and Human Services (HHS)
EXPIRED
NEUROBIOLOGY AND GENETICS OF FRAGILE X SYNDROME Release Date: April 6, 2000 RFA: HD-00-015 National Institute of Child Health and Human Development (http://www.nichd.nih.gov) National Institute of Mental Health (http://www.nimh.nih.gov) Letter of Intent Receipt Date: June 1, 2000 Application Receipt Date: July 17, 2000 THIS RFA USES THE MODULAR GRANT AND JUST-IN-TIME CONCEPTS. IT INCLUDES DETAILED MODIFICATIONS TO STANDARD APPLICATION INSTRUCTIONS THAT MUST BE USED WHEN PREPARING APPLICATIONS IN RESPONSE TO THIS RFA. PURPOSE The National Institute of Child Health and Human Development (NICHD), through its Mental Retardation and Developmental Disabilities (MRDD) Branch, and the National Institute of Mental Health (NIMH), in collaboration with the FRAXA Research Foundation, invite investigators to submit new, innovative research grant applications addressing the epidemiology, genetics, and neurobiology of Fragile X syndrome. This initiative was developed primarily in response to the 1998 NICHD- sponsored Workshop on Fragile X: Future Research Directions. Although considerable progress has been made recently in several areas of research on Fragile X syndrome, there was consensus among workshop participants that further progress in those and other areas is now needed. Fragile X syndrome, one of the most common causes of mental retardation and neuropsychiatric disease in humans, occurs as a result of the production of fragile sites by trinucleotide repeat expansion of at least one gene located on the X chromosome. While several genes affected by the expansion have been identified, the prevalence, risk factors, and nature of the high allele repeats, as well as the mechanism and timing of repeat amplifications in various populations, need further study. Mechanisms by which the expression of these genes is dysregulated, e.g., by methylation and acetylation, need further study. Proteins whose function is altered by interaction with the products of these genes need to be identified and the nature of the interaction further clarified. Further correlation of the degree of expansion and expression of clinical manifestations of the Fragile X phenotype, particularly behavioral manifestations such as autism, autism spectrum disorders, attention deficit hyperactivity disorder (ADHD), and anxiety disorders, is needed. Experimental systems in model organisms to enable the study of neurobiologic, neuroendocrinologic, and reproductive system alterations need to be developed and/or studied further at the organismal, cellular, and molecular level at various developmental stages. The purpose of this RFA is to stimulate research designed to increase our knowledge base relevant to Fragile X syndrome in these and other research areas by encouraging applications that include, but are not limited to, developmental neurobiology, pathophysiology, genetics, proteomics, epidemiology, structure-function correlations, and clinical studies that have a direct link to Fragile X syndrome. HEALTHY PEOPLE 2010 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, Neurobiology and Genetics of Fragile X Syndrome, is related to one or more of the priority areas. Potential applicants may obtain Healthy People 2010 at http://www.health.gov/healthypeople. 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 and organizations may apply for an R01 grant, but are not eligible to apply for a small grant (R03). Racial/ethnic minority individuals, women, and persons with disabilities are encouraged to apply as Principal Investigators. MECHANISM OF SUPPORT This RFA will use the National Institutes of Health (NIH) Research Project Grant (R01) and the NICHD and NIMH Small Grant (R03) award mechanisms. Information and application instructions for the NICHD Small Grant are available in the NIH Guide for Grants and Contracts at: http://grants.nih.gov/grants/guide/pa-files/PAR-99-126.html. Information and application instructions for the NIMH Small Grant are available in the NIH Guide for Grants and Contracts at http://grants.nih.gov/grants/guide/pa-files/PAR-99-140.html. Responsibility for the planning, direction, and execution of the proposed project will be solely that of the applicant. 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 customary NIH peer-review procedures. Awards resulting from this solicitation will be made and administered by either NICHD or NIMH, as appropriate to the research focus of the application. The anticipated date of award is April 1, 2001. Specific application instructions have been modified to reflect MODULAR GRANT and JUST-IN-TIME streamlining efforts being examined by the NIH. Complete and detailed instructions and information on Modular Grant applications can be found at http://grants.nih.gov/grants/funding/modular/modular.htm. FUNDS AVAILABLE The NICHD intends to commit approximately $1 million, the NIMH $200,000, and the FRAXA Research Foundation $200,000 in total costs [direct plus facilities and administrative (F&A) costs] in FY 2001 to fund six to eight new grants in response to this RFA. An applicant for an R01 grant may request a project period of up to five years and a budget for direct costs of up to $200,000 per year. An applicant for an R03 grant may request a project period of up to two years and a budget for direct costs of $50,000 per year. Because the nature and scope of the research proposed may vary, it is anticipated that the size of R01 awards also will vary. Although the financial plans of NICHD, NIMH, and the FRAXA Research Foundation provide support for this program, awards pursuant to this RFA are contingent upon the availability of funds for this purpose and the receipt of a sufficient number of meritorious applications. RESEARCH OBJECTIVES Background Fragile X syndrome, one of the most common causes of inherited mental retardation and neuropsychiatric disease in human beings, affects as many as one in 2000 males and one in 4000 females. Trinucleotide repeat expansion of at least three genes located on the X chromosome has been associated with the formation of fragile sites. Trinucleotide expansions within two of these genes, FRAXA (within the FMR1 gene) and FRAXE (within the FMR2 gene), are associated with mental retardation, while that at a third, FRAXF (not yet associated with a specific gene) is not. Mutations in the FMR1 gene, for example, produce expansion of CGG repeats in the 5 untranslated region of the gene and lead to a severely disabling neurodevelopmental disorder. Such expansion leads to physical, neurocognitive, and emotional characteristics linked to, but not exclusively determined by, alterations in the FMR1 gene or the level of its protein, FMRP. While such expansions can be detected in all races and ethnic groups, epidemiological studies to assess prevalence, risk factors, and the nature of the high allele repeats are needed, populations may not be equivalent with respect to the Fragile X expansion. The mechanism and timing of repeat amplifications in various populations, similarly, are not known. Approximately 15-25 percent of individuals with Fragile X syndrome also are diagnosed with mild to moderate autism and autism spectrum disorders. FMRP expression and autistic status appear to be associated with developmental outcome. Other clinical abnormalities include attention deficit hyperactivity disorder (ADHD) and anxiety disorders. Current methods for prenatal diagnosis of gene expansion of FRAXA, associated with FMR1 and its encoded protein, FMRP, are accurate, sensitive, and relatively inexpensive. For such methods to be applied as general screening techniques, more knowledge about prevalence, risk factors, and nature of high repeat alleles needs to be obtained. Because populations may not be equivalent with respect to Fragile X expansion, consideration of ethical issues related to variability of phenotype, the possibility of mislabeling, and the value of screening if there is no definitive therapy, is required. Although FMR1 is subject to X inactivation, abnormal methylation appears to contribute to the phenotype observed in mosaic patients. These individuals experience upregulation of the FMR1 gene. Further, expanded repeats appear to be abnormally methylated from the start, although the mechanism by which such abnormal methylation occurs remains unknown. Expanded FMR1 genes are also silenced through a process of deacetylation. Studies focusing on alteration of both of these processes are needed. FMRP is found in both nucleus and cytoplasm, where it binds with mRNAs associated with ribonucleoproteins (RNPs) specifically associated with polyribosomes. FMRP-associated RNPs are located in the cell body, as well as in the dendrites, at the base of dendritic spines. Thus, FMRP may play a role in synaptic function and plasticity. Studies to determine the specific RNAs bound by FMRP, particularly those to which the expanded FMRP binds, are needed to identify how FMRP modulates translation of interacting messages, and whether the messages modulated differ in cell body and dendrite. Individuals with Fragile X syndrome also exhibit neuroendocrinological and reproductive disorders. Macroorchidism occurs in males with overt Fragile X syndrome. Premature ovarian failure occurs in females who do not have the number of CGG repeats to produce overt Fragile X syndrome, but have an expanded number of repeats with few or no apparent neurological symptoms (premutation carriers). Structural, neurochemical, and hormonal abnormalities, therefore, need to be put together with a specific pathophysiological or neurodevelopmental mechanism. Variation in the cognitive and behavioral phenotype of the Fragile X syndrome has been demonstrated in intellectual functioning, learning disability, executive function, attention, hyperactivity, depression, anxiety, and autistic behaviors. The explanation for this variation in phenotypic expression may depend on understanding the role of genetics and brain development in cognition and behavior. Therefore, further studies are needed correlating the clinical manifestations of the Fragile X phenotype with the neurodevelopmental processes that underlie the Fragile X syndrome. This will lead, in turn, to a model of neurodevelopmental variation in specific cognitive and behavioral dysfunction. For treatment modalities to be instituted, suppression of expansion, restoration of expression, small molecule agents, and gene replacement need to be considered. Animal models are necessary for the evaluation of therapeutic strategies. For animal models to be effective, definition of the animal phenotype is only as good as the characterization of the human phenotype. The human phenotype includes deficits in executive function and social-behavioral problems. Sensitivity to stimuli needs to be determined. Research Scope This RFA focuses on neurobiological and epidemiological studies relevant to understanding the genetic and pathophysiologic basis of Fragile X syndrome. Examples of the types of studies addressing Fragile X syndrome that may be proposed in response to this RFA include, but are not limited to, the following: o Development of methods to better refine the definition of the clinical phenotype of Fragile X syndrome, focusing on its characteristic component behavioral and cognitive features. o Environmental studies including the influence of culture and ethnicity as variables in developing a better understanding of the correlation between genotype-phenotype and patient outcome. o Neurodevelopmental and longitudinal studies to characterize the neuropathological progression and inherent variability in Fragile X patients in order to develop specific hypotheses about the initial (primary) abnormality, and to address the degree to which phenotypic variation relates to postnatal brain development. o Histological, neurochemical, brain-imaging, and structure-function studies to define the molecular, cellular, and/or biochemical basis of this disorder and facilitate development of specific hypotheses about the basic abnormalities involved in Fragile X syndrome. o Studies examining the mechanism by which Fragile X genetic status affects the development, function, and dysfunction of the nervous system, particularly with respect to cognition and behavior. o Studies applying imaging, electrophysiology, pharmacology, molecular biology, and behavioral science techniques to follow the developmental trajectories of different brain functions onto developing cognitive and motor skills. Animal models are important resources for studying pathology and therapeutic strategies. Although some animal models have been created, there is still need for models for behavioral screening as well as therapeutic interventions that include suppression of expansions and restoration of expression. Specifically, topics that may be addressed include, but are not limited to: o Creation of conditional tissue-specific targeted knock-out animal models. o Development and use of animal models that have specific relevance to Fragile X based on clear neurodevelopmental, pathophysiological, genetic, and/or functional homology. o Development and use of animal models to test existing medications and develop new psychopharmacologic medications that are safe and effective for Fragile X patients. 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 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, published in the Federal Register of March 28, 1994 (FR 59 14508- 14513) and in the NIH Guide for Grants and Contracts, Volume 23, Number 11, March 18, 1994, and available on the Internet at: http://grants.nih.gov/grants/guide/notice-files/not94-100.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/or 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 Inclusion of Children as Participants in Research Involving Human Subjects, published in the NIH Guide for Grants and Contracts, March 6, 1998, and available at: http://grants.nih.gov/grants/guide/notice-files/not98-024.html. Investigators also may obtain copies of these policies from the program staff under INQUIRIES. Program staff also may provide additional relevant information concerning these policies. LETTER OF INTENT Prospective applicants are asked to submit 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 this RFA. 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 NICHD staff to estimate the potential review workload and plan the review. The letter of intent is to be sent to Dr. Mary Lou Oster-Granite at the address listed under INQUIRIES, below, by June 1, 2000. URLs IN NIH GRANT APPLICATIONS OR APPENDICES All applications and proposals for NIH funding must be self-contained within specified page limitations. Unless otherwise specified in an NIH solicitation, Internet addresses (URLs) should not be used to provide information necessary to the review because reviewers are under no obligation to view the Internet sites. Reviewers are cautioned that their anonymity may be compromised when they directly access an Internet site. APPLICATION PROCEDURES The research grant application form PHS 398 (rev. 4/98) is to be used in applying for these grants. These forms are available at most institutional offices of sponsored research, on the Internet at http://grants.nih.gov/grants/funding/phs398/phs398.html, 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, E-mail: [email protected]. Application Instructions for NICHD Small Grant (R03) Applications The small grant (R03) research mechanism should be used for support of pilot studies and/or exploration of novel hypotheses and strategies that are sound and justifiable, but not sufficiently developed for the R01 mechanism. A description of the NICHD Small Grants Program and complete application instructions are available from the program contact listed under INQUIRIES and on the Internet at http://grants.nih.gov/grants/guide/pa-files/PAR-99-126.html. These applications must be submitted according to the Modular Grant application instructions included in the NICHD Small Grant program announcement. Application Instructions for NIMH Small Grant (R03) Applications The NIMH Small Grants Program provides research support in areas of high relevance to the mission of the NIMH. Small grants are short-term awards designed to answer specific and targeted research questions. Both new and more experienced investigators are encouraged to apply for grants under this announcement. Newer investigators may use the award to generate new or additional preliminary data for future research grants (e.g., R01). Priority will be given to applications in any of the following four categories: 1. Newer, less experienced investigators. 2. Investigators at institutions without well-developed research traditions and resources. 3. More experienced investigators, for exploratory studies that represent significant change in research direction for them. 4. More experienced investigators, for developing and testing new methods or techniques. A description of the NIMH Small Grants Program and complete application instructions are available from the program contact listed under INQUIRIES and on the Internet at http://grants.nih.gov/grants/guide/pa-files/PAR-99-140.html. These applications must be submitted according to the Modular Grant application instructions included in the NIMH Small Grant program announcement. Modular Grant Application Instructions for Research Project Grant (R01) Applications The modular grant concept establishes specific modules in which direct costs may be requested as well as a maximum level for requested budgets. Only limited budgetary information is required under this approach. The just-in- time concept allows applicants to submit certain information only when there is a possibility for an award. It is anticipated that these changes will reduce the administrative burden for the applicants, reviewers, and NIH staff. The research grant application form PHS 398 (rev. 4/98) is to be used in applying for these grants, with the modifications noted below. Modular Grant applications will request direct costs in $25,000 modules, up to a total direct cost request of $200,000 per year. The total direct costs must be requested in accordance with the program guidelines and the modifications made to the standard PHS 398 application instructions described below: o FACE PAGE: Items 7a and 7b should be completed, indicating Direct Costs (in $25,000 increments up to a maximum of $200,000) and Total Costs [Modular Total Direct plus Facilities and Administrative (F&A) costs] for the initial budget period. Items 8a and 8b should be completed indicating the Direct and Total Costs for the entire proposed period of support. o DETAILED BUDGET FOR THE INITIAL BUDGET PERIOD: Do not complete Form Page 4 of the PHS 398. It is not required and will not be accepted with the application. o BUDGET FOR THE ENTIRE PROPOSED PERIOD OF SUPPORT: Do not complete the categorical budget table on Form Page 5 of the PHS 398. It is not required and will not be accepted with the application. o NARRATIVE BUDGET JUSTIFICATION: Prepare a Modular Grant Budget Narrative page. (See http://grants.nih.gov/grants/funding/modular/modular.htm for sample pages.) At the top of the page, enter the Total Direct Costs requested for each year. This is not a Form Page. Under Personnel, list key project personnel, including their names, percent of effort, and roles on the project. No individual salary information should be provided. However, the applicant should use the NIH appropriation language salary cap and the NIH policy for graduate student compensation in developing the budget request. For Consortium/Contractual costs, provide an estimate of Total Costs (Direct plus F & A) for each year, each rounded to the nearest $1,000. List the individuals/organizations with whom consortium or contractual arrangements have been made, the percent effort of key personnel, and the role on the project. Indicate whether the collaborating institution is foreign or domestic. The total cost for a consortium/contractual arrangement is included in the overall requested modular direct cost amount. Include the Letter of Intent to establish a consortium. Provide an additional narrative budget justification for any variation in the number of modules requested. o BIOGRAPHICAL SKETCH: The Biographical Sketch provides information used by reviewers in the assessment of each individual"s qualifications for a specific role in the proposed project, as well as to evaluate the overall qualifications of the research team. A biographical sketch is required for all key personnel, following the instructions below. No more than three pages may be used for each person. A sample biographical sketch may be viewed at: http://grants.nih.gov/grants/funding/modular/modular.htm. - Complete the educational block at the top of the Form Page, - List position(s) and any honors, - Provide information, including overall goals and responsibilities, on research projects ongoing or completed during the last three years, - List selected peer-reviewed publications, with full citations. o CHECKLIST: This page should be completed and submitted with the application. If the F&A rate agreement has been established, indicate the type of agreement and the date. All appropriate exclusions must be applied in the calculation of the F&A costs for the initial budget period and all future budget years. o The applicant should provide the name and telephone number of the individual to contact concerning fiscal and administrative issues if additional information is necessary following the initial review. Submission Instructions The RFA label available in the PHS 398 (rev. 4/98) application form must be stapled to the bottom of the face page of the application and must display the RFA number HD-00-015. A sample RFA label is available at http://grants.nih.gov/grants/funding/phs398/label-bk.pdf. Please note this is in the pdf format. 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 should be sent to: L. R. Stanford, Ph.D. Director, Division of Scientific Review National Institute of Child Health and Human Development 6100 Executive Boulevard, Room 5E03, MSC 7510 Bethesda MD 20892-7510 Rockville MD 20852 (for express/courier service) Applications must be received by July 17, 2000. 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 for responsiveness to this RFA by NICHD and NIMH. Incomplete and/or non- responsive applications will be returned to the applicant without further consideration. 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 NICHD in accordance with the review criteria stated below. As part of the initial merit review, all applications will receive a written critique and may undergo a process in which only those applications deemed to have the highest scientific merit will be discussed, assigned a priority score, and receive a second level review by the National Advisory Child Health and Human Development Council and/or the National Advisory Mental Health Council. 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 an important work that is by its nature 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 methods? 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? In addition to the above criteria, in accordance with NIH policy, all applications also will 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 also will be evaluated. o The reasonableness of the proposed budget and its duration in relation to the proposed research. o The adequacy of the proposed protection for humans, animals or the environment, to the extent that they may be adversely affected by the project proposed in the application. SCHEDULE Letter of Intent Receipt Date: June 1, 2000 Application Receipt Date: July 17, 2000 Peer Review Date: October 2000 Council Review: January 2001 Earliest Anticipated Start Date: April 1, 2001 AWARD CRITERIA The following factors will be considered in making award decisions: Scientific merit of the proposed project as determined by peer review, availability of funds, and program priority. INQUIRIES Inquiries concerning this RFA are encouraged. The opportunity to clarify any issues or questions from potential applicants is welcome. Applicants may also consult with NIH staff for advice about collaborations and access to patients and patient material. Direct inquiries regarding programmatic issues to: Mary Lou Oster-Granite, Ph.D. Mental Retardation and Developmental Disabilities Branch National Institute of Child Health and Human Development 6100 Executive Boulevard, Room 4B-09, MSC 7510 Bethesda, MD 20892-7510 Telephone: (301) 435-6866 FAX: (301) 496-3791 E-mail: [email protected] Steven O. Moldin, Ph.D. Division of Neuroscience and Basic Behavioral Science National Institute of Mental Health 6001 Executive Blvd., Room 7189, MSC 9643 Bethesda, MD 20892-9643 Telephone: (301) 443-2037 FAX: (301) 443-9890 E-mail: [email protected] Direct inquiries regarding fiscal matters to: Mr. Douglas Shawver Grants Management Branch National Institute of Child Health and Human Development 6100 Executive Boulevard, Room 8A-17, MSC 7510 Bethesda, MD 20892-7510 Telephone: (301) 435-6999 FAX: (301) 402-0915 E-mail: [email protected] Ms. Diana S. Trunnell Grants Management Branch National Institute of Mental Health 6001 Executive Blvd., Room 6115, MSC 9605 Bethesda, MD 20892-9605 Telephone: (301) 443-2805 FAX: (301) 443-6885 E-mail: [email protected] AUTHORITY AND REGULATIONS This program is described in the Catalog of Federal Domestic Assistance No. 93.865, (NICHD) and 93.242 (NIMH). Awards are made under authorization of Sections 301 and 405 of the Public Health Service Act, as amended (42 USC 241 and 284) and administered under NIH grants policies and Federal Regulations 42 CFR 52 and 45 CFR Parts 74 and 92. 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 portions 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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