Full Text HL-96-013 MITOCHONDRIAL DNA MUTATIONS IN HEART, LUNG AND BLOOD DISEASES NIH Guide, Volume 25, Number 26, August 2, 1996 RFA: HL-96-013 P.T. 34 Keywords: Nucleic Acids Cardiovascular Diseases Blood Diseases Pulmonary Diseases National Heart, Lung, and Blood Institute Letter of Intent Receipt Date: January 24, 1997 Application Receipt Date: March 12, 1997 THIS RFA USES "MODULAR GRANT" AND "JUST-IN-TIME" CONCEPTS. THE FULL RFA INCLUDES DETAILED MODIFICATIONS TO STANDARD APPLICATION INSTRUCTIONS AND MUST BE USED WHEN PREPARING APPLICATIONS IN RESPONSE TO THIS RFA. PURPOSE This initiative will foster research on molecular, cellular, genetic, and epidemiologic approaches to elucidate the role of mitochondrial DNA (mtDNA) mutations in heart, blood vessels, blood and lung diseases. Its goals are to define mechanisms by which mtDNA mutations cause tissue-specific, progressive diseases, and to elucidate the cause and effect relationships between alterations in this genome and pathological phenotypes. The ultimate purpose of this initiative is the development of effective strategies for prevention and treatment of cardiovascular, pulmonary, and hematologic disorders due to mitochondrial DNA mutations in humans. Although this Request for Applications (RFA) is sponsored by the National Heart, Lung, and Blood Institute (NHLBI), other Institutes and Centers of the NIH may also have an interest in mitochondrial research. Applications will be assigned to the most appropriate Institute/Center on the basis of established PHS referral guidelines. 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 Request for Applications (RFA), Mitochondrial DNA Mutations in Heart, Blood and Lung Diseases, is related to the priority areas of heart disease and stroke, diabetes and chronic disabling conditions, and environmental health. 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. Racial/ethnic minority individuals, women, and persons with disabilities are encouraged to apply as Principal Investigators. All current policies and requirements that govern the research grant programs of the NIH will apply to grants awarded under this RFA. Awards under this RFA to foreign institutions will be made only for research of very unusual merit, need, and promise, and in accordance with Public Health Service policy governing such awards. MECHANISM OF SUPPORT This RFA will use the NIH individual research project grant (R01) mechanism of support. Newly independent investigators who wish to apply are encouraged to consult with a program representative (see INQUIRIES below). Specific application instructions have been modified to reflect "MODULAR GRANT" and "JUST-IN-TIME" streamlining efforts being examined by the NIH. The "MODULAR GRANT" concept establishes specific modules (increments) 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, applicant institutions, reviewers, and Institute staff. For this RFA, funds must be requested in $25,000 direct cost modules. Up to a maximum of seven modules ($175,000 direct costs) per year may be requested. A feature of the modular grant concept is that no escalation is provided for future years, and all anticipated expenses for all years of the project must be included within the number of modules being requested. Only limited budget information will be required and any budget adjustments made by the Initial Review Group will be in modules of $25,000. Instructions for completing the Biographical Sketch have also been modified. In addition, Other Support information and the application Checklist page are not required as part of the initial application. If there is a possibility for an award, necessary budget, Other Support, and Checklist information will be requested by NHLBI staff following the initial review. The APPLICATION PROCEDURES section of this RFA provides specific details of modifications to standard PHS 398 application kit instruction. 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 four 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. It is anticipated that support for this program will begin in September 1997. Administrative adjustments in project period and/or amount may be required at the time of the award. FUNDS AVAILABLE It is anticipated that for fiscal year 1997, approximately $1,800,000 total costs will be available for the first year of support for this initiative. Award of grants pursuant to this RFA is contingent upon receipt of such funds for this purpose. It is anticipated that approximately six new grants will be awarded under this program. The specific number to be funded will, however, depend on the merit and scope of the applications received and on the availability of funds. Direct costs will be awarded in modules of $25,000, less any overlap or other necessary administrative adjustments. Indirect costs will be awarded based on the negotiated rates. RESEARCH OBJECTIVES Background There is now convincing evidence that proper functioning of human mitochondrial DNA (mtDNA) is critical to normal cellular metabolism and that mutations in mtDNA can result in severe disease phenotypes. Recently, a large number of mtDNA mutations have been catalogued and linked to human degenerative diseases. Mitochondrial defects may be inherited or acquired. Phenotypic abnormalities in individuals bearing genetic defects may be evident at birth or may not be apparent until middle age. Although it is clear that mutations in mtDNA can cause devastating symptoms affecting different organ systems, many clinically relevant questions concerning pathophysiology remain unanswered. Quantitative relationships between the abundance of mutated forms of mtDNA relative to normal mitochondrial genome and dysfunction of different cell types remain to be defined. In terms of cardiovascular diseases, evidence suggests that an accumulation of mutant forms of mtDNA in the myocardium frequently results in cardiac conduction block and sudden cardiac death. It is apparent that certain types of cardiac diseases may be caused by the mtDNA mutations, but the pathophysiological events that give rise to specific forms of heart disease in association with these mtDNA mutations still remain obscure. The current view is that abnormalities in mitochondrial structure and function, and mutations in mtDNA are associated with a large number of cardiac pathologies including ischemic heart disease, idiopathic dilated cardiomyopathy, hypertrophic cardiomyopathy, and cardiomyopathy of aging. However, strict causal relationships among abnormalities in mtDNA and/or abnormalities in mitochondrial biogenesis and these cardiac abnormalities are not fully elucidated. Resolution of this problem can come from study of animal models, which have not yet been developed. Such models will also provide the opportunity to test potential therapeutic strategies, including the development of mitochondrial gene therapy. Some studies suggest that abnormalities in mtDNA not only cause the rare but devastating syndromes that have been identified as mitochondrial diseases, but contribute to the pathophysiology of other widely prevalent diseases. A deficiency of mtDNA has been observed in HIV-infected patients treated with antiviral nucleoside analogues (ANA), and is proposed to contribute to myopathic symptoms in these individuals. Evidence suggests that short-term usage of ANA drugs is relatively safe; however, long term usage reveals that they can become toxic and affect oxidative phosphorylation, which appears to be attributable to a defect in mitochondrial replication. This defect resembles certain mitochondrial genetic diseases that have been associated with cardiomyopathy, mitochondrial myopathy, neuropathy, lactic acidosis, exocrine pancreas failure, pancreas failure, liver failure and bone marrow failure. It has been suggested that mitochondrial toxic ANAs may serve as experimental tools to clarify mtDNA replication. In the area of hematology, evidence for the association of mitochondrial DNA mutations and blood diseases is fragmentary. One exception is Pearson's syndrome, a progressive congenital disorder involving the hematopoietic system, exocrine pancreas, liver and kidneys. Within the blood, it is characterized by bone marrow failure, hypoproliferative sideroblastic anemia, and pancytopenia. It is associated with enzymatic deficiencies in some of the respiratory chain enzymes within blood cells that occur in conjunction with large-scale, single deletions of the mitochondrial genes encoding these enzymes. This is the first reported mitochondriopathy with a non-neuromuscular expression. The reported abnormalities of both erythroid and myeloid precursors in the arrow of Pearson's Syndrome patients suggests a potential role of mtDNA in hematopoiesis. Although Pearson's syndrome itself is relatively rare, it is certainly possible that other forms of sideroblastic or aplastic anemias may also be associated with acquired or inherited mtDNA mutations. Sideroblastic anemias in general have the unique characteristic of amorphous iron deposits in erythroblast mitochondria. The role of iron in mitochondria and the ineffective erythropoiesis in these anemias needs further study. Iron in red cell membranes has been reported in thalassemia and sickle cell disease. This iron deposition causes significant oxidation of membrane proteins in these disorders, but little has been reported on possible oxidative damage to mitochondria in the red blood cell precursors. In addition, little is known about possible mitochondrial damage in other diseases involving iron overload or in the blood of individuals undergoing chronic transfusion. Many dysfunctions of electron transport chain enzymes as well as mutant mtDNA have also been found in platelets and/or lymphocytes of patients with diseases associated with aging, including Parkinson's, Huntington's, and Alzheimer's diseases. Furthermore, this phenomenon has been reported in Down syndrome, which is characterized by an accelerated aging process. Some of these enzymatic dysfunctions have been linked to mutations in mitochondrial genes encoding these proteins. Most of these mutations have been discovered as a result of using blood cells because of their accessibility as a "diagnostic test" to screen for mutations that may also occur in tissues more directly involved in the disease, but are less accessible, such as brain tissue from Parkinson's Disease patients. It is quite possible that the function of the blood cells themselves may be affected by the mtDNA mutations. Elucidating how the bioenergetic defects in blood cells affect their own function may have implications for other diseases involving mtDNA mutations. The role of mutations in mtDNA in etiology and pathogenesis of lung disease is virtually unexplored. The lung might be particularly prone to mitochondrial DNA damage as a result of its oxidative environment, rapidly turning over epithelium, and constant exposure to environmental agents. The consequences on mtDNA of exposure of potential therapeutic agents such as nitric oxide are not understood. Damage or loss of specific mitochondrial genes associated with energy generation could potentially affect many aspects of pulmonary cell function, particularly under stressful conditions. Examples of lung cell functions that might be impaired include surfactant and extracellular matrix biosynthesis, cell repair processes, mucociliary transport, ion gradients, and neural control of airway smooth muscle function. Thus, one objective of future research should be to establish whether mtDNA damage occurs in the lung in association with disease states, and if so, to determine the role of mtDNA damage and repair in the etiology of lung disease. Although much of the evidence involving a link between mtDNA mutations and certain diseases is unequivocal, there is still a compelling need to determine the extent to which mtDNA mutations affect the natural history of heart, blood vessels, blood, and lung diseases. There have been few epidemiological studies of mitochondrial disorders and thus the extent of the problem in general populations is unknown. The attributable risk of myocardial, hypertensive, and other cardiovascular diseases due to mitochondrial gene mutations is also unknown. The lack of an easy screening test, other than the blood cell diagnostic test' mentioned above, which may miss certain types of mtDNA mutations, has hampered this research. However, maternal transmission of inherited mtDNA defects and the apparent mendelian pattern of inheritance for certain mtDNA deletions (implying nuclear gene involvement in mtDNA replication) suggests that pedigree studies could be informative. Family studies could be used to elucidate susceptibility markers and factors associated with phenotypic expression of mtDNA diseases. Preexisting population studies that have already collected DNA could assess mitochondrial DNA variation in a relatively cost-effective manner. Research Goals and Scope The following examples of potential research projects are given for illustrative purposes only and are not intended to define the scope of relevant topics. Investigators are expected to use their expert knowledge of the field in developing responses to this initiative o Establish animal and cellular models of mutant mtDNA relevant to heart, vascular, lung and blood disorders o Identify genes important for mtDNA replication or repair, segregation of mitochondrial genomes during cell division, and control of mtDNA copy numbers in cell types found in heart, vascular, lung and blood disorders o Develop methods to transfer exogenous genes into mammalian mitochondria or to complement mitochondrial gene defects by gene transfer to the nucleus of cardiovascular, lung and blood cells. o Establish mechanisms of damage in relationship to the etiology of the heart, vascular, lung and blood disease states in animals or humans o Elucidate mechanisms that promote mitochondrial DNA mutations in ischemic heart disease and hyperoxic lung disease. o Elucidate the role of mtDNA damage in early development of cardiovascular, lung and blood cells o Identify markers for susceptibility to mitochondrial diseases of heart, vascular, lung and blood and development of preventive strategies o Elucidate the reasons that some mitochondrial mutations and deletions give rise to clinically different heart, vascular, lung and blood disorders and some have no effect. o Elucidate quantitative relationships between mutant forms of mtDNA and heart and lung dysfunction. o Define the pathways for ATP synthesis and utilization changes in blood cells, cardiovascular, and lung tissues with defective mitochondrial genes. o Identify mtDNA determinants of heart, vascular, lung, and blood disease and risk factors. o Define the pathways for ATP synthesis and utilization changes in blood cells, cardiovascular and lung tissues with defective genes. SPECIAL REQUIREMENTS Upon initiation of the program, the NHLBI will sponsor periodic meetings to encourage exchange of information among investigators who participate in this program. In the budget for the grant application, applicants should request travel funds for a 1-day meeting each year, most likely to be held in Bethesda, Maryland. Applicants should also include a statement in their applications indicating their willingness to participate in these meetings. 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 28, 1994 (FR 59 14508-14513) 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. LETTER OF INTENT Prospective applicants are asked to submit, by January 24, 1997, a letter of intent that includes a descriptive title of the proposed research, the name, address, and telephone number of the Principal Investigator, the identities of other key personnel and participating institutions, and the number and title of the RFA in response to which the application may be submitted. Although a letter of intent is not required, is not binding, and does not enter into the review of a subsequent application, the information that it contains allows NIH staff to estimate the potential review workload and avoid conflict of interest in the review. A faxed letter of intent may be used in place of a posted one. The letter of intent is to be sent to: Dr. C. James Scheirer Division of Extramural Affairs National Heart, Lung, and Blood Institute 6701 Rockledge Drive, Room 7220, MSC 7924 Bethesda, MD 20892-7924 Telephone: (301) 435-0266 FAX: (301) 480-3541 Email: James_Scheirer@NIH.GOV APPLICATION PROCEDURES The research grant application form PHS-398 (rev. 5/95) is to be used in applying for these grants. Applications kits are available at most institutional offices of sponsored research; 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; and from NHLBI program staff listed under INQUIRIES. The RFA label available in the application kit must be affixed to the bottom of the face page. 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 title of the application and the RFA number must be typed on line 2 of the face page of the application form. Submit a signed, typewritten original of the application, including the Checklist, and three signed, exact photocopies in one package to DIVISION OF RESEARCH GRANTS NATIONAL INSTITUTES OF HEALTH 6701 ROCKLEDGE DRIVE, SUITE 1040 - MSC 7710 BETHESDA, MD 20892-7710 BETHESDA, MD 20817 (for express/courier service) Submit an additional two copies of the application to Dr. Scheirer at the address listed under LETTER OF INTENT. It is important to send these two copies at the same time as the original and three copies are sent to the Division of Research Grants; otherwise, the NHLBI cannot guarantee that the application will be reviewed in competition for this RFA. Sample budgets and justification page will be provided upon request or following the submission of a letter of intent. BUDGET INSTRUCTIONS 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 DETAILED BUDGET FOR THE INITIAL BUDGET PERIOD Do not complete Form Page 4 of the PHS 398 (rev 5/95). It is not required nor will it be accepted at the time of application. o BUDGET FOR THE ENTIRE PROPOSED PERIOD OF SUPPORT Do not complete the categorical budget tables on Form page 5 of the PHS 398 (rev. 5/95). Only the requested total direct costs line for each year must be completed based on the number of $25,000 modules being requested. Applicants may not request a change in the amount of each module. A maximum of seven modules ($175,000 direct costs) per year may be requested and each applicant may request up to four years of support for this RFA. Direct cost budgets will remain constant throughout the life of the project (i.e. the same number of modules requested for all budget periods). Any necessary escalation should be considered when determining the number of modules to be requested. However, in the event that the number of modules requested must change in any future year due to the nature of the research proposed, appropriate justification must be provided. Total Direct Costs for the Entire Proposed Project Period should be shown in the box provided. o BUDGET JUSTIFICATION Budget justifications should be provided under "Justifications" on Form Page 5 of the PHS 398. List the names, role on the project and proposed percent effort for all project personnel (salaried or unsalaried)and provide a narrative justification for each person based on his/her role on the project. Identify all consultants by name and organizational affiliation and describe the services to be performed. Provide a general narrative justification for individual categories (equipment, supplies, etc.) required to complete the work proposed. More detailed justifications should be provided for high cost items. Any large one-time purchases, such as large equipment requests, must be accommodated within these limits. o CONSORTIUM/CONTRACTUAL COSTS - If collaborations or subcontracts are involved that require transfer of funds from the grantee to other institutions, it is necessary to establish formal subcontract agreements with each collaborating institution. A letter of intent from each collaborating institution should be submitted with the application. Only the percentage of the consortium/contractual TOTAL COSTS (direct and indirect) relative to the total DIRECT COSTS of the overall project needs to be stated at this time. The following example should be used to indicate the percentage cost of the consortium, "The consortium agreement represents 27% of overall $175,000 direct costs requested in the first year.". A budget justification for the consortium should be provided as described in the "Budget Justification" section above (no Form Page 5 required for the consortium). Please indicate whether the consortium will be in place for the entire project period and identify any future year changes in the percentage relative to the parent grant. If there is a possibility for an award, the applicant will be requested to identify actual direct and indirect costs for all years of the consortium. Please note that total subcontract costs need not be calculated in $25,000 modules. However, when subcontract funds are added to the parent grant budget, the total direct cost amount must be included in the number of $25,000 modules requested. o BIOGRAPHICAL SKETCH - A biographical sketch is required for all key personnel, following the modified instructions below. Do not exceed the two-page limit for each person. Complete the educational block at the top of the form page; List current position(s) and those previous positions directly relevant to the application; List selected peer-reviewed publications directly relevant to the proposed project, with full citation; The applicant has the option to provide information on research projects completed and/or research grants participated in during the last five years that are relevant to the proposed project. o OTHER SUPPORT - Do not complete the "Other Support" pages (Form Page 7). Selected other support information relevant to the proposed research may be included in the Biographical Sketch as indicated above. Complete Other Support information will be requested by NHLBI staff if there is a possibility for an award. o CHECKLIST - No "Checklist" page is required as part of the initial application. A completed Checklist will be requested by NHLBI staff if there is a possibility for an award. o The applicant should provide the name and phone number of the individual to contact concerning fiscal and administrative issues if additional information is necessary following the initial review. Applications not conforming to these guidelines will be considered unresponsive to this RFA and will be returned without further review. Applications must be received by March 12, 1997. If an application is received after that date, it will be returned to the applicant without review. The Division of Research Grants (DRG) will not accept any application in response to this RFA that is essentially the same as one currently pending initial review, unless the applicant withdraws the pending application. The DRG will not accept any application that is essentially the same as one already reviewed. This does not preclude the submission of substantial revisions of applications already re-viewed, but such applications must include an introduction addressing the previous critique. REVIEW CONSIDERATIONS Applications that are complete and responsive to the RFA will be evaluated for scientific and technical merit by an appropriate peer-review group convened by the NHLBI 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 National Heart, Lung, and Blood Advisory Council. The personnel category will be reviewed for appropriate staffing based on the requested percent effort. The direct costs budget request will be reviewed for consistency with the proposed methods and specific aims. Any budgetary adjustments recommended by the reviewers will be in $25,000. The duration of support will be reviewed to determine if it is appropriate to ensure successful completion of the recommended scope of the project. Other review criteria will include: 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 adequacy of plans to include both genders and minorities and their subgroups as appropriate for the scientific goals of the research. Plans for the recruitment and retention of subjects will also be evaluated. The initial review group will also examine the provisions for the protection of human and animal subjects and the safety of the research environment. AWARD CRITERIA Applications will compete for available funds with all other approved applications. The following will be considered in making funding decisions: quality 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. Direct inquiries regarding programmatic issues to: Dr. Isabella Liang Division of Heart and Vascular Diseases National Heart, Lung, and Blood Institute 6701 Rockledge Drive, Suite 9142, MSC 7940 Bethesda, MD 20892-7940 Telephone: (301) 435-0520 FAX: (301) 480-1335 Email: liangi@gwgate.nhlbi.nih.gov Dr. Carol Letendre Division of Blood Diseases and Resources National Heart, Lung, and Blood Institute 6701 Rockledge Drive, Suite 10162, MSC 7950 Bethesda, MD 20892-7950 Telephone: (301) 435-0080 FAX: (301) 480-0867 Email: letendrc@gwgate.nhlbi.nih.gov Dr. Dorothy Gail Division of Lung Diseases National Heart, Lung, and Blood Institute Two Rockledge Center, Suite 10100 6701 Rockledge Drive, MSC 7952 Bethesda, MD 20892-7952 Telephone: 301-435-0222 Fax: 301-480-3557 Email: gaild@gwgate.nhlbi.nih.gov Ms. Phyliss Sholinsky Division of Epidemiology and Clinical Applications National Heart, Lung, and Blood Institute Two Rockledge Center, Suite 8151 6701 Rockledge Drive, MSC 7934 Bethesda, MD 20892-7934 Telephone: 301-435-0701 Fax: 301-480-1667 Email: sholinsp@gwgate.nhlbi.nih.gov Direct inquiries regarding fiscal matters and requests for sample budgets to: Ms. Marie Willett Grants Operations Branch National Heart, Lung, and Blood Institute Two Rockledge Center, Suite 7128 6701 Rockledge Drive, MSC 7926 Bethesda, MD 20892-7926 Phone: 301-435-0144 Fax: 301-480-3310 E-mail: willettm@gwgate.nhlbi.nih.gov AUTHORITY AND REGULATIONS This program is described in the Catalog of Federal Domestic Assistance No. 93.837, 93.838, and 93.839. 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 the PHS mission to protect and advance the physical and mental health of the American people. .
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