AIRWAY REMODELING AND REPAIR IN ASTHMA Release date: November 19, 1998 RFA: HL-99-005 P.T. National Heart, Lung, and Blood Institute Letter of Intent Receipt Date: January 6, 1999 Application Receipt Date: February 24, 1999 THIS RFA USES "MODULAR GRANT" AND "JUST-IN-TIME" CONCEPTS. THIS RFA INCLUDES DETAILED MODIFICATIONS TO STANDARD APPLICATION INSTRUCTIONS THAT MUST BE FOLLOWED WHEN PREPARING APPLICATIONS IN RESPONSE TO THIS RFA. PURPOSE The National Heart, Lung, and Blood Institute (NHLBI) invites research grant applications to conduct cell biologic, molecular biologic, and molecular pathologic investigations designed to elucidate the mechanisms underlying airway remodeling and repair in asthma. The goal is to understand the pathogenesis, regulation, and consequences of airway responses in asthma. Among the disciplines and expertise that are appropriate for this research program are molecular biology, molecular pathology, cell biology, immunology, microbiology, biochemistry, allergy, asthma, genetics, pulmonary medicine, pulmonary physiology, and pediatrics. 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), "Airway Remodeling and Repair in Asthma," is related to the priority area of Chronic Disabling Conditions. 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 or 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 National Institutes of Health (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 PHS policy governing such awards. MECHANISM OF SUPPORT This RFA will use the NIH individual research project grant (R01) mechanism of support. However, 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 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 Institute staff. For this RFA, funds must be requested in $25,000 direct cost modules with a maximum of nine modules ($225,000 direct costs) per R01 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 instructions. Responsibility for the planning, direction, and execution of the proposed project will be solely that of the applicant. It is anticipated that support for this program will begin in September 1999. Administrative adjustments in project period and/or amount may be required at the time of the award. 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. Applicants from institutions that have a General Clinical Research Center (GCRC) funded by the NIH National Center for Research Resources may wish to identify the GCRC as a resource for conducting the proposed research. If so, a letter of agreement either from the GCRC program director or principal investigator should be included with the application. FUNDS AVAILABLE It is anticipated that for fiscal year 1999, approximately $2,700,000 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 8 new grants will be awarded under this program. Applicants may request up to 4 years of support. 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. Facilities and administrative costs will be awarded based on the negotiated rates. RESEARCH OBJECTIVES Background Chronic airway inflammation and it's consequences play a major role in the pathogenesis of asthma. Although the airways obstruction found in asthma has, until recently, been considered reversible, new data suggests that some patients with asthma may have permanent abnormalities in lung function. These permanent changes are postulated to arise as a consequence of airway injury and repair, a process felt to represent airway remodeling. For many years, pathologists have described basement membrane thickening in asthmatic airways. It now appears that the basement membrane is actually normal in asthmatic airways and the thickening is the result of a sub-epithelial fibrotic response. More recent studies have highlighted the importance of other structural alterations in asthmatic airways including myocyte and myofibroblast hyperplasia and hypertrophy, and epithelial alterations. However, the mechanisms responsible for these alterations, their physiologic and biologic consequences, the role of these changes in the natural history of asthma, and the amenability of these alterations to therapeutic intervention have not been adequately investigated. Study of airway remodeling and its consequences at cellular, subcellular, and molecular levels will provide additional insight into the role of airway injury and its abnormal repair in the pathogenesis of asthma, eventually leading to preventive or therapeutic strategies. Research Scope: This RFA is designed to stimulate cell biologic, molecular biologic, and molecular pathologic studies of airway remodeling and repair in asthma, with the overall goal of elucidating the pathogenesis, regulation, and consequences of these airway responses in asthma. Areas of investigation relevant to these objectives include, but are not limited to, the following: 1. Relationship of the pathologic, ultrastructure and morphometric features of the remodeled airway to asthma: Our knowledge of the pathology, ultrastructural features and morphometric relationships in the remodeled airway in humans and animals is incomplete. In addition to large airway involvement, abnormalities in small airways and associated parenchyma may occur in asthma. Better definition of these changes utilizing molecular pathologic approaches is needed. Although structural changes (subepithelial fibrosis, matrix accumulation, myocyte and myofibroblast hyperplasia, mucous gland and goblet cell hyperplasia, and epithelial cell proliferation) in the airways have been linked to chronic asthma, the spectrum of pathologic alterations in asthmatic airways has not been well characterized nor the degree to which these remodeling responses have occurred been determined. Information is required about the types of matrix molecules that accumulate and cellular abnormalities that result, as well as their effects on airway structure. For example, what types of collagens are deposited? What cells produce these collagens? Are there specific patterns of elaboration and locations of matrix metalloproteinases, collagenases and hyaluronidases in the asthmatic airway? Are there specific cell types whose location and number are altered? Does airway remodeling alter the resident cells of the airway such as dendritic cells and goblet cells? What is the relationship of the cellular changes to remodeling of the airway? Is remodeling relevant to airflow obstruction? Does remodeling compromise airway lumen size or the thickness of the airway between the smooth muscle layer and lumen? What are the pathologic correlates of incompletely reversible asthma? 2. Role of airway remodeling in the natural history of asthma: Asthma is thought to be a syndrome comprising multiple different subtypes rather than a single disease entity. Each of these may very well have different natural histories and sequelae. Airway remodeling in each of these subtypes is likely to differ in the specific alterations of various structural elements. Studies are needed to define the multiple components/locations of the structural abnormalities which may exist in the different subgroups of asthmatics. The relationship between these abnormalities and the deterioration in lung function and/or diminished reversibility of airway obstruction experienced by some patients with asthma also needs to be clarified. 3. Pathogenetic events involved in airway remodeling in asthma: The cellular and molecular events underlying the fibrotic, myocyte/myofibroblast and epithelial alterations characteristic of the remodeled asthmatic airway are poorly understood, as well as their exact functional consequences. It is now believed that airways hyperresponsiveness, the hallmark of asthma, may be, in a large part, the consequence of the inflammation and subsequent structural changes in the airways. Hence, what is the relationship of inflammation and these structural changes in the airway to the development of airways hyperresponsiveness? How is mucous gland and goblet cell differentiation, proliferation, and secretion regulated in the lung? What is the relationship of inflammation to airway remodeling. Do immune responses contribute to these processes? How does airway remodeling contribute to the chronicity, severity, and physiologic alterations of asthma. Is oxidantant and/or NO-mediated injury, chronic antigen exposure, and the interactions of viruses and antigens important in the mediation of these processes? Which cytokines and other mediators are involved in the pathogenesis of the fibrotic/extracellular matrix response and the myocyte, myofibroblast and epithelial (goblet cell) abnormalities in the remodeled asthmatic airway? What role do proteases play in the generation of airway injury and repair? It is known that the fibrotic response in the interstitium is heightened by interventions that block the proliferation of alveolar type II cells and their eventual differentiation into type I cells. Is re-epithelialization of the airway a crucial event that determines the degree of fibrosis that occurs in response to a given injury? If so, what are the events involved in epithelial repair? Which cytokines and other mediators stimulate epithelial proliferation and differentiation? What is the stem cell(s) in the airway, if any? How does this stem cell(s) allow epithelial repair to occur with the restoration of an appropriate frequency and distribution of ciliated vs non-ciliated and goblet cells? Information is also required concerning the role of development in the generation of the remodeling response, and the types of interventions that can block it. Attention must be directed toward therapeutic interventions against all of the features of the remodeling response including fibrosis, myocyte and myofibroblast abnormalities and epithelial alterations. Additionally, the effects of these interventions on the physiologic consequences of this response need to be defined. Since early childhood events play a crucial role in the development of chronic asthma, it is important to determine whether there are crucial periods in respiratory development at which injury predisposes to severe remodeling consequences. 4. Genetics factors in airway remodeling: There is a significant variability in host response to stimuli that cause airway remodeling. Recent studies have demonstrated that genetic polymorphisms exist that can explain variations in host responses to injury and pharmacologic intervention. It is important to determine whether there are genetic explanations for the variations in the extent and severity of airway remodeling. For example, are there polymorphisms in the promoters of genes encoding matrix molecule, matrix degrading enzymes etc., that predict the severity of these responses? Are the genes that determine susceptibility to fibrosis in the pulmonary interstitium ( for example: bleomycin susceptibility) also relevant to the fibrotic response in the airway? 5. Development of models for airway remodeling in asthma: Animal models of asthma have, to date, focused almost exclusively on acute airway inflammation and physiologic dysregulation. Very few models that reproduce the pathologic features of the remodeled asthmatic airway have been developed and characterized. There is a particular need for models that investigate the relationship between immune events and airway remodeling, as well as the relation between viral infection and airway remodeling. In addition, models (such as transgenic models) that allow direct cause and effect relationships to be defined and allow individual features of airway remodeling (i.e., sub-epithelial fibrosis, myocyte, myofibroblast abnormalities, epithelial alterations) to be generated need to be established and characterized. Also, computerized models of asthma that explore the impact of the various structural alterations on airway function need to be developed. These are examples only. Investigators should not feel limited to the subjects mentioned above and are encouraged to submit other topics pertinent to the objectives of the RFA. Although studies involving humans and/or human materials are preferable, investigations with mammalian models that provide convincing evidence they are relevant to asthma will also be suitable for addressing the mechanistic information sought in this RFA. 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. Travel funds for a one day meeting each year, most likely to be held in Bethesda, Maryland, should be included in the modules. Applicants should also include a statement in their applications indicating their willingness to participate in these meetings. Applications that propose descriptive studies and do not contain hypothesis driven studies directed at understanding the mechanisms associated with airway remodeling and repair in asthma will not responsive to the RFA. Applications that focus on these mechanisms at the molecular level are of particular interest. Studies in human subjects are strongly encouraged, but large clinical studies or long term (greater than 4 years) epidemiology studies are not within the scope of this RFA. Applicants who propose to test hypotheses in animal or in vitro models must provide a strong rationale for relevance to the human and to asthma. This program will not support studies solely directed at development of animal models unaccompanied by mechanistic studies that address the goals of this RFA. 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 follow 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 in the NIH GUIDE FOR GRANTS AND CONTRACTS of March 18, 1994, Volume 23, Number 11. 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. INCLUSION OF CHILDREN AS PARTICIPANTS IN RESEARCH INVOLVING HUMAN SUBJECTS It is the policy of the 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. LETTER OF INTENT Prospective applicants are asked to submit, by January 6, 1999, 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 subsequent applications, the information that it contains allows NHLBI staff to estimate the potential review workload and to avoid conflict of interest in the review. Applicants without prior R01 support are urged to identify themselves in the letter of intent. The letter of intent is to be mailed or faxed to Dr. C. James Scheirer, at the address listed under INQUIRIES. APPLICATION PROCEDURES The research grant application form PHS 398 (rev. 4/98) is to be used in applying for these grants, with the modifications noted below. These forms are available at most institutional offices of sponsored research; 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; and on the Internet at https://grants.nih.gov/grants/forms.htm 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 (Airway Remodeling and Repair in Asthma) and number (HL-99-005) must be typed on line 2 of the face page of the application form and the YES box must be marked. 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: FACE PAGE As a reminder, Items 7a and 8a should be completed to indicated Modular Direct Costs requested and Items 7b and 8b should reflect Total Costs (Modular Direct plus F&A costs). Item 7 should reflect costs for the Initial Budget Period and item 8 should reflect costs for the Total Budget Period. DETAILED BUDGET FOR THE INITIAL BUDGET PERIOD Do not complete Form Page 4 of the PHS 398 (rev 4/98). It is not required nor will it be accepted at the time of application. BUDGET FOR THE ENTIRE PROPOSED PERIOD OF SUPPORT Do not complete the categorical budget tables on page 5 of the PHS 398 (rev. 4/98) Form. Only the requested total direct costs line for each year should 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 9 modules ($225,000 direct cost) per year may be requested for each R01 application. Applicants may request for 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. BUDGET JUSTIFICATION o Budget justifications should be provided under "Justifications" on Form Page 5 of the PHS 398. o 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. o Identify all consultants by name and organizational affiliation and describe the services to be performed. o 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. 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 facilities and administrative costs) 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 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 of 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. 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. o Complete the educational block at the top of the form page; o List current position(s) and those previous positions directly relevant to the application; o List selected peer-reviewed publications directly relevant to the proposed project, with full citation; o 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. 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. 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. 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. Submit a signed, typewritten original of the application 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. C. James Scheirer, at the address listed under INQUIRIES. Applications must be received by February 24, 1999. 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 CSR and responsiveness by NHLBI. Incomplete and/or unresponsive applications will be returned to the applicant without further consideration. Applications that are complete and responsive to the RFA may be subjected to a streamlined review process by a Special Emphasis Panel convened by NHLBI Scientific Review Office to determine their scientific merit relative to other applications received in response to the RFA. The roster of reviewers for the RFA will be available on the NHLBI home page approximately four weeks prior to the scheduled review date. Applications determined to be meritorious will be evaluated for scientific and technical merit by the review committee, be discussed and receive a priority score. All other applications will not be discussed or scored. Secondary review of the applications will be conducted by the National Heart, Lung, and Blood Advisory Council (NHLBAC). 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 review, comments on the following aspects of the application will be made 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 the assignment of the overall score. 1) Significance. Does this study address an important problem? If the aims of the application are achieved, how will scientific knowledge be advanced? What will be the effect of these studies on the concepts or methods that drive this field? 2) Approach. Are the conceptual framework, design, methods, and analyses adequately developed, well integrated, and appropriate to the aims of the project? Does the applicant acknowledge potential problem areas and consider alternative tactics? 3) Innovation. Does the project employ novel concepts, approaches or method? Are the aims original and innovative? Does the project challenge existing paradigms or develop new methodologies or technologies? 4) Investigator. Is the investigator appropriately trained and well suited to carry out this work? Is the work proposed appropriate to the experience level of the principal investigator and other researchers (if any)? 5) Environment. Does the scientific environment in which the work will be done contribute to the probability of success? Do the proposed experiments take advantage of unique features of the scientific environment or employ useful collaborative arrangements? Is there evidence of institutional support? As part of the scientific and technical merit evaluation of the research plan, reviewers will be instructed to address the adequacy of plans for including both genders, minorities and their subgroups, and children as appropriate for the scientific goals of the research, or justification for exclusion. 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 modules. The duration of support will be reviewed to determine if it is appropriate to ensure successful completion of the requested scope of the project. AWARD CRITERIA Applicants should be aware that, in addition to scientific merit, program priorities and program balance, the total costs of the proposed project and the availability of funds will be considered by NHLBI staff as well as NHLBAC in making funding recommendations. In circumstances in which applications have similar scientific merit, but vary in cost competitiveness, NHLBI is likely to select the more cost competitive application for funding. Schedule Letter of Intent Receipt Date: January 6,1999 Application Receipt Date: February 24, 1999 Date of Initial Review: June/July 1999 Review by NHLB Advisory Council: September 1999 Anticipated Award Date: September 1999 INQUIRIES Inquiries concerning this RFA are encouraged. Potential applicants may request sample budget pages. The opportunity to clarify any issues or questions from potential applicants is welcome. Direct inquiries regarding programmatic issues to: Susan Banks-Schlegel, Ph.D. Division of Lung Diseases National Heart, Lung, and Blood Institute 6701 Rockledge Drive, Room 10018, MSC 7952 Bethesda, MD 20892-7952 Telephone: (301) 435-0202 FAX: (301) 480-3557 Email: Schleges@gwgate.nhlbi.nih.gov Direct inquiries regarding review matters, address the letter of intent, and mail two copies of the application to: C. James Scheirer, Ph.D. 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: SchreireJ@nih.gov Direct inquiries regarding fiscal matters to: Raymond L. Zimmerman Division of Extramural Affairs National Heart, Lung, and Blood Institute 6701 Rockledge Drive, Room 7154, MSC 7926 Bethesda, MD 20892-7926 Telephone: (301) 435-0171 FAX: (301) 480-3310 Email: ZimmermR@gwgate.nhlbi.nih.gov AUTHORITY AND REGULATIONS This program is described in the Catalog of Federal Domestic Assistance, No. 93.838. Awards are made under authorization of the Public Health Service Act, Title IV, Part A (Public Law 78-410, 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 a 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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