SCOR: Molecular Genetics of Hypertension Release Date: November 2, 1999 RFA: HL-00-002 National Heart, Lung, and Blood Institute Letter of Intent Receipt Date: February 1, 2000 Application Receipt Date: March 28, 2000 PURPOSE The objective of this initiative is to establish or continue to support closely interacting, multiproject Specialized Centers of Research (SCORs) to study the molecular genetics of hypertension. This initiative represents the recompetition of an existing SCOR program and covers the second five-year funding period of a ten-year program. Three broad areas will be considered responsive to the initiative: (1) mapping and identification of genes responsible for high blood pressure or its complications in humans and in experimental animal models; (2) mechanistic studies on the biological consequences of variations in genes linked to hypertension or its complications; and, (3) studies utilizing molecular genetic techniques to elucidate basic mechanisms of normal and altered regulation of blood pressure. Collaboration and interaction among centers are encouraged. 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), entitled "Specialized Centers of Research on Molecular Genetics of Hypertension", is related to the priority area of heart disease and stroke. Potential applicants may obtain a copy of "Healthy People 2000" at "http://odphp.osophs.dhhs.gov/pubs/hp2000". ELIGIBILITY REQUIREMENTS Applications may be submitted by for-profit and non-profit domestic institutions, public and private, such as universities, colleges, hospitals, laboratories, units of state or local governments, and eligible agencies of the Federal government. This RFA is intended to support SCOR grants for basic and clinical investigations; therefore, applications that include only basic or only clinical research will not be responsive to this announcement. In addition, clinical research projects focused on large epidemiologic studies or large clinical trials will be considered unresponsive to this RFA. Awards will not be made to foreign institutions. However, under exceptional circumstances, a foreign component critical to a project may be included as a part of that project. Racial/ethnic minority individuals, women, and persons with disabilities are encouraged to apply as principal investigators. The Principal Investigator should be an established research scientist with the ability to ensure high quality research and the experience to administer effectively and integrate all components of the program. A minimum time commitment of 25 percent is expected for this individual. The Principal Investigator must also be the project leader of one of the component research projects. If, through peer review, this project is not recommended for further consideration, the overall SCOR application will not be considered further. If this project is judged by peer review to be of low scientific merit, it will markedly reduce the overall scientific merit ranking assigned to the entire application by the review committee. Project leaders must agree to commit at least 20 percent effort to each project for which they are responsible. MECHANISM OF SUPPORT This RFA will use the National Heart, Lung, and Blood Institute (NHLBI) SCOR (P50) grant award mechanism. Responsibility for the planning, direction, and execution of the proposed project will be solely that of the applicant. All current policies and requirements that govern the research grant programs of the NIH will apply to grants awarded under this RFA. The anticipated award date is February 1, 2001. Basic and Clinical Research The overall concept of a SCOR program focuses on scientific issues related to diseases relevant to the mission of the NHLBI. It is essential, therefore, that all applications include both basic and clinical research projects. Interactions between basic and clinical scientists are expected to strengthen the research, enhance transfer of fundamental research findings to the clinical setting, and identify new research directions. Plans for transfer of findings from basic to clinical studies should be described. Each SCOR grant application and award must include research involving human patients/subjects. Support may be provided for human biomedical and behavioral studies of etiology, pathogenesis, prevention and prevention strategies, diagnostic approaches, and treatment of diseases, disorders, or conditions. Small population-based studies, where the research can be completed within five years, may also be proposed. In addition, basic research projects must be included that relate to the clinical focus. A SCOR may also contain one or more core units that support the research projects. Length of SCOR Programs Each NHLBI SCOR program is limited to 10 years of support. The current SCOR program on Molecular Genetics of Hypertension was funded in 1996 and, therefore, this RFA covers the second five-year funding period. Under this policy, SCOR grants funded in response to this RFA will only be for five years without the possibility of renewal. Exceptions to this policy will be made only if a thorough evaluation of needs and opportunities, conducted by a committee composed of non-federal experts, determines that there are extraordinarily important reasons to continue a specific SCOR program. The NHLBI comprehensive evaluation of the Molecular Genetics of Hypertension SCOR program will be conducted during the second project period according to the following timetable: Program Announced October 1999 Project Period (Second Competition) February 2001 to January 2006 Letter to SCOR Directors Regarding SCOR Evaluation Plans September 2002 SCOR Evaluation Meeting November 2002 Notification of SCOR Directors of NHLBI Decision September 2003 The NHLBI does not limit the number of SCOR applications in a given SCOR program from one institution provided there is a different SCOR principal investigator for each application and each application is self-contained and independent of the other(s). This does not preclude cooperation, planned or possible, among participants of SCORs after awards are made. Scientific overlap among applications will not be accepted. If more than one application is envisioned from an institution, the institution is encouraged to discuss its plans with the NHLBI SCOR program administrator. FUNDS AVAILABLE The NHLBI intends to commit approximately $ 11 million in FY 2001 to fund up to six new and/or competitive continuation SCOR grants in response to this RFA. Applicants may request a project period of up to five years and a budget for direct cost of up to $1,280,000 or 10% over the final year budget of the current funding period, whichever is greater, in the first year. The facilities and administrative costs for collaborating institutions are excluded from this ceiling and a maximum increase of no more than three percent is allowed in each additional year requested in the application. Although the financial plans of the NHLBI provide support for this program, awards pursuant to this RFA are contingent upon the availability of funds and the receipt of sufficient number of applications of outstanding scientific and technical merit. Equipment is included in the budget limitation. However, requests for major equipment that cause an application to exceed this limit may be permitted on a case-by-case basis following staff consultation. Such equipment requires in-depth justification. Final decisions will depend on the nature of the justification and the Institute's fiscal situation. Consortium Arrangements When a grant application includes research activities that involve institutions other than the grantee institution, it is considered a consortium effort. Such activities may be included in a SCOR grant application, but it is imperative that a consortium application be prepared so that the programmatic, fiscal, and administrative considerations are explained fully. Applicants of SCOR grants should exercise great diligence in preserving the interactions of the participants and the integration of the consortium project(s) with those of the parent institution, because synergism and cohesiveness can be diminished when projects are located outside of the group at the parent institution. Facilities and administrative costs paid as part of a consortium agreement are excluded from the limit on the amount of direct costs that can be requested. The published policy governing consortia is available in the business offices of institutions that are eligible to receive Federal grants-in-aid. Consult the latest published policy governing consortia before developing the application. If clarification of the policy is needed, contact Ms. Jane Davis, Grants Operations Branch, NHLBI, 301-435- 0166. RESEARCH OBJECTIVES Background Hypertension, a complex disease that involves the interplay of genetic and environmental factors, affects an estimated 50 million Americans and is a major predisposing factor for myocardial infarction, heart failure, vascular disease, stroke, and renal failure. Judging from the results from segregation analysis and twin studies, genetic factors undoubtedly play a major role in the interindividual differences in blood pressure. The identification of the genes whose variants contribute to high blood pressure will have far-reaching effects on the understanding of the pathophysiology of the circulation and may suggest new therapeutic approaches and preventive measures, and thereby shift the national health focus in hypertension from post-onset therapy to prevention. In addition, the genetic approach may lead to the identification of primary molecular defects that will form the basis for mechanistic studies in humans and animals on normal blood pressure regulation and on the pathophysiology of hypertension. The genetic approach may also offer crucial new insights into the biochemical and physiological pathways that link various risk factors to high blood pressure. The division of the general population suffering from essential hypertension into subgroups, defined by genotypes, may allow for the evaluation of therapies in more homogeneous groups. Knowledge of target subgroups can provide new targets for specifically-designed therapies. Additionally, it may be possible to use existing therapies in a more directed way to treat individuals with specific genotypes. It may not be necessary to negate the effects of all the genes contributing to hypertension to treat the disease in an individual. It is likely that many genetic effects act in concert and that neutralizing one or two of the genetic determinants operating in an individual may be sufficient to reduce blood pressure to a level that has less associated cardiovascular and renal risk. An understanding of the basis for genetic susceptibility to hypertension and its mechanisms would help identify individuals at risk for developing the disease before the manifestation of clinical symptoms. A major challenge of the future in the hypertension field will be the development and implementation of effective preventive measures. Furthermore, molecular genetic studies will help investigators characterize the prevalence of genetic variants associated with hypertension at the population level. Interventions based on this information applied in advance of the rise in blood pressure have the greatest potential for preventing the disease. The identification of hypertension genes provides the basis for an understanding of the interactions between genes and environmental factors. It is very likely that particular environmental variables exert effects only in the presence of certain genotypes. Moreover, the effects of certain environmental factors may be difficult to detect in a genetically heterogeneous group. Several recent advances in technology and analytical methods, together with the rapid construction of genetic and physical maps in mice, rats and humans, have substantially improved the likelihood of detecting the genetic determinants of high blood pressure and for studying the molecular and physiological consequences of gene variation. For example, large-scale surveys of human genomic variation is now possible with efficient high- throughput methods using hybridization to high-density DNA probe arrays. Furthermore, polymorphism screening can serve to identify single-nucleotide polymorphisms in the identification of complex disease genes. The identification of hypertension genes and a mechanistic analysis of how these genes contribute to blood pressure regulation and to the pathophysiology of hypertension will require the collaboration of investigators with expertise in genetics, biostatistics, clinical science with an emphasis on hypertension, molecular biology, biochemistry, and physiology. Economies of scale can be accomplished by sharing technology, data, skills, and biological materials. Although some research centers will have access to all necessary resources, many of the investigators critical to the success of the project may be located in different institutions. Therefore, all of the necessary expertise, resources, and infrastructure need not be localized at one geographical site. The center will provide the cohesion and coordination that will link the best people in several locations, covering such expenses as the exchange of scientists, travel costs of participating groups, shipping costs of samples and probes, data transmission and data storage costs, and the costs of regular meetings to coordinate the activities of the participants. Applicants from institutions that have a General Clinical Research Center (GCRC) funded by the 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 from either the GCRC program director or Principal Investigator could be included with the application. Proposed Research The principal research aim of this RFA is to encourage basic and clinical research that is oriented toward mechanisms of blood pressure control and hypertension at the genetic level. Three broad areas will be considered responsive to the initiative: (1) mapping and identification of genes responsible for high blood pressure or its complications in humans and in experimental animal models; (2) mechanistic studies on the biological consequences of variations in genes linked to hypertension or its complications; and (3) studies utilizing molecular genetic techniques to elucidate basic mechanisms of normal and altered regulation of blood pressure. Each SCOR will require a close association of basic bench-level and clinical research. At times, the clinical studies will act as the driving force and lead the overall direction of the center by identifying genes that are closely associated or linked to the hypertension or to an intermediate phenotype related to high blood pressure in humans. However, animal models will continue to play crucial roles. The expanded availability of micro-satellite markers on the rat genome makes possible detailed mapping of potential candidate genes. Tissue-specific knockout, mutant and recombinant inbred mice will continue to be the major tools to better define the function of putative candidate genes. During the last few years, an increasing number of quantitative trait loci, which exhibit highly significant linkage with hypertension, have been identified. The time is ripe to develop congenic strains necessary to narrow the regions and to evaluate the functional significance of these regions. Furthermore, new candidate genes within the regions can now be identified in the animal models with positional cloning and the translation of these findings to human can be achieved by homology mapping. Animal models might also be used subsequent to primary identification of human genes related to high blood pressure as a means to clarify pathophysiological mechanisms. Confirmation of the pathophysiology derived from animal studies can then be undertaken in human subjects. Mapping and identification of genes responsible for hypertension, whether conducted initially in humans or in animals, will continually provide candidate loci and hypotheses for testing in humans. 1. Mapping and Identification of Genes Mapping of relevant genetic loci and identification of underlying genetic mutations responsible for high blood pressure in humans or in experimental animal models of hypertension is an area that may be supported through the SCOR mechanism. Gene mapping and identification will be complementary to other scientific efforts to be supported by the NHLBI or through other sources. Two principal approaches may be used to map genes that may be linked to hypertension: the first entails a whole genome search using anonymous highly informative genetic markers spread throughout the genome; the second approach involves the systematic study of candidate genes. Mapping can be carried out with methodologies such as linkage in affected sib pairs, genetic linkage analysis of large pedigrees, and association methods. To reduce the impact of genetic heterogeneity, the study population may be subdivided by defining intermediate phenotypes (characteristics that have greater heritability than the complex trait itself), or a population may be studied that has originated from a restricted founder population or has been isolated in some way as to limit the number of genetic variants present. 2. Mechanistic Studies on the Consequences of Genetic Variation Investigators may select genetic variations for mechanistic studies from a number of sources. For instance, SCOR investigators may choose to study allelic variations linked to high blood pressure that have been identified and reported in the literature or that have been identified from mapping activities within the SCOR program. In addition, candidate genes that are well justified in the application may also be studied, even if they have not yet been linked to hypertension in humans or specific animal models. Mendelian forms of hypertension, while rare and, perhaps, limited in its general application, continue to be useful models for studying the impact of single gene mutation. Studies may be conducted at any level of investigation, from the molecular to the whole animal. For example, consideration may be given to approaches examining the implications of genetic mutations on: cellular function, including changes in the processing of genetic information, synthesis or degradation of vasoactive substances, signal transduction pathways, receptor structure and function, and response to cytokines and growth factors; and whole animal integrated function, using genetically altered animals, such as congenics, transgenics, and knockouts, to clarify modifications of organ function and implications for acute and chronic blood pressure control. 3. Molecular Genetic Studies on Basic Mechanisms of Normal and Altered Blood Pressure Control Molecular and genetic approaches that focus on the genes for which there is ample evidence of possible involvement in blood pressure regulation are excellent areas for study. However, mechanistic studies should address the implications of genetic alterations on normal blood pressure regulation and the pathophysiology of hypertension. Understanding the genetic regulation of cellular and organ responses to elevated blood pressure is an additional area that may be supported through the Hypertension SCORs. Research on cellular and organ responses to hypertension includes studies on the complications associated with the disease, such as investigation at a genetic level on conditions such as nephropathy or cardiac hypertrophy. Other topics, such as genetic determinants of vascular remodeling as a function of high blood pressure, are also appropriate responses. Other examples of possible research areas are: development and refinement of techniques to introduce and express new genetic information and to abolish or modify the expression of endogenous genes; development of more efficient tissue-specific vectors; antisense and ribozyme approaches; recombinant inbred animals; model systems comprised of multiple cell types; and, isolation, characterization, propagation of embryonic stem cells from rats, rabbits, and other species in order to study various forms of blood pressure regulation and dysfunction. Identification of the consequences of long-term hypertension on organ adaptation and eventually on end stage target organ disease is another important objective of this solicitation. It will be particularly interesting to determine how organ adaptations to high blood pressure are affected by predisposing genetic factors. Some of the sequelae to hypertension that may be studied include kidney disease, stroke, myocardial infarction, heart failure, vascular disease, and retinal disease. It is increasingly recognized that certain cluster of genes are often shared as common heritable factors by related diseases. Examples are the complex interplay between insulin resistance, diabetes and hypertension. Furthermore, with the completion of the human genome project expected in the near future, applicants are encouraged to seize the opportunity and to enhance the translation of findings from animal models to human studies. Biennial Research Meetings Upon initiation of the program, the NHLBI will sponsor periodic meetings to encourage exchange of information among investigators who participate in this program and to stimulate collaboration. Applicants should request additional travel funds for a two-day meeting every other 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 policy results from the NIH Revitalization Act of 1993 (Section 492B of Public Law 103-43). All investigators proposing research involving human subjects should read the "NIH Guidelines for Inclusion of Women and Minorities as Subjects in Clinical Research," which was first published in the Federal Register of March 28, 1994 (FR 14508-14513) and in the NIH Guide for Grants an Contracts, Vol. 23, No. 11, March 18, 1994, available on the web 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 ethical reasons not to include them. This policy applies to all initial (Type 1) applications submitted for receipt dates after October 1, 1998. 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: http://grants.nih.gov/grants/guide/notice-files/not98-024.html However, in view of the low prevalence of hypertension in children, applications in response to this RFA are not expected to include children as participants in study populations. LETTER OF INTENT Prospective applicants are asked to submit, by February 1, 2000, 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. The letter of intent is to be mailed, or faxed, by the letter of intent receipt date listed in the heading of this RFA 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: js110j@nih.gov. 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 and from the Division of Extramural Outreach and Information Resources, Center for Scientific Review, National Institutes of Health, 6701 Rockledge Drive, MSC 7910, Bethesda, MD 20892-7910, telephone 301/435-0714, e-mail: grantsinfo@nih.gov. Special supplemental instructions for the preparation of grant applications for SCORs may be obtained by contacting the Hypertension SCOR Program Administrator listed under INQUIRIES. 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. Type the RFA number on the label. 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, to identify the application as a response to this RFA, check "YES", enter the title "Specialized Centers of Research -- Molecular Genetics of Hypertension," and the RFA number HL-00-002 on Line 2 of the face page of the application. The sample RFA label available at: http://grants.nih.gov/grants/funding/phs398/label-bk.pdf has been modified to allow for this change. Please note this is in pdf format. Submit a signed, typewritten original of the application, including the checklist, and three signed photocopies, in one package to: CENTER FOR SCIENTIFIC REVIEW NATIONAL INSTITUTES OF HEALTH 6701 ROCKLEDGE DRIVE, ROOM 1040, MSC 7710 BETHESDA, MD 20892-7710 BETHESDA, MD 20817 (FOR EXPRESS/COURIER SERVICE) At the time of submission, two additional copies of the application must be sent to the Chief, Review Branch 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 Center for Scientific Review (CSR), otherwise the NHLBI cannot guarantee that the application will be reviewed in competition for this RFA. Applications must be received by March 28, 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 announcement that is essentially the same as one currently pending initial review, unless the applicant withdraws the pending application. CSR will not accept any application that is essentially the same as one already reviewed. This does not preclude the submission of substantial revisions of applications already reviewed, but such applications must include an introduction addressing the previous critique. REVIEW CONSIDERATIONS Upon receipt, applications will be reviewed for completeness by the CSR, and responsiveness by NHLBI. Incomplete and/or non-responsive applications will be returned to the applicant without further consideration. Applications that are complete and responsive to this RFA may be subjected to a streamlined review process by an appropriate peer review group convened by the National Heart, Lung, and Blood Institute to determine their scientific merit relative to other applications received in response to the RFA. 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. Review Criteria: The goals of NIH-supported research are to advance our understanding of biological systems, improve the control of disease, and enhance health. In the written comments reviewers will be asked to discuss the following aspects of the application in order to judge the likelihood that the proposed research will have a substantial impact on the pursuit of these goals. Each of these criteria will be addressed and considered in assigning the overall score, weighting them as appropriate for each application. Note that the application does not need to be strong in all categories to be judged likely to have major scientific impact and thus deserve a high priority score. For example, an investigator may propose to carry out important work that by its nature is not innovative but is essential to move a field forward. (1) Significance Does this study address an important problem? If the aims of the application are achieved, how will scientific knowledge be advanced? What will be the effect of these studies on the concepts or methods that drive this field? (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)? Does the Program Director have the appropriate scientific statue and proven leadership to serve in such capacity ? (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? (6) Collaboration Does the submitted proposal represent collaborative research among investigators from basic and clinical research with necessary disciplines? What are the likelihood of effective collaboration among the investigators, and the likelihood of success of the research objectives proposed? In addition to the above criteria, in accordance with NIH policy, all applications will also be reviewed with respect to the following: o The adequacy of plans to include both genders, minorities and their subgroups, and children as appropriate for the scientific goals of the research. Plans for the recruitment and retention of subjects will also be evaluated. o The reasonableness of the proposed budget and duration in relation to the proposed research o The adequacy of the proposed protection for humans, animals or the environment, to the extent they may be adversely affected by the project proposed in the application. 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: February 1, 2000 Application Receipt Date: March 28, 2000 Peer Review Date: June/July 2000 Review by NHLB Advisory Council: September/October 2000 Anticipated Award Date: February 1, 2001 INQUIRIES Inquiries concerning this RFA are encouraged. The opportunity to clarify any issues or questions from potential applicants is welcome. Direct inquiries regarding scientific issues to: Michael C. Lin, Ph.D. Division of Heart and Vascular Diseases National Heart, Lung and Blood Institute 6701 Rockledge Drive, MSC 7956 Bethesda, MD 20892 Telephone: (301) 435-0560 FAX: (301) 480-2849 E-mail: michael_lin@nih.gov Direct inquiries regarding fiscal and administrative matters to: Ms. Jane Davis Division of Extramural Affairs National Heart, Lung and Blood Institute 6701 Rockledge Drive, MSC 7926 Bethesda, MD 20892 Telephone: (301) 435-0166 FAX: (301) 480-3310 E-mail: jane_davis@nih.gov AUTHORITY AND REGULATIONS This program is described in the Catalog of Federal Domestic Assistance No. 93.837, Heart and Vascular Diseases. Awards will be made under the authorization of the Public Health Service Act, Title V, 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 requirement of Executive Order 12372 or Health Systems Agency review. The PHS strongly encourages all grant recipients to provide a smoke-free workplace and promote the non-use of all tobacco products. In addition, Public Law 103-227, the Pro-Children Act of 1994, prohibits smoking in certain facilities (or in some cases, any portion of a facility) in which regular or routine education, library, day care, health care or early childhood development services are provided to children. This is consistent with the PHS mission to protect and advance the physical and mental health of the American people.
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