Full Text HL-96-018 HOMOCYST(E)INEMIA AND ATHEROSCLEROSIS NIH GUIDE, Volume 25, Number 25, July 26, 1996 RFA: HL-96-018 P.T. 34 Keywords: Cardiovascular Diseases Molecular Genetics National Heart, Lung, and Blood Institute Letter of Intent Receipt Date: September 15, 1996 Application Receipt Date: November 20, 1996 THIS RFA USES "MODULAR GRANT" AND "JUST-IN-TIME" CONCEPTS. THE FULL RFA INCLUDES DETAILED MODIFICATIONS TO STANDARD APPLICATION INSTRUCTIONS THAT MUST BE USED WHEN PREPARING APPLICATIONS IN RESPONSE TO THIS RFA. PURPOSE The purpose of this solicitation is to promote research into the precise mechanisms by which homocysteine induces arterial occlusive disease as well as to investigate the role of hyperhomocyst(e)inemia in the development of atherosclerotic lesions. Additionally, this solicitation will encourage the development of enzymatic assays and molecular genetic diagnostic tests for cystathionine - synthase, methylenetetrahydrofolate reductase and methionine synthase in homocyst(e)inemic individuals. 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), Homocyst(e)inemia and Atherosclerosis, is related to the priority area of heart disease and stroke. Potential applicants may obtain a copy of "Healthy People 2000" (Full Report: Stock No.017-001-00474-0 or Summary Report: Stock No. 017-001-00473-1) through the Superintendent of Documents, Government Printing Office, Washington, DC 20402-9325 (telephone 202-512-1800). ELIGIBILITY REQUIREMENTS Applications may be submitted by domestic and foreign, for-profit and nonprofit organizations, public and private, such as universities, colleges, hospitals, laboratories, units of State and local governments, and eligible agencies of the Federal government. Racial/ethnic minority individuals, women, and persons with disabilities are encouraged to apply as Principal Investigators. All current policies and requirements that govern the research grant programs of the NIH will apply to grants awarded under this RFA. Awards under this RFA to foreign institutions will be made only for research of very unusual merit, need, and promise, and in accordance with Public Health Service policy governing such awards. Cell biology, molecular biology, biochemistry, physiology, pathology, and genetics. are among the disciplines and expertise that may be appropriate for this research program. MECHANISM OF SUPPORT This RFA will use the NIH individual research project grant (R01) mechanism of support. However, specific application instructions have been modified to reflect "MODULAR GRANT" and "JUST-IN-TIME" streamlining efforts being examined by the NIH. The modular grant concept establishes specific modules in which direct costs may be requested as well as a maximum level for requested budgets. Only limited budgetary information is required under this approach. The just-in-time concept allows applicants to submit certain information only when there is a possibility for an award. It is anticipated that these changes will reduce the administrative burden for the applicants, reviewers and Institute staff. For this RFA, funds must be requested in $25,000 direct cost modules and a maximum of seven modules ($175,000 direct costs) per year may be requested. A feature of the modular grant concept is that no escalation is provided for future years, and all anticipated expenses for all years of the project must be included within the number of modules being requested. Only limited budget information will be required and any budget adjustments made by the Initial Review Group will be in modules of $25,000. Instructions for completing the Biographical Sketch have also been modified. In addition, Other Support information and the application Checklist page are not required as part of the initial application. If there is a possibility for an award, necessary budget, Other Support and Checklist information will be requested by NHLBI staff following the initial review. The APPLICATION PROCEDURES section of this RFA provides specific details of modifications to standard PHS 398 application kit instructions. This RFA is a one-time solicitation. Future unsolicited competing continuation applications will compete with all investigator-initiated applications and be reviewed according to the customary peer review procedures. It is anticipated that support for this program will begin in July 1997. Administrative adjustments in project period and/or amount may be required at the time of the award. FUNDS AVAILABLE It is anticipated that for fiscal year 1997, approximately $1,500,000 total costs will be available for the first year of support for this initiative. Award of grants pursuant to this RFA is contingent upon receipt of such funds for this purpose. It is anticipated that approximately six new grants will be awarded under this program. Applicants may request up to four years of support. The specific number to be funded will, however, depend on the merit and scope of the applications received and on the availability of funds. Direct costs will be awarded in modules of $25,000, less any overlap or other necessary administrative adjustments. Indirect costs will be awarded based on the negotiated rates. RESEARCH OBJECTIVES Background Atherosclerotic cardiovascular disease is a major cause of mortality and morbidity in the United States. Risk factors such as hyperlipidemia, hypertension and cigarette smoking account for a high proportion of cardiovascular deaths. However, some cases cannot be explained by these conventional risk factors. The presence of raised levels of homocyst(e)ine may help explain these cases. The interest in homocysteine and its relation to cardiovascular disease was initially stimulated by the discovery of homocystinuria. Homocystinuria due to a cystathionine beta-synthase (CBS) deficiency is an autosomal recessive condition characterized by elevated plasma concentrations of homocysteine in urine and blood and premature arteriosclerosis. CBS is the enzyme required for the conversion of homocyst(e)ine to cystathionine. Without this enzyme, homocyst(e)ine builds up in the blood and in tissues. Four organ systems show major involvement: the eye, skeletal, central nervous, and vascular systems. Homocystinuria is usually associated with serious thromboembolic complications at an early age; thrombosis of extracranial and intracranial arteries, veins and sinuses as well as coronary occlusion are common fatal occurrences. For untreated patients the risk of thromboembolism is approximately 25 percent by the age of 15 years old. Premature arteriosclerotic lesions in most large and medium sized arteries are common in these patients. The lesions are composed of proliferating smooth muscle cells surrounded by large amounts of collagen, elastic fibers, and glycosaminoglycans. Fatty atheromatous plaques have only occasionally been observed in homocystinuric patients. The frequency for CBS homozygosity in the normal population is between 1 in 100,000 and 1 in 335,000 live births whereas the frequency for heterozygosity is 1 in 200. The normal concentration of homocysteine in plasma is about 10 nmol/ml. In contrast, homocystinuric patients may attain homocysteine concentration levels as high as 200-400 nmol/ml. Patients with cardiovascular disease may have "hyperhomocyst(e)inemia" or moderately elevated homocysteine (13-25 nmol/ml) levels. Similar to the role of cholesterol in coronary artery disease, homocysteine is a graded risk factor and vascular risk rises with increasing homocysteine levels. Depending upon the cutoff level selected as indicating hyperhomocyst(e)inemia, 10 to 50 percent of patients with arteriosclerotic vascular disease have "elevated" levels. The determinants of moderately elevated levels of homocysteine are not completely understood. Hyperhomocyst(e)inemia could be due to dietary deficiencies such as folate, vitamin B6 and vitamin B12, and/or due to genetic or acquired defects in the absorption and utilization of these vitamins. Genetic functional defects in various enzymes involved in folic acid, methionine and Vitamin B12 metabolism might account for other cases. In the last five years there has been a growing body of literature relating homocyst(e)inemia to vascular disease and indicating that the relation is independent of other risk factors. The most recent studies have suggested that elevated plasma concentrations of homocysteine are associated with coronary atherosclerosis and thrombosis. The frequency of putative heterozygosity for hyperhomocyst(e)inemia among patients with clinical signs of ischemic disease was investigated in 1985. Approximately 30 percent of the patients with occlusive peripheral arterial and cerebrovascular disease had homocysteine levels in heterozygote range. Similar findings were reported (1991) in a study involving l23 patients with vascular disease. Hyperhomocyst(e)inemia was detected in 42 percent of patients with cerebrovascular disease, in 30 percent of patients with coronary vascular disease and in 28 percent of patients with peripheral vascular disease but in none of the 27 normal subjects. This study strongly suggested that hyperhomocyst(e)inemia was an independent risk factor for vascular disease, including coronary vascular disease. Recently, a nested case-control study using previously collected blood samples was published. Samples from 271 physicians who subsequently developed myocardial infarction were analyzed for homocyst(e)ine levels together with paired controls. They found that men with homocyst(e)ine levels above 15.8 nmoles/ml (95th percentile) had a three fold increased risk for myocardial infarction compared with those in the bottom 95% of the control distribution (<14.1 nmoles/ml). However, only seven percent of the cases was attributable to elevated levels of homocyst(e)ine. It was suggested that the reason the percentage was less than found in other studies may reflect the better nutritional state of physicians over the general population. High vitamin intake was correlated with lower homocyst(e)ine levels in the population. By contrast, individuals in the population with low normal folate levels may develop hyperhomocyst(e)inemia and thus be at risk for thrombosis and coronary disease. Several hypotheses have been advanced to explain the mechanisms involved in the pathology caused by homocysteine. Homocysteine may increase the adhesiveness of platelets which leads to increased thrombogenesis or it may be toxic and cause endothelial injury. Homocysteine has also been shown to stimulate the binding of Lp(a) to fibrin. This may decrease the fibrinolytic potential of the blood vessel wall and promote thrombosis. Furthermore, it has been suggested that homocysteine may produce reactive oxygen species which modify LDL to oxidized LDL, and thus accelerate the process of atherogenesis. However, no single mechanism has been definitively shown to lead to the pathology associated with hyperhomocyst(e)inemia. The potential atherogenic properties of homocysteine have been evaluated by both in vivo and in vitro experiments. Short term injection of homocysteine caused patchy loss of arterial endothelium in baboons. In contrast, sustained treatment induced arterial damages resembling those observed in early human arteriosclerosis. Endothelial damage, platelet sequestration, and venous thrombosis were also observed in rats given a single homocysteine injection. Homocysteine also promotes detachment of human endothelial cells from tissue culture dishes suggesting that homocysteine may contribute to atherogenesis by diminishing cell adhesion. The pathology of the vascular lesions has been mainly examined in patients with the homocystinuria. A notable pathological feature in these patients is the intimal thickening and the presence of fibrous plaques in the vessel walls. No lipid deposits have been observed in the arterial lesions. However, it should be pointed out that most of these autopsy data come from young patients. Additional characterization of the pathology of vascular lesions in hyperhomocyst(e)inemia would be helpful in the elucidation of the mechanisms responsible for vascular diseases in these patients. Choline-deficient rats, pyridoxine-deficient monkeys and pigs, and homocysteine- injected rabbits have been used to study the pathogenesis of arteriosclerosis associated with hyperhomocyst(e)inemia. But for unknown reasons the experimentally- induced arteriosclerosis in these animal models cannot always be reproduced. Recently, a CBS knockout mouse was developed and is being used to study cellular and molecular mechanisms of hyperhomocyst(e)inemia. However, animal models are still needed in which cellular and molecular mechanisms involved in the pathogenesis of arterial damage associated with hyperhomocyst(e)inemia can be tested. There has been increasing interest in the genetic defects that cause hyperhomocyst(e)inemia. Recently, a mutation inmethylenetetrahydrofolate reductase (MTHFR) has been identified. This enzyme catalyzes the reduction of methylenetetrahydrofolate to methyltetrahydrofolate, a cofactor for homocysteine methylation to methionine. Since the identification of this mutation several (but not all) studies have shown an association of this thermo-labile MTHFR defect in homocysteine metabolism with premature coronary disease. Individuals homozygous for the mutation have elevated plasma homocysteine levels. Interestingly, 10-15% of the population are homozygous, and thus may represent an important genetic risk factor in vascular disease. Methionine synthase (MS) is another important enzyme involved in homocysteine metabolism. MS is involved in the remethylation of homocysteine to methionine. However, the gene for MS has not been cloned yet, and thus few studies have been done on this enzyme. While techniques are available to measure homocyst(e)ine levels, better molecular methods are needed to determine heterozygosity and homozygosity for various CBS and MTHFR mutations. The exact role of mutations and polymorphisms of these and other enzymes (such as MS) in various types of vascular disease, needs further definition. At the present time, heterozygosity for CBS deficiency, even though claimed to be common in vascular disease by measurement of homocysteine levels, could not be detected using more definitive direct molecular testing. Treatment of elevated levels of homocyst(e)ine is simple and apparently innocuous. Hyperhomocyst(e)inemia is readily treated with folate (0.4 to 10mg), a vitamin that normalizes homocyst(e)ine metabolism. Folate seems to have a universal potential for reducing fasting plasma levels of homocysteine regardless of etiology. Other therapies such as supplementation with B12 and B6 produce biochemical and clinical improvement in patients who have elevated levels due to B12 and B6 deficiencies. Thus, hyperhomocyst(e)inemia is potentially a treatable risk factor for vascular diseases. It has not been proven, however, whether identification and treatment of hyperhomocyst(e)inemic subjects will reduce the risk of coronary disease. However, it is important to understand the mechanisms involved in this disease as well as to develop the technology to identify better those individuals with hyperhomocyst(e)inemia who may be at risk. Objectives Many aspects of the relationship between homocysteine and vascular diseases remain to be determined. Studies are required to determine the precise mechanisms by which homocysteine induces arterial occlusive disease as well as to investigate the role of hyperhomocyst(e)inemia in the development of atherosclerotic lesions. Examples of topics that would be appropriate for this initiative are given below. This list is not to be regarded as complete or exclusive, and other research areas proposed by applicants that meet the objectives of this program will be considered by the NHLBI. Active collaboration among molecular and cell biologists, physiologists, pathologists, geneticists and biochemists are highly encouraged. Representative areas of research might include: o Investigation of the action of homocysteine on the fibrinolytic and coagulation processes leading to atherosclerosis and/or thromboembolism. For example, homocysteine has been shown to stimulate the binding of Lp(a) to plasmin-treated fibrin which may contribute to the thrombotic disease seen in patients with homocyst(e)inemia. Homocysteine also enhances endothelial cell factor V activity which initiates blood coagulation. o Investigation of the interaction of homocysteine with plasma proteins. For example, can homocysteine modify apo B100 or LDL and promote its atherogenicity? Protein-bound homocysteine accounts for greater than 85% of total plasma homocyst(e)ine. Homocysteine can form mixed disulfide linkages with plasma proteins. Albumin appears to be a primary carrier, but other proteins may also interact with homocysteine, particularly when there is excess production. The role that "homocysteinylated" proteins might play in atherogenesis is unknown. o Examination and characterization of the vascular lesions in hyperhomocyst(e)inemia. There are no studies that have examined the vascular lesions found in hyperhomocyst(e)inemic individuals, and tried to correlate the severity of the lesion with the levels of homocysteine. o Development of animal models in which the cellular and molecular mechanisms involved in the pathogenesis of arterial damage associated with homocyst(e)inemia could be tested. Present models that are produced through chemical modifications do not give consistent results. Thus far only one animal model, CBS knockout mouse, has been produced which could be used to study cellular and molecular mechanisms. o Investigation of the molecular genetics of CBS, MTHFR and MS deficiencies. The human gene has been cloned for the CBS and MTHFR deficiencies, and mutations in these genes can now be identified using established molecular techniques. The gene has not yet been cloned for the MS deficiency. Further molecular studies on these and related genes and their respective enzymes, with attention to diagnostic screening, would be desirable. o Investigation of homocysteine metabolism in humans. Little is known about homocysteine metabolism in cardiovascular cells and tissues. For example, rat heart has little or no detectable CBS activity, but what is the situation in human cardiovascular tissues? Cells unable to metabolize homocysteine by the transsulfuration pathway may be particularly sensitive to increased plasma levels seen in hyperhomocyst(e)inemia. o Investigation of the short term effects of homocyst(e)ine on vascular tone and vascular reactivity. o Investigation of the primary and secondary causes of hyperhomocyst(e)inemia in homocyst(e)inemic patients with atherosclerosis and cardiovascular diseases. This initiative will not support grants that focus on large epidemiological studies or clinical trials. In addition, any application that focuses on cerebrovascular disease or stroke should be addressed to the National Institute of Neurological Disorders and Stroke. SPECIAL REQUIREMENTS Upon initiation of the program, the NHLBI will sponsor periodic meetings to encourage exchange of information among investigators who participate in this program. In the budget for the grant application, applicants should request travel funds for a one day meeting each year, most likely to be held in Bethesda, Maryland. Applicants should also include a statement in their applications indicating their willingness to participate in these meetings. INCLUSION OF WOMEN AND MINORITIES IN RESEARCH INVOLVING HUMAN SUBJECTS It is the policy of the NIH that women and members of minority groups and their subpopulations must be included in all NIH supported biomedical and behavioral research projects involving human subjects, unless a clear and compelling rationale and justification is provided that inclusion is inappropriate with respect to the health of the subjects or the purpose of the research. This new policy results from the NIH Revitalization Act of 1993 (Section 492B of Public Law 103-43) and supersedes and strengthens the previous policies (Concerning the Inclusion of Women in Study Populations, and Concerning the Inclusion of Minorities in Study Populations), that have been in effect since 1990. The new policy contains some provisions that are substantially different from the 1990 policies. All investigators proposing research involving human subjects should read the "NIH Guidelines for Inclusion of Women and Minorities as Subjects in Clinical Research," which have been published in the Federal Register of March 28, 1994 (FR 59 14508-14513) and reprinted in the NIH Guide to Grants and Contracts, Volume 23, Number 11, March 18, 1994. Investigators also may obtain copies of the policy from the program staff listed under INQUIRIES. Program staff may also provide additional relevant information concerning the policy. LETTER OF INTENT Prospective applicants are asked to submit, by September 15, 1996, 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 staff to estimate the potential review workload and to avoid conflict of interest in the review. The letter of intent is to be sent to: Dr. C. James Scheirer Division of Extramural Affairs National Heart, Lung, and Blood Institute 6701 Rockledge Dr., Room 7220, MSC 7924 Bethesda, MD 20892-7924 Telephone: (301) 435-0266 FAX: (301) 480-3541 Email: James_Scheirer@NIH.GOV APPLICATION PROCEDURES The research grant application form PHS 398 (rev. 5/95) is to be used in applying for these grants, with the modifications noted below. Applications kits are available at most institutional offices of sponsored research and may be obtained from the Grants Information Office, Office of Extramural Outreach and Information Resources, National Institutes of Health, 6701 Rockledge Drive, MSC 7910, Bethesda, MD 20892-7910, telephone 301/710-0267, email: ASKNIH@odrockm1.od.nih.gov; and from the program administrator listed under INQUIRIES. The RFA label found in the PHS 398 application form must be affixed to the bottom of the face page of the application. Failure to use this label could result in delayed processing of the application such that it may not reach the review committee in time for review. In addition, the RFA title and number must be typed on line 2 of the face page of the application form and the YES box must be marked. Sample budgets and justification page will be provided upon request or following the submission of a letter of intent. BUDGET INSTRUCTIONS The total direct costs must be requested in accordance with the program guidelines and the modifications made to the standard PHS 398 application instructions described below: o DETAILED BUDGET FOR THE INITIAL BUDGET PERIOD - Do not complete Form Page 4 of the PHS 398 (rev 5/95). It is not required nor will it be accepted at the time of application. o BUDGET FOR THE ENTIRE PROPOSED PERIOD OF SUPPORT - Do not complete the categorical budget tables on Form page 5 of the PHS 398 (rev. 5/95). Only the requested total direct costs line for each year must be completed based on the number of $25,000 modules being requested. Applicants may not request a change in the amount of each module. A maximum of seven modules ($175,000 direct costs) per year may be requested and each applicant may request up to four years of support for this RFA. Direct cost budgets will remain constant throughout the life of the project (i.e., the same number of modules requested for all budget periods). Any necessary escalation should be considered when determining the number of modules to be requested. However, in the event that the number of modules requested must change in any future year due to the nature of the research proposed, appropriate justification must be provided. Total Direct Costs for the Entire Proposed Project Period should be shown in the box provided. BUDGET JUSTIFICATION - Budget justifications should be provided under "Justifications" on Form Page 5 of the PHS 398. - List the names, role on the project and proposed percent effort for all project personnel (salaried or unsalaried)and provide a narrative justification for each person based on his/her role on the project. - Identify all consultants by name and organizational affiliation and describe the services to be performed. - Provide a general narrative justification for individual categories (equipment, supplies, etc.) required to complete the work proposed. More detailed justifications should be provided for high cost items. Any large one-time purchases, such as large equipment requests, must be accommodated within these limits. CONSORTIUM/CONTRACTUAL COSTS If collaborations or subcontracts are involved that require transfer of funds from the grantee to other institutions, it is necessary to establish formal subcontract agreements with each collaborating institution. A letter of intent from each collaborating institution should be submitted with the application. Only the percentage of the consortium/contractual TOTAL COSTS (direct and indirect) relative to the total DIRECT COSTS of the overall project needs to be stated at this time. The following example should be used to indicate the percentage cost of the consortium, "The consortium agreement represents 27% of overall $175,000 direct costs requested in the first year.". A budget justification for the consortium should be provided as described in the "Budget Justification" section above (no Form Page 5 required for the consortium). Please indicate whether the consortium will be in place for the entire project period and identify any future year changes in the percentage relative to the parent grant. If there is a possibility for an award, the applicant will be requested to identify actual direct and indirect costs for all years of the consortium. Please note that total subcontract costs need not be calculated in $25,000 modules. However, when subcontract funds are added to the parent grant budget, the total direct cost amount must be included in the number of $25,000 modules requested. BIOGRAPHICAL SKETCH A biographical sketch is required for all key personnel, following the modified instructions below. Do not exceed the two-page limit for each person. - Complete the educational block at the top of the form page; - List current position(s) and those previous positions directly relevant to the application; - List selected peer-reviewed publications directly relevant to the proposed project, with full citation; - The applicant has the option to provide information on research projects completed and/or research grants participated in during the last five years that are relevant to the proposed project. OTHER SUPPORT - Do not complete the "Other Support" pages (Form Page 7). Selected other support information relevant to the proposed research may be included in the Biographical Sketch as indicated above. Complete Other Support information will be requested by NHLBI staff if there is a possibility for an award. CHECKLIST No "Checklist" page is required as part of the initial application. A completed Checklist will be requested by NHLBI staff if there is a possibility for an award. The applicant should provide the name and phone number of the individual to contact concerning fiscal and administrative issues if additional information is necessary following the initial review. Applications not conforming to these guidelines will be considered unresponsive to this RFA and will be returned without further review. Submit a signed, typewritten original of the application and three signed, photocopies, in one package to: DIVISION OF RESEARCH GRANTS NATIONAL INSTITUTES OF HEALTH 6701 ROCKLEDGE DRIVE, ROOM 1040 - MSC 7710 BETHESDA, MD 20892-7710 BETHESDA, MD 20817 (for express courier service) At the time of submission, two additional copies of the application must be sent to Dr. C. James Scheirer, at the same address listed under LETTER OF INTENT. Applications must be received by November 20, 1996. If an application is received after that date, it will be returned to the applicant without review. The Division of Research Grants (DRG) will not accept any application in response to this RFA that is essentially the same as one currently pending initial review, unless the applicant withdraws the pending application. The DRG will not accept any application that is essentially the same as one already reviewed. This does not preclude the submission of substantial revisions of applications already reviewed, but such applications must include an introduction addressing the previous critique. REVIEW CONSIDERATIONS Applications that are complete and responsive to the RFA will be evaluated for scientific and technical merit by an appropriate peer review group convened in accordance with NIH peer review procedures. As part of the initial merit review, all applications will receive a written critique and undergo a process in which only those applications deemed to have the highest scientific merit, generally the top half of applications under review, will be discussed, assigned a priority score, and receive a second level review by the National Heart, Lung, and Blood Advisory Council. The personnel category will be reviewed for appropriate staffing based on the requested percent effort. The direct costs budget request will be reviewed for consistency with the proposed methods and specific aims. Any budgetary adjustments recommended by the reviewers will be in $25,000 modules. The duration of support will be reviewed to determine if it is appropriate to ensure successful completion of the requested scope of the project. Other review criteria will include: o scientific, technical or medical significance and originality of proposed research o appropriateness and adequacy of the experimental approach and methodology proposed to carry out the research o qualifications and research experience of the Principal Investigator and staff, particularly, but not exclusively, in the area of the proposed research o availability of the resources necessary to perform the research The initial review group will also examine the provisions for the protection of human and animal subjects and the safety of the research environment. AWARD CRITERIA Applications will compete for available funds with all other approved applications. The following will be considered in making funding decisions: quality of the proposed project as determined by peer review, availability of funds, and program priority. Schedule Letter of Intent Receipt Date: September 15, 1996 Application Receipt Date: November 20, 1996 Initial Review: February/March 1997 Review by NHLBI Advisory Council: May 1997 Anticipated Award Date: July 1, 1997 INQUIRIES Inquiries concerning this RFA are encouraged. The opportunity to clarify any issues or questions from potential applicants is welcome. Direct inquiries regarding programmatic issues and requests for sample budget pages to: Sonia Skarlatos, Ph.D. Division of Heart and Vascular Diseases National Heart, Lung, and Blood Institute Two Rockledge Center, Suite 10186 6701 Rockledge Drive Bethesda, MD 20892-7956 Telephone: (301)435-0550 FAX: (301) 480-2848 Email: SKARLATS@GWGATE.NHLBI.NIH.GOV Direct inquiries regarding fiscal matters to: Mr. William Darby Grants Operations Branch National Heart, Lung, and Blood Institute Two Rockledge Center, Suite 7128 6701 Rockledge Drive Bethesda, MD 20892-7128 Telephone: (301)435-0177 FAX: (301)480-3310 Email: William_Darby@NIH.GOV AUTHORITY AND REGULATIONS This program is described in the Catalog of Federal Domestic Assistance No. 93.837. Awards are made under authorization of the Public Health Service Act, Title IV, Part A (Public Law 78-410, as amended by Public Law 99-158, 42 USC 241 and 285) and administered under PHS grants' policies and Federal Regulations 42 CFR 52 and 45 CFR Part 74. This program is not subject to the intergovernmental review requirements of Executive Order 12372 or Health Systems Agency review. The PHS strongly encourages all grant and contract recipients to provide a smoke-free workplace and promote the non-use of all tobacco products. In addition, Public Law 103-227, the Pro-Children Act of 1994, prohibits smoking in certain facilities (or in some cases, any portion of a facility) in which regular or routine education, library, day care, health care or early childhood development services are provided to children. This is consistent with the PHS mission to protect and advance the physical and mental health of the American people. .
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