TECHNOLOGIES FOR GENE EXPRESSION ANALYSIS IN THE NERVOUS SYSTEM Release Date: December 11, 1998 RFA: NS-99-003 P.T. National Institute of Neurological Disorders and Stroke National Institute of Mental Health National Center for Research Resources National Eye Institute National Human Genome Research Institute National Institute on Alcohol Abuse and Alcoholism National Institute on Aging National Institute of Child Health and Human Development National Institute on Deafness and Other Communication Disorders National Institute on Drug Abuse National Institute of Environmental Health Sciences Letter of Intent Receipt Date: February 15, 1999 Application Receipt Date: March 18, 1999 PURPOSE The purpose of this Request for Applications (RFA) is to solicit applications for research grants to develop new technologies or refine established technologies for gene discovery and gene expression analysis in the nervous system. The nervous system poses unique challenges to gene expression analysis because of its extreme cellular heterogeneity and complex distributions of messenger RNAs within individual cells. In addition, the nervous system is unusual in the degree to which it uses alternative splicing and RNA editing as mechanisms for regulating the spatial and temporal specificity of gene function. The development of methods suited to the anatomical and molecular complexities of the nervous system is therefore critical for quantifying gene expression in this system, and for understanding how changes in gene expression may correlate with different developmental, pathological, or functional states. Methods of interest would include, but are not limited to: 1) isolation of mRNA from single cells or small cell populations, 2) creation of high quality cDNA libraries from small amounts of tissue, 3) high throughput methods for quantifying the expression of large numbers of genes, 4) methods for quantifying multiple spliced or edited variants of a given transcript, 5) methods for comparing protein levels to corresponding mRNA levels for a given transcript within a cell or tissue sample, and 6) techniques for visualizing RNA distribution within cells and tissues. The development of these methods is expected to improve our understanding of nervous system function in normal and disease conditions, and will aid in the diagnosis and treatment of neurological disorders. 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, Technologies for Gene Expression Analysis in the Nervous System, is related to several of the priority areas, including mental health and mental disorders, alcohol and other drugs/ substance abuse, heart disease and stroke, cancer, and maternal and infant health. Potential applicants may obtain a copy of "Healthy People 2000" at http://www.crisny.org/health/us/health7.html. 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. Racial/ethnic minority individuals, women, and persons with disabilities are encouraged to apply as Principal Investigators (PIs). MECHANISM OF SUPPORT This RFA will use the National Institutes of Health (NIH) research project grant (R01) and pilot project/feasibility study (R21) award mechanisms. Responsibility for the planning, direction, and execution of the proposed project will be solely that of the applicant. The total project period for an application submitted in response to this RFA may not exceed 3 years. This RFA is a one-time solicitation. Future unsolicited competing continuation applications will compete with all investigator-initiated applications and be reviewed according to the customary peer review procedures. The anticipated award date is September 30, 1999. FUNDS AVAILABLE The participating institutes and centers (ICs) intend to commit approximately $5 million in FY 1999 to fund new grants in response to this RFA. Budgets for R21 applications may not exceed $100,000 per year in direct costs. The direct cost per year for R01 applications may not exceed $500,000 without prior discussion with the relevant program officer. Because the nature and scope of the research proposed may vary, it is anticipated that the size of each award will also vary. Although the financial plans of the ICs provide support for this program, awards pursuant to this RFA are contingent upon the availability of funds and the receipt of a sufficient number of applications of outstanding scientific and technical merit. At this time, it is not known if competing renewal applications will be accepted and/or if this RFA will be reissued. RESEARCH OBJECTIVES Background The nervous system offers unparalleled opportunity for studying how genes drive cellular form and function. First, the nervous system is unique among organ systems in the complexity of cell types it contains. Although most of the cells of the nervous system can be grouped into two categories (neurons and glial cells), these cells exhibit an astonishing variety of shapes and sizes. Moreover, groups of cells that appear morphologically similar can have very different biochemical phenotypes and functional properties. It is clear from studies in many organ systems that the structures and functions of individual cells are largely determined by the genes they express; however, the precise mechanisms through which gene expression regulates form and function are still unclear in most cases. Because of the diversity of cell types it contains, the nervous system offers a particularly rich system in which to study this problem. The nervous system is also unrivaled in the sophistication of the functions it performs, which include sensory processing and integration, cognition, learning and memory, reasoning, emotional expression, and coordination of autonomic and motor functions. Like cellular form, these higher-order functions are critically dependent on gene expression. All, for example, require that the brain be properly wired during development. This process in turn is controlled by specific batteries of genes, which must be activated at precise times and places to generate correct numbers of neurons with functionally appropriate connections. Even after the basic wiring pattern of the brain has been established, its continued maintenance and function in adulthood and aging requires new gene expression. For example, the storage of memory requires the sequential activation of several sets of genes, which in turn direct long-term changes in the expression of other genes. Understanding how the activation of sets of genes controls developmental processes, neural plasticity, and intercellular communication will stretch the boundaries of informatics and computational biology. Thus, improved technologies for analyzing gene expression in the nervous system will have a major impact on other fields as well. A final and extremely important reason for studying gene expression in the brain is the insight it may bring to neurological and mental disease. Many diseases of the nervous system (including mental illnesses, dementias, and addictive disorders) are now known to result from the mutations in either one gene or several genes in combination. As mutations in genes continue to be identified, gene expression profiling in the context of time, place, and physiological state will be critical in defining the functional consequences of those genetic mutations. In addition, the ability to determine the genetic profile of a cell at various stages of disease progression will help reveal the molecular basis for the differential vulnerability of brain cells and regions to dysfunction, degeneration, and death. These findings in turn will be key to disease prevention, early detection, diagnosis, and treatment. The time is particularly ripe now for understanding gene expression in the nervous system because of two sets of technological developments. The first is the improvement in techniques and resources (e.g., genetic and physical maps) for cloning and sequencing genes, which in turn has led to an explosion in the identification of new genes and genetic mutations. The second is the recent development of techniques for monitoring the expression of many genes simultaneously, so that one can quantitatively compare levels of expression in cells under different physiological conditions. These techniques will allow powerful correlations to be made between the expression of particular groups of genes and the functional (or dysfunctional) state of a cell. Moreover, this technology will permit more effective diagnosis and treatment of diseases, such as stroke and schizophrenia, that have a complex genetic basis. The aim of the current RFA is to encourage the refinement of these new technologies for use in studies of the nervous system, and the development of additional novel technologies. This RFA is issued as one element of the Brain Molecular Anatomy Project (BMAP), a multi-institute, interdisciplinary initiative launched by the National Institutes of Health (NIH) in 1998. BMAP has two components: (1) gene discovery, and (2) gene expression analysis. The gene discovery component will use an expressed sequence tag (EST) sequencing approach to catalogue the full repertoire of genes that are expressed in the nervous system under both normal and abnormal conditions. The expression analysis component will use high throughput methods to compare the levels at which genes are expressed in the nervous system as a function of cell type, anatomical location, developmental stage, and physiological state. It is expected that both these components of BMAP will be stimulated by the novel technologies solicited in this RFA. Objectives and Scope Although many innovative methods have recently been developed for the analysis of gene expression, the nervous system offers special challenges because of its cellular heterogeneity and because of the complex distribution of mRNAs within individual cells. Additional difficulties are encountered when trying to analyze gene expression in the developing nervous system, where small amounts of tissue are available and cellular populations are spatially dynamic. Therefore, the NIH seeks the development of new tools and the refinement of existing techniques for examining gene expression in the nervous system. It is hoped that these techniques will be developed to a level where they can be used routinely and inexpensively by many different laboratories. Applications are solicited for technology development in the following areas: * Methods for microdissecting or otherwise removing defined cell populations or single cells from the nervous system for the purpose of preparing high quality RNA. * Techniques for extraction of RNA from small amounts of tissue (including small brain regions, embryonic tissue, single cells, or subcellular compartments) for the preparation of high quality cDNA libraries. * Strategies for preparing representational libraries or libraries that are optimized to detect rare or unique sequences (eg., subtractive and differential display-based libraries). * Methods for obtaining amino acid sequences from small amounts of protein for the purpose of identifying novel genes. * High throughput methods for quantifying the expression of large numbers of gene products (RNA and/or proteins) simultaneously in a single tissue or cell sample. Such methods could include (but are not limited to) expression array, RNA amplification, RT-PCR, and SAGE technologies for RNA expression, and mass spectrophotometric technologies for protein expression. * Methods for detecting and quantifying multiple spliced or edited variants of a given gene transcript within a single cell or tissue sample. * Methods for comparing mRNA and protein levels for a given transcript within a single cell or tissue sample. * New techniques for visualizing RNA distribution within tissue and cell samples, such as high throughput, multiprobe in situ hybridization, and high sensitivity methods for visualizing the subcellular distribution of RNAs. Also of interest would be methods for real-time imaging of gene expression in vivo and in vitro. As a secondary goal, this initiative is intended to encourage the development of integrated analytical systems, including sample analysis systems and informatics systems for data collection and analysis, where these are appropriate as components of proposals aimed at the areas listed above. BMAP will focus initially on the mouse, obtaining normative data about gene expression in adult and developing animals. (In view of the importance of studying disease processes in humans, BMAP will also include human studies as materials, resources, and opportunities arise.) However, it is also recognized that other species may offer unique advantages for developing methods to study gene expression. Thus, studies using species other than mouse will be considered responsive to this RFA provided that a rationale is given for using the alternate species. SPECIAL REQUIREMENTS During the course of the grant period, it is anticipated that technologies will improve and the rate of progress and focus of work supported by the grant(s) may change. During the course of the award period, the PIs may be invited to meet with NIH program staff in Bethesda, MD, to review scientific progress. Other scientists external to and knowledgeable about these studies may also be invited to participate. Budget requests should include travel funds for the PI to meet annually in the Washington, D.C. area, should such meetings be advisable. 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 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 was published in the Federal Register of March 28, 1994 (FR 59 14508-14513) and in the NIH Guide for Grants and Contracts, Vol. 23, No. 11, March 18, 1994, available on the web at: https://grants.nih.gov/grants/guide/notice-files/not94-105.html. INCLUSION OF CHILDREN AS PARTICIPANTS IN RESEARCH INVOLVING HUMAN SUBJECTS It is the policy of NIH that children (i.e., individuals under the age of 21) must be included in all human subjects research, conducted or supported by the NIH, unless there are scientific and ethical reasons not to include them. This policy applies to all initial (Type 1) applications submitted for receipt dates after October 1, 1998. All investigators proposing research involving human subjects should read the "NIH Policy and Guidelines on the Inclusion of Children as Participants in Research Involving Human Subjects" that was published in the NIH Guide for Grants and Contracts, March 6, 1998, and is available at the following URL address: https://grants.nih.gov/grants/guide/notice-files/not98-024.html Investigators also may obtain copies of these policies from the program staff listed under INQUIRIES. Program staff may also provide additional relevant information concerning these policies. LETTER OF INTENT Prospective applicants are asked to submit, by February 15, 1999, a letter of intent that includes a descriptive title of the proposed research, the name, address, and telephone number of the PI, 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 a subsequent application, the information that it contains allows National Institute of Neurological Disorders and Stroke (NINDS) staff to estimate the potential review workload and avoid conflict of interest in the review. The letter of intent is to be sent to: Dr. Gabrielle Leblanc Division of Fundamental Neuroscience and Developmental Disorders National Institute of Neurological Disorders and Stroke 7550 Wisconsin Avenue, Room 816, MSC 9165 Bethesda, MD 20892-9165 Telephone: (301) 496-5745 FAX: (301) 402-1501 Email: GL54h@nih.gov APPLICATION PROCEDURES The research grant application form PHS 398 (rev. 4/98) is to be used in applying for their grants. These forms are available at most institutional offices of sponsored research and from the Division of Extramural Outreach and Information Resources, National Institutes of Health, 6701 Rockledge Drive, MSC 7910, Bethesda, MD 20892-7910, telephone 301/710-0267, email: GrantsInfo@nih.gov. The RFA label available in the PHS 398 (rev. 4/98) application form 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. Submit a signed, typewritten original of the application, including the Checklist, and three signed photocopies in one package to: CENTER FOR SCIENTIFIC REVIEW NATIONAL INSTITUTES OF HEALTH 6701 ROCKLEDGE DRIVE, ROOM 1040, MSC 7710 BETHESDA, MD 20892-7710 BETHESDA, MD 20817 (for express/courier service) At the time of submission, two additional copies of the application must be sent to: Dr. Lillian Pubols Scientific Review Branch National Institute of Neurological Disorders and Stroke 7550 Wisconsin Avenue, Room 9C10, MSC 9165 Bethesda, MD 20892-9165 (for express/courier service) Telephone: (301) 496-9223 FAX: (301) 402-0182 Email: LP28E@nih.gov Applications must be received by the application receipt date listed in the heading of this RFA. If an application is received after that date, it will be returned to the applicant without review. The Center for Scientific Review (CSR) 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 CSR 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 CSR and responsiveness by NINDS. Incomplete applications will be returned to the applicant without further consideration. If the application is not responsive to the RFA, CSR 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 NINDS in accordance with the review criteria stated below. As part of the initial merit review, a process will be used by the initial review group in which applications 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 or Board. Review Criteria The goals of NIH-supported research are to advance our understanding of biological systems, improve the control of disease, and enhance health. In the written comments, reviewers will be asked to discuss the following aspects of the application 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 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 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? In particular, does this proposal address the development of a promising technology tailored to the special technical challenges posed by the anatomical and molecular complexities of the nervous system? Alternatively, does the technology offer increases in sensitivity, resolution, throughput volume, scalability or cost effectiveness that are applicable to many tissue types, including the nervous system? If the aims of the application are achieved, how will our ability to study gene expression in the nervous system be advanced? (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 methods? Are the aims original and innovative? Does the project develop novel 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 PI 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? A major goal of this RFA is the timely and broad dissemination of data, materials, and technologies for gene expression analysis in the nervous system. Thus, the initial review group will also be asked to comment on the degree to which the proposed technologies will be readily exportable to the biomedical research community, as well as the adequacy of plans for making available data and materials acquired during the proposed project. Any opinions expressed by reviewers about this aspect of the proposal will be recorded as an administrative note. In addition to the above criteria, in accordance with NIH policy, all applications will also be reviewed with respect to the following: o The adequacy of plans to include both genders, minorities and their subgroups, and children as appropriate for the scientific goals of the research. Plans for the recruitment and retention of subjects will also be evaluated. o The reasonableness of the proposed budget and duration in relation to the proposed research. o The adequacy of the proposed protection for humans, animals or the environment, to the extent they may be adversely affected by the project proposed in the application. Schedule Letter of Intent Receipt Date: February 15, 1999 Application Receipt Date: March 19, 1999 Peer Review Date: July 1999 Council Review: September 1999 Earliest Anticipated Start Date: September 30, 1999 AWARD CRITERIA Award criteria that will be used to make award decisions include: * scientific merit (as determined by peer review) * availability of funds * balance among the projects in addressing different experimental approaches and their complementarity to other ongoing efforts, and * extent to which the proposed technology supports the goals of BMAP. 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: Gabrielle Leblanc, Ph.D. Division of Fundamental Neuroscience and Developmental National Disorders Institute of Neurological Disorders and Stroke 7550 Wisconsin Avenue, Room 816, MSC 9165 Bethesda, MD 20892-9165 (for express/courier service) Telephone: (301) 496-5745 FAX: (301) 402-1501 Email: GL54h@nih.gov Hemin R. Chin, Ph.D. Division of Basic and Clinical Neuroscience Research National Institute of Mental Health 5600 Fishers Lane, Room 10C-26 Rockville, MD 20857 Telephone: (301) 443-1706 FAX: (301) 443-9890 Email: hemin@nih.gov Richard DuBois, Ph.D. National Center for Research Resources 6705 Rockledge Drive, Room 6148, MSC 7965 Bethesda, MD 20892-7965 Telephone: (301) 435-0758 FAX: (301) 480-3659 Email: RichardD@ncrr.nih.gov Maria Y. Giovanni, Ph.D. National Eye Institute 6120 Executive Boulevard, Suite 350, MSC 7164 Bethesda, MD 20892-7164 Telephone: (301) 496-0484 FAX: (301) 402-0528 Email: myg@nei.nih.gov Elise Feingold, Ph.D. Division of Extramural Research National Center for Human Genome Research 38 Library Drive, Room 614, MSC 6050 Bethesda, MD 20892-6050 Telephone: (301) 496-7531 FAX: (301) 480-2770 Email: Elise_Feingold@nih.gov Bradley C. Wise, Ph.D. Neuroscience and Neuropsychology of Aging Program National Institute on Aging 7201 Wisconsin Avenue, Suite 3C307, MSC 9205 Bethesda, MD 20892-9205 Telephone: (301) 496-9350 FAX: (301) 496-1494 Email: bw86y@nih.gov Robert W. Karp, Ph.D. Division of Basic Research National Institute on Alcohol Abuse and Alcoholism 6000 Executive Boulevard, Suite 402, MSC 7003 Bethesda, MD 20892-7003 Telephone: (301) 443-2239 FAX: (301) 594-0673 Email: rkarp@willco.niaaa.nih.gov Deborah Henken, Ph.D. Center for Research for Mothers and Children National Institute of Child Health and Human Development 6100 Executive Boulevard, Room 4B01, MSC 7510 Bethesda, MD 20892-7510 Telephone: (301) 496-5541 FAX: (301) 480-0303 Email: dh50g@nih.gov Nancy Pilotte, Ph.D. Division of Basic Research National Institute on Drug Abuse 5600 Fishers Lane, Room 10A-19 Rockville, MD 20857 Telephone: (301) 443-6975 FAX: (301) 594-6043 Email: np22f@nih.gov Rochelle Small, Ph.D. Division of Human Communication National Institute on Deafness and Other Communication Disorders 6120 Executive Boulevard, Room 400C, MSC 7180 Bethesda, MD 20892-7180 Telephone: (301) 402-3464 FAX: (301) 402-6251 Email: rochelle_small@nih.gov Annette Kirshner, Ph. D. Division of Extramural Research and Training National Institute of Environmental Health Sciences Box 12233, MD EC-23 Research Triangle Park, NC 27709 Telephone: (919) 541-0488 FAX: (919) 541-5064 email: kirshner@niehs.nih.gov Direct inquiries regarding fiscal matters to: Ms. Tina Carlisle Grants Management Branch National Institute of Neurological Disorders and Stroke 7550 Wisconsin Avenue, Room 1004, MSC 9165 Bethesda, MD 20892-9165 Telephone: (301) 496-9231 FAX: (301) 402-0219 Email: carlislt@ninds.nih.gov Ms. Diana S. Trunell Grants Management Branch National Institute of Mental Health 5600 Fishers Lane, Room 7C-08 Rockville, MD 20857 Telephone: (301) 443-2805 FAX: (301) 443-6885 Email: dtrunell@mail.nih.gov Ms. Joellen Harper Office of Grants Management National Center for Research Resources 6705 Rockledge Drive, Room 6210, MSC 7965 Bethesda, MD 20892-7965 Telephone: (301) 435-0836 FAX: (301) 480-3777 Email: jh41m@nih.gov Ms. Kathleen Moy Grants Management Branch National Eye Institute 6120 Executive Boulevard, Suite 350, MSC 7164 Bethesda, MD 20892-7164 Telephone: (301) 496-5884 FAX: (301) 496-9997 Email: klm@nei.nih.gov Ms. Jean Cahill Grants Management Office National Human Genome Research Institute Building 38A, Room 613, MSC 6050 Bethesda, MD 20892-6050 Telephone: (301) 402-0733 FAX: (301) 402-1951 Email: Jean_Cahill@nih.gov Mr. Joseph Ellis Grants Management Officer National Institute on Aging 7201 Wisconsin Avenue, Suite 2N212, MSC 9205 Bethesda, MD 20892-9205 Telephone: (301) 496-1472 FAX: (301) 402-3672 Email: ellisj@exmur.nia.nih.gov Ms. Linda Hilley Office of Planning and Resource Management National Institute on Alcohol Abuse and Alcoholism 6000 Executive Boulevard, Suite 504, MSC 7003 Bethesda, MD 20892-7003 Telephone: (301) 443-4703 FAX: (301) 443-3891 Email: lhilley@willco.niaaa.nih.gov Mr. E. Douglas Shawver Grants Management Branch National Institute of Child Health and Human Development 6100 Executive Boulevard, Room 8A17, MSC 7510 Bethesda, MD 20892-7510 Telephone: (301) 496-1303 FAX: (301) 402-0915 Email: Shawverd@exchange.nichd.nih.gov Gary Fleming, J.D., M.A. Grants Management Branch National Institute of Drug Abuse 5600 Fishers Lane, Room 8A-54 Rockville, MD 20857 Telephone: (301) 443-6710 FAX: (301) 594-6847 Email: gf6s@nih.gov Ms. Sharon Hunt Division of Extramural Activities National Institute on Deafness and Other Communication Disorders 6120 Executive Boulevard, Room 400B, MSC 7180 Bethesda, MD 20892-7170 Telephone: (301) 402-0909 FAX: (301) 402-1757 Email: sh79f@nih.gov Mr. David Mineo Division of Extramural Research and Training National Institute of Environmental Health Sciences Box 12233, MD EC-22 Research Triangle Park, NC 27709 Telephone: (919) 541-1373 FAX: (919) 541-2860 email: mineo@niehs.nih.gov AUTHORITY AND REGULATIONS This program is described in the Catalog of Federal Domestic Assistance Nos. 93.854, 93.242, 93.389, 93.867, 93.172, 93.866, 93.273, 93.865, 93.173, 93.279, and 93.113. 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 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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