to solicit proposals in which the hematologic abnormalities seen following HIV infection are examined at the cellular and molecular level. Particular encouragement is offered to investigators who are well-trained in the modern techniques of cell biology and molecular biology who currently may be pursuing other research interests. Investigators with interdisciplinary and collaborative arrangements already in place are encouraged to respond to this announcement. Applications should be focused on issues directly relevant to the understanding of the pathogenesis of cytopenia following HIV infection, and the role of hematopoietic precursor cells in the development of AIDS. Following is a description of the types of areas that may be appropriate to study. These descriptions are for illustrative purposes only and are not meant to be all inclusive or restrictive. Numerous hematologic abnormalities arise in individuals following HIV infection. Understanding how these abnormalities arise may be complicated by a variety of other infections, in addition to HIV, which usually are seen in these patients. Bone marrow dysplasia, anemia, thrombocytopenia, and leukopenia occur frequently in patients with HIV infection. Both ineffective hematopoiesis and peripheral destruction of blood cells may lead to cytopenia common in AIDS patients. The latter condition may be due to accelerated utilization and destruction of cells due to opportunistic infections, reticuloendothelial cell dysfunction, or to specific autoimmunity. Ineffective hematopoiesis in patients with AIDS has several potential causes which may include for example: (1)suppressive effects of infections; (2) the formation of circulating inhibitors; and (3) the effects of HIV on hematopoietic stem cells. The recent development of new technologies to make recombinant human hematopoietic growth factors has made it possible to correct some of the cytopenias associated with HIV infection and has also fostered studies of the role of growth factors in hematopoiesis, both in vitro and in vivo. Thrombocytopenia is seen in HIV infected patients with a high degree of incidence, and immune thrombocytic purpura has been recognized as a diagnostic category of the AIDS-Related Complex (ARC). The development of thrombopenia in HIV infections appears to be similar to that of other forms of idiopathic thrombocytopenic purpura. Antibody production against a 25,000 dayton protein of platelet membrane origin has been postulated to have a resemblance to an HIV precursor protein and may be involved in the formation of immune complexes which result in platelet destruction. Anemia is frequently present in HIV patients and its origin is unknown. The lack of reticulocyte response seen in these patients may be due to a hypoproliferative anemia or to ineffective hematopoiesis. Low erythropoietin levels and associated abnormalities seen in some AIDS patients may be a contributing factor to anemia. Neutropenia in AIDS patients is common. The recombinant human growth factor GM-CSF has been used in some clinical trials with AIDS patients and has been found to ameliorate the neutropenia of AIDS as well as that induced by treatment with zidovudine. Applications for support of clinical studies in humans are not requested at this time. In addition, the following studies would be considered unresponsive to this program announcement: (1) studies that do not emphasize the cellular and molecular basis of abnormal hematopoietic differentiation in AIDS; (2) general studies on hematopoiesis; and (3) phenomena associated with hematopoiesis in various disease states not related to AIDS. Program project grant applications (P01) are not suited to this program announcement. 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 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 20, 1994 (FR 59 1450814513) and reprinted in the NIH Guide for Grants and Contracts, Volume 23, Number 11, March 18, 1994. 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. ANIMAL WELFARE CONSIDERATIONS Investigators are encouraged to consider alternative methods and approaches in their research grant applications that do not require the use of whole animals, use alternative species such as nonmammals or invertebrates, reduce the number of animals required, and incorporate refinements to procedures that will result in the elimination or further minimization of pain and distress in animals. APPLICATION PROCEDURES Applications are to be submitted on the grant application form PHS 398 (rev. 5/95) and will be accepted at 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 Grants Information Office, 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. The program announcement title and number must be typed on line 2 of the face page of the application form and the YES box must be marked. Applications for the FIRST Award (R29) must include at least three sealed letters of reference attached to the face page of the original application. FIRST Award (R29) applications submitted without the required number of reference letters will be considered incomplete and will be returned without review. Potential R29 applicants should refer to the announcement on Just-in- Time Procedures for FIRST and Career Awards (NIH Guide for Grants and Contracts, Vol. 25, No. 10, March 29, 1996) for information on recent changes in guidelines for FIRST award format. The completed original application and five legible copies 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 (for express/courier service) REVIEW CONSIDERATIONS Applications will be assigned on the basis of established Public Health Service referral guidelines. Applications that are complete will be evaluated for scientific and technical merit by an appropriate peer review group convened in accordance with 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 applications under review, will be discussed, assigned a priority score, and receive a second level review by the appropriate national advisory council or board. Review Criteria o scientific, technical, or medical significance and originality of proposed research; o appropriateness and adequacy of the experimental approach and methodology proposed to carry out the research; o qualifications and research experience of the Principal Investigator and staff, particularly, but not exclusively, in the area of the proposed research; o availability of the resources necessary to perform the research; o appropriateness of the proposed budget and duration in relation to the proposed research; o 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. For Applications from Foreign Organizations: o availability of special opportunities for furthering research programs through the use of unusual talent resources, populations, or environmental conditions in other countries that are not readily available in the United States or that provide augmentation of existing U.S. resources. AWARD CRITERIA Applications assigned on the basis of Public Health Service referral guidelines will compete for available funds with other approved applications assigned to the National Institute of Diabetes and Digestive and Kidney Diseases or the National Heart, Lung, and Blood Institute. The following will be considered in making funding decisions: o Quality of the proposed project as determined by peer review; o Availability of funds; o Program priority. INQUIRIES Inquiries are encouraged. The opportunity to clarify any issues or questions from potential applicants is welcome. Direct inquiries regarding programmatic issues to: Ralph L. Bain, Ph.D. Division of Kidney, Urologic and Hematologic Diseases National Institute of Diabetes and Digestive and Kidney Diseases 45 Center Drive, Room 6AS-19B MSC 6600 Bethesda, MD 20892-6600 Telephone: (301) 594-7717 FAX: (301) 480-3510 Email: Ralph_Bain@nih.gov Helena O. Mishoe, Ph.D. Division of Blood Diseases and Resources Nation Heart, Lung, and Blood Institute 6701 Rockledge Drive, Room 10156 Bethesda, MD 20892-7950 Telephone: (301) 435-0050 FAX: (301) 480-0868 Email: hm31y@nih.gov Inquiries regarding fiscal matters may be directed to: Trude Hillard Division of Extramural Activities National Institute of Diabetes and Digestive and Kidney Diseases 45 Center Drive, Room 6AN-44J, MSC 6600 Bethesda, MD 20892-6600 Telephone: (301) 594-8859 Email: HillardT@ep.niddk.nih.gov Jane Davis Division of Extramural Affairs National Heart, Lung, and Blood Institute 6701 Rockledge Drive, Room 7174 Bethesda, MD 20892-7924 Telephone: (301) 435-0166 Email: davisj@gwgate.nhlbi.nih.gov AUTHORITY AND REGULATIONS This program is described in the Catalog of Federal Domestic Assistance No. 93.849. Awards are made under authorization of the Public Health Service Act, Title IV, Part A (Public Law 78-410, as amended by Public Law 99-158, 42 USC 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 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 PHS mission to protect and advance the physical and mental health of the American people. .
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