and Human Services (HHS)
EXPIRED
TRANSACTIVATION OF FETAL HEMOGLOBIN GENES FOR TREATMENT OF SICKLE CELL DISEASE AND COOLEY'S ANEMIA Release Date: January 17, 2001 RFA: RFA-HL-01-013 National Heart, Lung, and Blood Institute (http://www.nhlbi.nih.gov) National Institute of Diabetes and Digestive and Kidney Diseases (http://www.niddk.nih.gov) Letter of Intent Receipt Date: February 14, 2001 Application Receipt Date: March 15, 2001 THIS RFA USES THE "MODULAR GRANT" AND "JUST-IN-TIME" CONCEPTS. IT INCLUDES DETAILED MODIFICATIONS TO STANDARD APPLICATION INSTRUCTIONS THAT MUST BE USED WHEN PREPARING APPLICATIONS IN RESPONSE TO THIS RFA. PURPOSE The National Heart, Lung, and Blood Institute (NHLBI) and the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) invite applications for research grants to pursue the unambiguous identification of transactivator proteins that regulate the expression of fetal globin chains. Both the validation of existing candidate transactivators, and gene discovery to identify new ones are encouraged. Increased understanding of the trans- acting component of developmental stage-specific hemoglobin isoform switching will facilitate the development of new approaches to cure beta-chain hemoglobinopathies such as sickle cell disease and Cooley=s anemia. 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 Request for Applications (RFA), Transactivation of Fetal Hemoglobin Genes For Treatment of Sickle Cell Disease and Cooley=s Anemia, is related to one or more of the 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 RFA will use the National Institutes of Health (NIH) research project grant (R01) award 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 RFA may not exceed 4 years. This RFA is a one-time solicitation. Future unsolicited competing continuation applications will compete with all investigator- initiated applications and be reviewed according to the customary peer review procedures. The anticipated award date is September 30, 2001. Specific application instructions have been modified to reflect "MODULAR GRANT" and "JUST-IN-TIME" streamlining efforts being examined by the NIH. Complete and detailed instructions and information on Modular Grant applications can be found at http://grants.nih.gov/grants/funding/modular/modular.htm. FUNDS AVAILABLE The National Heart, Lung, and Blood Institute (NHLBI) intends to commit approximately $2,500,000 total costs and the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) intends to commit approximately $1,500,000 total costs in FY 2001 to fund 10 to 14 new grants in response to this RFA. An applicant may request a project period of up to 4 years and a budget for direct costs of up to $250,000 (10 modules) per year. Because the nature and scope of the research proposed may vary, it is anticipated that the size of each award will also vary. Although the financial plans of the NHLBI and NIDDK provide support for this program, awards pursuant to this RFA are contingent upon the availability of funds and the receipt of a sufficient number of meritorious applications. RESEARCH OBJECTIVES Background Sickle cell disease (SCD) and Cooley=s anemia (CA; beta-thalassemia) are among the most common inherited diseases in humans in the U.S. and worldwide, and are associated with a substantial cost burden to the healthcare system. SCD was the first human genetic disease to be characterized at the molecular level over 50 years ago. It was later shown to result from a point mutation in the beta-globin gene that gives rise to a dysfunctional hemoglobin protein, and that then becomes manifest clinically in early infancy. CA represents a second group of disorders characterized by abnormal beta-globin expression, in particular reduced levels of normal beta-globin chains, that result from genetic mutations in noncoding regions of the beta-globin gene. As with SCD, CA becomes manifest clinically in early infancy. Despite the fact that the molecular bases of these so-called beta-chain hemoglobinopathies have been known in many cases for decades, there are still no universal cures available for these very serious diseases that are associated with significant morbidity and in some cases mortality. Hydroxyurea, which does induce the expression of fetal hemoglobin, reduces the rate of painful crises in SCD, but is effective in only 2/3 of patients. It is largely ineffective for CA. In spite of the slow rate of progress toward universal cures, one strategy that has proven to be effective in numerous isolated cases is the induction of fetal hemoglobin. The reason that SCD and CA are not clinically manifest before early infancy is that the qualitative and quantitative defects in beta- globin chains are compensated for by gamma-globin chains, that are expressed from early embryonic to early infancy stages. Before early infancy, gamma chains complex with alpha chains to form fetal hemoglobin protein tetramers that are functionally normal, and that in the case of SCD may actually inhibit the polymerization of sickle hemoglobin tetramers (comprised of alpha plus beta-S chains). As human development proceeds beyond the early infancy period, gamma-globin expression is variably extinguished (see below), and beta-globin expression is activated. This then provides a rationale for developing pharmacologic or genetic approaches to reinduce gamma-globin chains (and thus fetal hemoglobin tetramers) in adult clients with SCD or CA. Currently, hydroxyurea and butyrates benefit some patients with SCD or CA, and are thought to work at least in part through fetal hemoglobin induction, but they do not benefit all patients, and they have limitations due to toxicity and route of administration (butyrate). A well-designed epidemiologic study has demonstrated that any increase in synthesis of fetal hemoglobin is beneficial to the patients with SCD. Clinical observations in patients who are compound heterozygotes for a sickle cell gene, and a gene for hereditary persistence of fetal hemoglobin (HPFH) or delta-beta-thalassemia indicate that production of 25 to 30% of total hemoglobin present as fetal hemoglobin can cure SCD. Likewise in the case of CA, when the synthesis of fetal hemoglobin is abundant, as in the case of delta-beta-thalassemia syndromes, the clinical manifestations of the disease are mild. Significant progress has been achieved in the last ten years in the understanding of the control of globin gene activity during human development and the control of fetal hemoglobin synthesis in particular. The existing evidence suggests that the fetal globin genes are activated in early embryonic development through interactions of transcription factors with sequences of the promoters of the gamma-globin genes as well as the sequences of the major regulatory element of the beta-globin locus, the locus control region (LCR). Gamma-globin genes are turned off in development through a phenomenon of autonomous silencing which most likely involves interactions of sequences of the promoters of the gamma-globin genes with DNA binding proteins that act as suppressors. Gamma-globin genes are not completely turned off, but remain active at a low but variable level in adults. It is expected that delineation of the exact mechanism of gamma-globin gene activation (the focus of this RFA), as well as the exact mechanism of gamma-globin gene silencing will allow the development of therapeutic methods of fetal hemoglobin induction. Such therapeutic methods could in theory act either through activation of gamma- globin gene transcription, or through inhibition of gamma-globin gene silencing. It has been shown that a specific transcriptional factor, EKLF (erythroid Kruppel-like factor), is responsible for activation of the beta-globin gene. It is therefore expected that specific transcriptional factors will be responsible for the activation of the gamma-globin genes. Preliminary evidence implicates four such candidate factors, designated as SSP (stage-selector protein), FKLF (fetal Kruppel-like factor), FKLF-2, and NF-E4 (nuclear factor erythroid-4). The research scope of this RFA (see below for specific examples) will include confirmation that these four factors are important, as well as identification of new regulatory factors through gene discovery efforts. The timely use of new genome-wide, or high-throughput methods such as microarrays, and of new genomic tools for preliminary gene mapping (e.g. chromosome substitution strains of mice), will be encouraged. Also encouraged will be the use of new genomic sequence resources such as the draft human and mouse genome sequences, and online public databases that will include more and more genomic information on red blood cell progenitors in the near future. In addition, grantees supported through this RFA may be able in the next several years to take timely advantage of the functional genomic resources generated through NHLBI=s Programs for Genomic Applications (PGA), in particular those expressed sequences, or mutant mouse strains associated with increased levels of fetal hemoglobin-containing red blood cells (i.e. so called F cells). The purpose of the PGA program, that was initiated in September 2000, is to make functional genomic resources related to heart, lung, and blood diseases freely available to investigators working in these areas in a timely fashion. It is expected that the work supported by this RFA will include as systems of study established and primary cell culture, fetal and adult tissue from animal models, discarded human fetal tissue, adult human samples and clinical samples from patients exhibiting HPFH. Further study of the role of transactivator proteins in the phenotypes conferred by the many known human HPFH mutations is encouraged. Much remains to be learned about the mechanism by which HPFH mutations lead to increased levels of F cells in adults. Research supported through this RFA will clarify molecular pathways that activate fetal hemoglobin expression. Potential target molecules (transactivators) for new approaches to fetal hemoglobin modulation in adults will be validated, or identified anew. Finally, these targets will then form the foundation of new drug-based and/or genetic approaches to reinduction of fetal hemoglobin in adult clients with SCD or CA, to ultimately provide universal cures for these common beta-chain hemoglobinopathies. Other The objectives of this program will be optimally met with an interdisciplinary team approach. The formation of multidisciplinary teams of investigators comprised of individuals with expertise in many of the following areas is encouraged: genetics, genomics, biostatistics, gene regulation, and hematology. Applications from new investigators, and from established investigators working outside of this field are especially encouraged. Research Scope Some research topics that will be responsive to this RFA are shown below. These are examples only, and potential applicants are encouraged to develop other proposals that meet the stated objectives of this program. Research with either animals or human subjects will be responsive to this RFA. The following are examples of areas of research that will be responsive to this RFA: o validation of existing candidate transactivators (e.g. SSP, FKLK, FKLF-2, NF-E4) via clear demonstration that the transactivator gene or protein activates a gamma-globin gene o investigation of the specificity of induction activity linked to a validated gamma-globin transactivator (are other genes coinduced, or is the induction gamma-globin specific?) o investigation of the mechanism of action of a validated gamma-globin transactivator o investigation of the mechanism of induction/regulation of the structural gene for a validated gamma-globin transactivator o gene discovery for new transactivator molecules using high-throughput or genome-wide methods (e.g. microarrays) and developmental stage-specific probes from normal or HPFH tissues; subsequently, validation of these transactivators with respect to mechanism of action, and/or mechanism of induction of the structural gene for the transactivator o gene discovery for unlinked genetic modifiers of the expression or activity of validated gamma- globin transactivators o identification of drugs that modulate the expression or activity of validated gamma-globin transactivators, and demonstration of fetal hemoglobin induction and phenotypic correction in model systems of SCD or CA o development of new experimental systems to model the activation of gamma globin genes that occurs in human embryonic development, and validation of transactivators of gamma-globin in these systems ALL POTENTIAL APPLICANTS ARE STRONGLY ENCOURAGED TO CONTACT ONE OF THE PROGRAM OFFICIALS LISTED UNDER INQUIRIES BELOW TO DISCUSS THE RESPONSIVENESS OF THEIR PROPOSALS, IN ADVANCE OF THE RECEIPT DATE FOR THE LETTER OF INTENT. SPECIAL REQUIREMENTS Applications that do not specifically include gamma-globin genes to validate candidate transactivator proteins at some stage of their research plan will be judged unresponsive to this RFA and will be returned to the applicant. Applications that include beta-globin genes only will be judged unresponsive to this RFA, and will be returned to the applicant. Applicants must adequately demonstrate the physiologic relevance of the proposed research to activation of the gamma-globin gene. Applications proposing human subjects research, animal research, or combinations thereof will be responsive to this RFA. Upon initiation of the program, the NHLBI AND NIDDK will sponsor periodic meetings to encourage exchange of information among investigators who participate in this program. This is especially critical if more than one group focuses on similar studies, systems, or animal models to avoid unnecessary duplication and to expedite progress as a program. Travel funds should be included in the budget modules for the Principal Investigator to attend a one day meeting once each year, most likely to be held in Bethesda, Maryland. Applicants should also include a statement in their application indicating their willingness to participate in these meetings and to interact openly with other study participants in sharing approaches/strategies and findings among awardees so as to provide the greatest promise for scientific advances from the approved research scope of the awards. 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 sub-populations must be included in all NIH-supported biomedical and behavioral research projects involving human subjects, unless a clear and compelling rationale and justification are provided indicating 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 UPDATED "NIH Guidelines for Inclusion of Women and Minorities as Subjects in Clinical Research," published in the NIH Guide for Grants and Contracts on August 2, 2000 (http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-048.html); a complete copy of the updated Guidelines are available at http://grants.nih.gov/grants/funding/women_min/guidelines_update.htm: The revisions relate to NIH defined Phase III clinical trials and require: a) all applications or proposals and/or protocols to provide a description of plans to conduct analyses, as appropriate, to address differences by sex/gender and/or racial/ethnic groups, including subgroups if applicable; and b) all investigators to report accrual, and to conduct and report analyses, as appropriate, by sex/gender and/or racial/ethnic group differences. 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. 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: http://grants.nih.gov/grants/guide/notice-files/not98-024.html. Investigators also may obtain copies of these policies from the program staff listed under INQUIRIES. Program staff may also provide additional relevant information concerning the policy. GUIDELINES FOR RESEARCH USING HUMAN PLURIPOTENT STEM CELLS All investigators proposing research using human pluripotent stem cells should read the National Institutes of Health Guidelines for Research Using Human Pluripotent Stem Cells (the Guidelines) published in the Federal Register on August 25, 2000 and is available at the following URL address: http://stemcells.nih.gov/news/newsArchives/fr25au00-136.asp. Details on the approval process and the procedures for submitting the required documentation of compliance are at the following URL address: http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-050.html 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. LETTER OF INTENT Prospective applicants are asked to submit, by February 14, 2001, a letter of intent that includes a descriptive title of the proposed research, the name, address, and telephone number of the Principal Investigator, the identities of other key personnel and participating institutions, and the number and title of the RFA in response to which the application may be submitted. Although a letter of intent is not required, is not binding, and does not enter into the review of a subsequent application, the information that it contains allows NHLBI staff to estimate the potential review workload and plan the review. The letter of intent is to be FAXed, mailed, or e-mailed to Dr. Deborah Beebe 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. These forms 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. 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. SPECIFIC INSTRUCTIONS FOR MODULAR GRANT APPLICATIONS BUDGET INSTRUCTIONS Modular Grant applications will request direct costs in $25,000 modules, up to a maximum total direct cost request of $250,000 (10 modules) per year. An R01 grant application may include research activities that involve institutions other than the sponsoring organization, creating a consortium effort. The consortium costs should be included in the direct cost limit ($250,000). The total direct costs must be requested in accordance with the program guidelines and the modifications made to the standard PHS 398 application instructions described below: o FACE PAGE: Items 7a and 7b should be completed, indicating Direct Costs (in $25,000 increments up to a maximum of $250,000) and Total Costs [Modular Total Direct plus 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-DD of the PHS 398 (rev 4/98). It is not required nor will it be accepted at the time of application. o BUDGET FOR THE ENTIRE PROPOSED PERIOD OF SUPPORT - Do not complete the categorical budget table on Form Page 5 of the PHS 398. It is not required and will not be accepted with the application. o NARRATIVE BUDGET JUSTIFICATION - Prepare a Modular Grant Budget Narrative page. (See http://grants.nih.gov/grants/funding/modular/modular.htm for sample pages). At the top of the page, enter the total direct costs requested for each year. This is not a Form page. 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. For Consortium/Contractual Costs, provide an estimate of total costs (direct plus facilities and administrative) for each year, each rounded to the nearest $1,000. For this RFA, the consortium costs should be included in the $250,000 cost limit. 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 collaborative 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 modified 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 citation; 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 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, the RFA title and number must be typed on line 2 of the face page of the application form and the YES box must be marked. 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 Dr. Deborah Beebe, at the listing under INQUIRIES. Applications must be received by the application receipt date listed in the heading of this RFA. If an application is received after that date, it will be returned to the applicant without review. The Center for Scientific Review (CSR) will not accept any application in response to this RFA that is essentially the same as one currently pending initial review, unless the applicant withdraws the pending application. The CSR will not accept any application that is essentially the same as one already reviewed. This does not preclude the submission of substantial revisions of applications already reviewed, but such applications must include an introduction addressing the previous critique. REVIEW CONSIDERATIONS Upon receipt, applications will be reviewed for completeness by the CSR and responsiveness by the NHLBI. Incomplete and/or non-responsive applications will be returned to the applicant without further consideration. Applications that are complete and responsive to the RFA will be evaluated for scientific and technical merit by an appropriate peer review group convened by the NHLBI in accordance with the review criteria stated below. 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 the applications under review, will be discussed, assigned a priority score, and receive a second level review by the National Heart, Lung, and Blood Advisory Council and/or the National Diabetes and Digestive and Kidney Diseases 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)? (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 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. Schedule Letter of Intent Receipt Date: February 14, 2001 Application Receipt Date: March 15, 2001 Peer Review Date: June/July, 2001 Council Review: September, 2001 Anticipated Start Date: September 30, 2001 AWARD CRITERIA Award criteria that will be used to make award decisions include: o scientific merit (as determined by peer review) o availability of funds o programmatic priorities. INQUIRIES Inquiries concerning this RFA are strongly encouraged. The opportunity to clarify any issues or answer questions from potential applicants is welcome. Direct inquiries regarding programmatic issues to: Greg Evans, Ph.D. Division of Blood Diseases and Resources National Heart, Lung, and Blood Institute 6701 Rockledge Drive, Room10152, MSC 7950 Bethesda, Maryland 20892-7950 Telephone: (301) 435-0055 FAX: (301) 480-0868 E-Mail: EvansG@nih.gov David G. Badman, Ph.D. Division of Kidney, Urologic and Hematologic Diseases National Institute of Diabetes and Digestive and Kidney Diseases 6707 Democracy Blvd, Room 621, MSC 5458 Bethesda, Maryland 20892-5458 Telephone:(301) 594-7717 FAX: (301) 480-3510 E-mail: db70f@nih.gov Direct inquiries regarding review matters, address the letter of intent, and send two copies of the application to: Deborah Beebe, Ph.D. Division of Extramural Affairs National Heart, Lung, and Blood Institute 6701 Rockledge Drive, Room 7178, MSC 7924 Bethesda, Maryland 20892-7924 Telephone: (301) 435-0270 FAX: (301) 480-3541 E-mail: BeebeD@nhlbi.nih.gov Direct inquiries regarding fiscal matters to: Mary S. Page Division of Extramural Affairs National Heart, Lung, and Blood Institute 6701 Rockledge Drive, Room 7162, MSC 7926 Bethesda, MD 20892-7926 Telephone: (301) 435-0152 FAX: (301) 480-3310 E-mail: pagem@nhlbi.nih.gov AUTHORITY AND REGULATIONS This program is described in the Catalog of Federal Domestic Assistance No. 93.839 and 93.848. Awards are made under authorization of Sections 301 and 405 of the Public Health Service Act as amended (42 USC 241 and 284) and administered under NIH grants policies and Federal Regulations 42 CFR 52 and 45 CFR Parts 74 and 92. This program is not subject to the intergovernmental review requirements of Executive Order 12372 or Health Systems Agency review. The PHS strongly encourages all grant 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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