STRATEGIES FOR GERM-LINE MODIFICATION IN THE RAT Release Date: April 3, 2001 PA NUMBER: PAR-01-077 National Center for Research Resources National Cancer Institute National Heart, Lung, and Blood Institute National Institute of Child Health and Human Development National Institute of Neurological Disorders and Stroke National Institute on Aging National Institute on Drug Abuse Letter of Intent Receipt Dates: September 1, 2001; September 1, 2002 and September 1, 2003. Application Receipt Dates: October 1, 2001; October 1, 2002 and October 1, 2003. THIS PA USES "MODULAR GRANT" AND "JUST-IN-TIME" CONCEPTS. THIS PAR INCLUDES DETAILED MODIFICATIONS TO STANDARD APPLICATION INSTRUCTIONS THAT MUST BE USED WHEN PREPARING AN APPLICATION IN RESPONSE TO THIS PAR. PURPOSE The National Center for Research Resources, National Cancer Institute, National Heart, Lung and Blood Institute, National Institute of Child Health and Human Development, National Institute of Neurological Disorders and Stroke, National Institute on Aging, and National Institute on Drug Abuse, invite applications for the purpose of establishing methods for the efficient production of rat models that contain germ-line mutations that will facilitate the transfer of biological concepts to human health problems. Development of rat embryonic stem cell (ESC) technology by modification of current techniques or development of new approaches will meet the needs of researchers using the rat to study human health and disease. This initiative is designed for rat models only and should not include human subjects or tissues. HEALTHY PEOPLE 2010 The Public Health Service (PHS) is committed to achieving the health promotion and disease prevention objectives of "Healthy People 2010," a PHS- led national activity for setting priority areas. This Program Announcement (PAR), STRATEGIES FOR GERM-LINE MODIFICATION IN THE RAT, is related to several priority areas. Potential applicants may obtain a copy of "Healthy People 2010" at http://www.health.gov/healthypeople/. ELIGIBILITY REQUIREMENTS Applications may be submitted by domestic and foreign, for-profit and non- profit organizations, public and private, such as universities, colleges, hospitals, laboratories, units of State and local governments, and eligible agencies of the Federal government. Racial/ethnic minority individuals, women, and persons with disabilities are encouraged to apply as principal investigators. MECHANISM OF SUPPORT This PAR will use the National Institutes of Health (NIH) Research Project Grant (R01) mechanism. 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 PAR may not exceed five years. For all competing R01 applications requesting up to $250,000 per year in direct costs, specific application instructions have been modified to reflect MODULAR GRANT and JUST-IN-TIME streamlining efforts being examined by NIH. Complete and detailed instructions and information on Modular Grant applications can be found at http://grants.nih.gov/grants/funding/modular/modular.htm. Applications that request more than $250,000 in any year must use the standard PHS 398 (rev. 4/98) application instructions. RESEARCH OBJECTIVES The ability to engineer custom mutants, transgenic, and knockout animals has opened up a new era of scientific discovery and now allows testing of hypotheses previously limited by the available animal models. Recent extensions of the knockout technology using homologous recombination have included tissue-specific knockouts and knock-in mutations to allow generation of custom made mutations. A complete functional analysis of genes requires both gain of function and loss of function mutations. The ability to produce these mutations for genes of choice is proving to be extremely important to exploiting gene discovery by creating animal models of human disease. Gain of function mutations through transgenic mice and rats are now routine. However, creation of loss of function mutations by knock-out technology is only routine in the mouse. Hence, germ-line modification in the rat is critically important to assigning function to specific genes and to identifying gene alterations responsible for specific phenotypes. The analysis of phenotypes from gain of function and loss of function has been the most direct and useful way to connect specific genes to phenotypes relevant to human disease. The accessibility to technologies for modifying the rat germ line is limited and needs to be extended. Rats are widely used as a scientific model of human physiology because of several unique characteristics including size, extensive phenotype data, and importantly, relevance to many aspects of human biology. Size alone makes a strong argument for continuing to use the laboratory rat, particularly for procedures involving manipulations such as intravenous cannulation, nerve recordings, collection of tissue from small structures, and serial blood sampling. There is an impressive array of well characterized rat strains utilized for the study of public health concerns. For example, there are nine inbred strains used in studies of arterial pressure regulation and hypertension alone. Two of the strains, Dahl’s and Brown Norway, have been employed successfully in multiple cosegregation analysis leading to the identification of more than 30 regions on 16 chromosomes that affect likely determinants of blood pressure. Because of the extensive genomic tools available for the rat and the high degree of conserved linkage between the rat and humans, these chromosomal regions were quickly translated to both known human chromosomal regions that affect blood pressure and to gene discovery. Rats provide very important and useful models in the area of neurobehavior and addiction. This is because of the extensive extant data on neuropharmacology and neuroanatomy in the rat, because the size of the brain structures allows a higher degree of anatomical resolution in molecular studies than in other common laboratory animals, and because the rat is particularly well suited to reproducible training in drug self- administration. In learning studies such as mazes, it is now apparent that the rat learns in a manner much more like humans than do some other mammals. The rat is the most important model of human arthritis and related autoimmune diseases, with more than 200 inbred, congenic and mutant strains with important variations in disease related variables. Gender related variables and gender differences in arthritis in the rat are more similar to humans than are those of other mammals. There are extensive toxicological and pharmacological data in the rat with high relevance to the human condition. Considering the significant use of rat models in cardiovascular biology, renal and pulmonary disease, reproduction, neurobiology, immunology, cancer, diabetes, arthritis and autoimmune disease, and endocrinology, to name a few, it is imperative that the ability to manipulate the rat genome be developed. The application of genetic engineering technologies to the rat is an important step for understanding the pathology underlying many human diseases. There are many examples that illustrate the power and importance of targeted, germ-line modification. One example is the series of studies performed a few years ago with calcium/calmodulin kinase II gene knockout mice. These mice were used to demonstrate the role of this gene in neural transmission, synaptic plasticity, learning, and behavior. Studies on the role of specific neurotransmitter systems in learning and memory have in the past relied on the use of inhibitors and agonists to dissect the pathways. As a second example, the isolation of human renin genes led to the production of renin transgenic rats. These animals provided important insight into the quantitative traits that the gene product regulates. However, the studies had to be done in the presence of the endogenous rat renin genes. Complete functional analysis of the human renin genetic system will require knocking out the renin system one element at a time and inserting the human genes. The ability to generate specific genetic modifications in rats would contribute rapidly to our understanding of development, physiology and pathobiology. Many genetic engineering techniques have proven to be equally efficient in a variety of mammalian species, including the rat. However, in one very important area, ESCs, it has not been possible to adapt the mouse technology to the rat. Cells are cultured from the inner cell mass of mouse blastocysts and those cells are propagated under conditions that maintain them in an undifferentiated pluripotent state. The cells can be manipulated genetically, typically by homologous recombination, and selected for heterozygous loss of function mutations. When the cells are injected into normal preimplantation embryos and transferred to surrogate mothers, live offspring bearing the mutation can be obtained. These are mated to homozygosity for study. The success of this procedure depends on the ability to obtain germ-line transmission of the modified genome. Unfortunately, it appears likely that the mouse is the exception rather than the rule regarding the ability to culture totipotent ESCs, as germ-line transmission has not yet been reported with ESCs from any species other than mouse and chicken. Several rat ESC lines have been developed, but these have not yet proven to be pluripotent. Nuclear transfer (NT) technology has resulted in live cloning in several species, including mice, sheep, cattle and monkeys. These successes demonstrate the wide species-applicability of nuclear transfer technology, unlike the ESC technology. Moreover, genetically modified cells have been successfully used as nuclear donors. Therefore, cells that can be used to develop live born clones of the rat could be used in conjunction with homologous recombination or other mutational strategies to develop cells with desired mutations necessary for functional analysis of critical genes. These cells could then be used for nuclear donors in NT and thereby directly generate mutant animals. NT could provide a flexible means for modifying the rat genome in that there is the potential to use many different kinds of cells for the genetic modifications, including cells from adult tissues. This flexibility also makes cryopreservation of the modified genome much easier, as most cultured cells are easier to store than embryos. NT can be used in principle to enhance repository services as well, since a variety of cells could be used to preserve or transport rare strains. The addition of a variety of standard approaches, like cloning, can be used to further enhance the availability of rat animal models. Since the development of pluripotent ESCs appears to be limited to certain species, technological advancements for producing gene knockouts in the rat should be emphasized. The development of genetic modification technology will allow investigators using the rat model to capitalize on related initiatives in progress or recently completed, including the Rat Genome Project, the Rat EST Project, and the Rat Genome Sequencing Project. Some illustrative examples of research topics that could be addressed under this program announcement are: o Strategies for culturing pluripotent rat ESCs to allow genetic manipulation and to create rats with germ-line transmission of genetic modifications. o Development of alternative technologies to create null mutations or gene replacement in the rat. o Development of cost-effective NT procedures in the rat. o Studies that demonstrate mutation transfer to rat stem cells or other cells for transfer into embryos or germ cells. o Methods for targeting engineered introns into rat chromosomal DNA to support the study of gene function. SHARING OF MATERIALS GENERATED UNDER THIS PA To address the joint interest of the government in the availability of, and access to, the results of publicly funded research, NIH requires applicants who respond to this PAR to propose detailed plans for sharing the research resources generated through the grant. It is expected that the resources to be shared will include, among others, cell lines, mutant animals, germplasm, nucleic acid sequences, and novel reagents and techniques useful for meeting the goals of this PAR. These various research resources will be of great value to the broader research community, beyond the laboratories that create them. It is preferable that resources generated under this PAR should be placed in common, public repositories and databases that are widely accessible to investigators in the scientific community. The required resource sharing plan will include a description of the mechanisms proposed for wide distribution of resources with investigators in the scientific community, as described in more detail, below. The reviewers will provide an administrative comment evaluating the adequacy and feasibility of the resource sharing plan. This comment will not affect the priority score of the proposal. NIH staff will consider the adequacy of the plan in determining whether to recommend an application for award. The sharing plan as approved, after negotiation with the applicant as necessary, will become a condition of the grant award. Progress reports must contain information on sharing of resources as they are developed. For more detailed guidance on NIH policies on resource sharing, applicants are referred to Principles and Guidelines for Recipients of NIH Research Grants and Contracts on Obtaining and Disseminating Biomedical Research Resources, http://www.ott.nih.gov/policy/rt_guide_final.html. INTELLECTUAL PROPERTY Applicants should refer to the NIH Principles and Guidelines for Recipients of NIH Research Grants and Contracts on Obtaining and Disseminating Biomedical Research Resources, as referenced above. When a recipient’s research is funded by NIH, the activity is subject to various laws and regulations, including the Bayh-Dole Act (35 U.S.C. 200, et seq). The Bayh- Dole Act is implemented through Department of Commerce regulations 37 CFR 401. These regulations define terms, parties, responsibilities, prescribe the order of disposition of rights, prescribe a chronology of reporting requirements, and delineate the basis for and extent of government actions to retain rights. In accordance with statute, these rights should be used to promote free competition and enterprise without unduly encumbering future research and discovery. The patent rights clauses are found at 37 CFR Part 401.14 and are accessible from the Interagency Edison web page, http://www.iedison.gov/. LETTER OF INTENT Prospective applicants are strongly encouraged to submit, by the dates listed on page one of this program announcement, 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 PAR in response to which the application will 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 to plan the review. The letter of intent is to be sent to: John D. Harding, Ph.D. Division of Comparative Medicine National Center for Research Resources 6705 Rockledge Drive, Suite 6050, MSC 7965 Bethesda, MD 20892-7965 (Bethesda MD 20817 for express service) Telephone: (301) 435-0776 FAX: (301) 480-3819 Email: hardingj@ncrr.nih.gov URLS IN NIH GRANT APPLICATIONS OR APPENDICES All applications and proposals for NIH funding must be self-contained within specified page limitations. Unless otherwise specified in an NIH solicitation, Internet addresses (URLs) should not be used to provide information necessary to the review because reviewers are under no obligation to view the Internet sites. Reviewers are cautioned that their anonymity may be compromised when they directly access an Internet site. APPLICATION PROCEDURES Applicants are strongly encouraged to contact the program staff listed under INQUIRIES with any questions regarding their proposed project and the goals of this PAR. Applications are to be submitted on the grant application form PHS 398 (rev.4/98 or latest revision) and will be accepted on the dates listed on page one of this PAR. Application kits are available at most institutional offices of sponsored research and from the Division of Extramural Outreach and Information Resources, National Institutes of Health, 6701 Rockledge Drive, MSC 7910, Bethesda, MD 20892-7910, telephone (301) 710-0267, Email: GrantsInfo@nih.gov. Applications are also available on the World Wide Web at: http://grants.nih.gov/grants/forms.htm. Applicants planning to submit an investigator-initiated new (type 1), competing continuation (type 2), competing supplement, or any amended/revised version of the preceding grant application types requesting $500,000 or more in direct costs for any year are advised that he or she must contact the Institute or Center (IC) program staff before submitting the application, i.e., as plans for the study are being developed. Furthermore, the applicant must obtain agreement from the IC staff that the IC will accept the application for consideration for award. Finally, the applicant must identify, in a cover letter sent with the application, the staff member and IC who agreed to accept assignment of the application. This policy requires an applicant to obtain agreement for acceptance of both any such application and any such subsequent amendment. Refer to the NIH Guide for Grants and Contracts, March 20, 1998 at http://grants.nih.gov/grants/guide/notice-files/not98-030.html. ADDITIONAL INSTRUCTIONS: SHARING OF MATERIALS In addition to the instructions contained in the PHS 398, an application must include a section describing plans for sharing of materials. This section can not exceed three pages in length and should directly follow the Research Design and Methods section of the research plan. The text of the section on Sharing of Materials will not be considered part of the 25 page limit of the research plan. The section on Sharing of Materials should include the following information: 1) A listing of the research resources that the applicant expects to derive. Both tangible items such as cell lines, mutant animals, germplasm and reagents, as well as non-tangible items such as techniques and nucleic acid sequences, should be considered as research resources that should be shared with other investigators. 2) A description of the mechanisms proposed for wide distribution of resources with investigators in the scientific community, and 3) a timetable for distribution of the resources. As discussed above, the reviewers will evaluate this section and their comments will be incorporated into an Administrative Note in the Summary Statement that will be used by NIH Program personnel to help make funding decisions. Information in this section will not be used by reviewers to determine the priority score for the application. SPECIFIC INSTRUCTIONS FOR MODULAR GRANT APPLICATIONS The modular grant concept establishes specific modules in which direct costs may be requested as well as a maximum level for requested budgets. Only limited budgetary information is required under this approach. The just-in- time concept allows applicants to submit certain information only when there is a possibility for an award. It is anticipated that these changes will reduce the administrative burden for the applicants, reviewers and Institute staff. The research grant application form PHS 398 (rev. 4/98) is to be used in applying for these grants, with the modifications noted below. BUDGET INSTRUCTIONS Modular Grant applications will request direct costs in $25,000 modules, up to a total direct cost request of $250,000 per year. (Applications that request more than $250,000 direct costs in any year must follow the traditional PHS 398 application 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: PHS 398: o FACE PAGE. Items 7a and 7b should be completed, indicating Direct Costs (in $25,000 increments up to a maximum of $250,000) and total Costs [Modular Total Direct plus Facilities and Administrative (F&A) costs] for the initial budget period. Items 8a and 8b should be completed, indicating the Direct and Total Costs for the entire proposed period of support. o DETAILED BUDGET FOR THE INITIAL BUDGET PERIOD. Do not complete Form Page 4 of the PHS 398. It is not required for modular grant applications and will not be accepted with the application. o BUDGET FOR THE ENTIRE PROPOSED PERIOD OF SUPPORT. Do not complete the categorical budget table on Form Page 5 of the PHS 398. It is not required for modular grant applications and will not be accepted with the application. o NARRATIVE BUDGET JUSTIFICATION. Prepare a Modular Grant Budget Narrative page. (See http://grants.nih.gov/grants/funding/modular/modular.htm for sample pages.) At the top of the page, enter the total direct costs requested for each year. This is not a Form page. o Under Personnel, list all project personnel, including their names, percent of effort, and roles on the project. No individual salary information should be provided. However, the applicant should use the NIH appropriation language salary cap and the NIH policy for graduate student compensation in developing the budget request. o For Consortium/Contractual costs, provide an estimate of total costs (direct plus F&A costs) for each year, each rounded to the nearest $1,000. List the individuals/organizations with whom consortium or contractual arrangements have been made, the percent effort of all personnel, and the role on the project. Indicate whether the collaborating institution is foreign or domestic. The total cost for a consortium/contractual arrangement is included in the overall requested modular direct cost amount. Include the Letter of Intent to establish a consortium. Provide an additional narrative budget justification for any variation in the number of modules requested. o BIOGRAPHICAL SKETCH. The Biographical Sketch provides information used by reviewers in the assessment of each individual's qualifications for a specific role in the proposed project, as well as to evaluate the overall qualifications of the research team. A biographical sketch is required for all key personnel, following the instructions below. No more than three pages may be used for each person. A sample biographical sketch may be viewed at: http://grants.nih.gov/grants/funding/modular/modular.htm. - Complete the educational block at the top of the form page. - List position(s) and any honors. - Provide information, including overall goals and responsibilities, on research projects ongoing or completed during the last three years. - List selected peer-reviewed publications, with full citations. o CHECKLIST. This page should be completed and submitted with the application. If the F&A rate agreement has been established, indicate the type of agreement and the date. All appropriate exclusions must be applied in the calculation of the F&A costs for the initial budget period and all future budget years. o The applicant should provide the name and phone number of the individual to contact concerning fiscal and administrative issues if additional information is necessary following the initial review. The title and number of the program announcement must be typed on line 2 of the face page of the application form and the YES box must be marked. SUBMITTING THE APPLICATION. Submit a signed, typewritten original of the application, including the Checklist, and four 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, one additional copy of the application must be sent to: John D. Harding, Ph.D. Division of Comparative Medicine National Center for Research Resources 6705 Rockledge Drive, Suite 6050, MSC 7965 Bethesda, MD 20892-7965 (Bethesda MD 20817 for express service) Telephone: (301) 435-0776 FAX: (301) 480-3819 Email: hardingj@ncrr.nih.gov REVIEW CONSIDERATIONS Applications will be assigned on the basis of established PHS referral guidelines and will be reviewed for completeness by the Center for Scientific Review (CSR). Applications will be evaluated for scientific and technical merit by an appropriate scientific review group convened by the Office of Review, NCRR, in accordance with standard 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 appropriate national 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 aspects of the application listed below, 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. Furthermore, because of the subject matter of this PA, some applications may have more of an applied component than does a typical investigator-initiated R01 application. This is appropriate as long as the applied component addresses the purposes of the PA. The specific review criteria are: 1) Significance: Does this study address an important problem? If the aims of the application are achieved, how will scientific knowledge be advanced? What will be the effect of these studies on the concepts or methods that drive this field? 2) Approach: Are the conceptual framework, design, methods, and analyses adequately developed, well-integrated, and appropriate to the aims of the project? Does the applicant acknowledge potential problem areas and consider alternative tactics? 3) Innovation: Does the project employ novel concepts, approaches or methods? Are the aims original and innovative? Does the project challenge existing paradigms or develop new methodologies or technologies? 4) Investigator: Is the investigator appropriately trained and well suited to carry out this work? Is the work proposed appropriate to the experience level of the principal investigator and other researchers (if any)? 5) Environment: Does the scientific environment in which the work will be done contribute to the probability of success? Do the proposed experiments take advantage of unique features of the scientific environment or employ useful collaborative arrangements? Is there evidence of institutional support? In addition to the above criteria, in accordance with NIH policy, all applications will also be reviewed with respect to the following: o The reasonableness of the proposed budget and duration in relation to the proposed research. o The adequacy of the proposed protection for animals or the environment, to the extent they may be adversely affected by the project proposed in the application. o The appropriateness of the plans for sharing of research resources. SCHEDULE Letter of Intent Receipt Date: September 1, 2001; September 1, 2002 or September 1, 2003. Application Receipt Date: October 1, 2001, October 1, 2002, or October 1, 2003. Peer Review Date: February - March of each respective year. Council Review: May June of each respective year. Earliest Anticipated Start Date: July of each respective year. AWARD CRITERIA Applications will compete for available funds with all other recommended applications assigned to the Institute. 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 are encouraged. The opportunity to clarify any issues or questions from potential applicants is welcome. Direct inquiries regarding programmatic issues to: John D. Harding, Ph.D. Division of Comparative Medicine National Center for Research Resources 6705 Rockledge Drive, Suite 6050, MSC 7965 Bethesda, MD 20892-7965 Telephone: (301) 435-0776 FAX: (301) 480-3819 E-mail: hardingj@ncrr.nih.gov Judy Mietz, Ph.D. Division of Cancer Biology National Cancer Institute 6130 Executive Boulevard, EPN 5032 Bethesda, MD 20892 Telephone: (301) 496-7028 FAX: (301) 402-1037 Email: mietzj@nih.gov Martha S. Lundberg, Ph.D. Division of Heart and Vascular Diseases National Heart, Lung and Blood Institute 6701 Rockledge Drive Rockledge II, Room 9146 Bethesda, MD 20892-7940 Telephone: (301) 435-0513 FAX: (301) 480-1335 E-mail: lundberm@nhlbi.nih.gov Mary Lou Oster-Granite, Ph. D. Mental Retardation and Developmental Disabilities Branch National Institute of Child Health and Human Development 6100 Executive Boulevard, Room 4B-09, MSC 7510 Bethesda, MD 20892-7510 Telephone: (301) 435-6866 FAX: (301) 496-3791 Email: mo96o@nih.gov Arlene Y. Chiu, Ph.D. Repair and Plasticity Program National Institute of Neurological Disorders and Stroke Neuroscience Center, Room 2206 6001 Executive Boulevard Bethesda, MD 20892 Telephone: (301) 496-1447 FAX: (301) 480-1080 Email: chiua@ninds.nih.gov Nancy L. Nadon, Ph.D. Biology of Aging Program National Institute on Aging 7201 Wisconsin Avenue, GW 2C231 Bethesda, MD 20892 Telephone: (301) 496-6402 FAX: (301) 402-0010 E-mail: nadonn@exmur.nia.gov Jonathan D. Pollock, Ph.D. Genetics and Molecular Neurobiology Branch Division of Neuroscience and Behavioral Research National Institute on Drug Abuse 6001 Executive Boulevard Rockville, MD 20892 Telephone: (301) 435-1309 FAX: (301) 594-6043 E-mail: jp183r@nih.gov Direct inquiries regarding fiscal matters to: Ms. Irene Grissom Office of Grants Management National Center for Research Resources 6705 Rockledge Drive, Room 6086 Bethesda, MD 20892 Telephone: (301) 435-0844 FAX: (301) 480-3777 Email: grissomi@ncrr.nih.gov Ms. Crystal Wolfrey Grants Administration Branch National Cancer Institute 6120 Executive Boulevard, Room 243 Bethesda, MD 20892 Telephone: (301) 496-8634 FAX: (301) 496-8601 Email: wolfreyc@gab.nci.nih.gov David Reiter Division of Extramural Affairs National Heart, Lung and Blood Institute 6701 Rockledge Drive Rockledge II, Room 7142 Bethesda, MD 20892-7940 Telephone: (301) 435-0177 FAX: (301) 480-3310 E-mail: reiterd@nhlbi.nih.gov Mr. Douglas Shawver Grants Management Branch National Institute of Child Health and Human Development 6100 Executive Boulevard, Room 8A-17, MSC 7510 Bethesda, MD 20892-7510 Telephone: (301) 435-6999 FAX: (301) 420-0915 E-mail: ex65o@nih.gov Ms. Rita Sisco Grants Management Branch, DER National Institute of Neurological Disorders and Stroke Neuroscience Center, Room 3290, MSC 9537 6001 Executive Boulevard Bethesda, MD 20892 Telephone: (301) 496-7488 FAX: (301) 402-0219 Email: rr46w@nih.gov Ms. Linda Whipp Grants and Contracts Management Office National Institute on Aging 7201 Wisconsin Avenue, GW 2N212 Bethesda, MD 20892 Telephone: (301) 496-1472 FAX: (301) 402-3672 E-mail: whippl@exmur.nia.nih.gov Gary Fleming, J.D., M.A. Grants Management Branch Office of Planning and Resource Management National Institute on Drug Abuse 6001 Executive Boulevard, Room 3131, MSC 9541 Bethesda, MD 20892-9541 Telephone: (301) 443-6710 FAX: (301) 594-6847 E-mail: gf6s@nih.gov AUTHORITY AND REGULATIONS This program is described in the Catalog of Federal Domestic Assistance No. 93.306, 93.396, 93.837, 93.865, 93.853, 93.866, and 93.279. Awards are made under authorization of Sections 301 and 405 of the Public Health Service Act as amended (42 USC 241 and 284) and administered under PHS grants policies and Federal Regulations 42 CFR 52 and 45 CFR Part 74 and 92. This program is not subject to the intergovernmental review requirements of Executive Order 12372 or Health Systems Agency review. The PHS strongly encourages all grant and contract recipients to provide a smoke-free workplace and promote the non-use of all tobacco products. In addition, Public Law 103-227, the Pro-Children Act of 1994, prohibits smoking in certain facilities (or in some cases, and 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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