GENETIC MODIFIERS OF SINGLE GENE DEFECT DISEASES Release Date: August 24, 2000 RFA: HL-01-001 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: January 18, 2001 Application Receipt Date: February 20, 2001 PURPOSE The objectives of this initiative are to stimulate research to identify and characterize the modifier genes responsible for variation in clinical progression and outcome of heart, lung and blood diseases due to single gene defects. Identification of the genes responsible for these differences would lead to better understanding of disease pathogenesis, early diagnosis, and improved treatment. 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), "Genetic Modifiers of Single Gene Defect Diseases," 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 or local governments, and eligible agencies of the Federal government. Racial/ethnic minority individuals, women, and persons with disabilities are encouraged to apply as Principal Investigators. 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 that is received in response to this RFA may not exceed five 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. Applicants from institutions that have a General Clinical Research Center (GCRC) funded by the NIH National Center for Research Resources may wish to identify the GCRC as a resource for conducting the proposed research. If so, a letter of agreement either from the GCRC program director or principal investigator should be included with the application. FUNDS AVAILABLE The National Heart, Lung, and Blood Institute (NHLBI) intends to commit approximately $10,000,000 total costs and National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) intends to commit approximately $1,000,000 total costs in FY 2001 to fund up to18 new grants in response to this RFA. An application may request a project period of up to five years. It is expected that applications will not exceed a budget of $500,000 in direct costs, excluding Facilities and Administrative costs on consortium arrangements, in the first year. Applications exceeding this budget cap must be appropriately justified. Annual increases in non-competing years are not allowed. 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 applications of appropriate scientific and technical merit. RESEARCH OBJECTIVES Background All diseases are variable in their presentation due to differences in the genetic makeup and the environmental exposure of the affected individual. For disorders inherited in a Mendelian fashion, a single gene plays the predominant role in the development of a disease phenotype. However, phenotype variation occurs even among those who have identical genotypes at a disease locus. To further our understanding of the molecular basis of monogenic disorders, it will be necessary to find other genes that contribute to phenotype variability. There are a number of heart, lung and blood disorders that are primarily due to alterations in a single gene. Examples include cystic fibrosis, alpha-1- antitrypsin deficiency, sickle cell disease, thalassemia, hemochromatosis, hemophilia, glucocorticoid remediable aldosteronism (GRA), Liddle=s Syndrome and other hypertensive conditions, as well as cardiac myopathies, dysplasias, and arrhythmias that result in Sudden Cardiac Death. Although individuals may have single gene defects, there can be tremendous variation in the progression, complications and outcome of the disease (even in an extended family) that may be due to the interaction of the disease gene with other genes, impacting on the final disease presentation. Defects in a single gene for cystic fibrosis transmembrane conductance regulator (CFTR) give rise to the disorder of CF, the nation’s number one genetic killer of children and young adults. A single nucleotide defect in the coding sequence gives rise to alpha-1-antitrypsin deficiency (AATD). However, increasing evidence suggests that these genes do not function alone in determining disease outcome. The severity of pulmonary disease can vary greatly among individuals, even with the identical mutations. Evidence suggests that this variation is due to the interaction of disease gene with other genes, impacting on the final disease presentation. Yet, relatively little is known about the identity of these genes and how other genes, distinct from the disease locus, modify the major gene involved in CF and AATD. The lack of a close correlation between the genotype and severity of pulmonary disease suggests that genetic determinants independent of the disease play a significant role in the development of the lung disease. Small-scale family studies of CF and AATD support the existence of modifiers for lung disease in humans. However, specific loci have not yet been identified. For CF, recent exploration of a potential candidate gene involved in the inflammatory and immune responses of the lung, e.g., mannose-binding lectin (MBL), showed a striking correlation between genetic variants that reduce the amount of this lectin and lung function in CF patients chronically infected with P. aeruginosa, survival rates, and median life expectancy among CF patients grouped according to MBL serum levels. A modifier gene for meconium ileus in CF has been localized to chromosome 19 and several candidate genes are being studied. Other manifestations of CF such as pancreatic insufficiency and degree of wasting may also be influenced by modifier genes. For AATD, evidence exists that co-inherited defects in the endoplasmic reticulum degradation make certain individuals susceptible to the development of the liver disease found in 12 to15 percent of AATD patients. These results confirm that genetic modifiers exist, and can be identified using current technologies. Sickle cell disease (SCD) is the earliest described and arguably best characterized disease at the molecular level. However, what is not well understood is the marked variability of the clinical manifestations. The clinical picture in some patients may be a devastating course of acute and chronic events, resulting in severe end organ damage, including pulmonary complications and stroke. However, in other patients, the disease may present with a relatively mild clinical phenotype and minimal morbidity. The cause of these differences is unclear and cannot be explained by the substitution of valine for glutamic acid at position 6 in the beta-globin chain, the common molecular link among all patients. A priori, both genetic and nongenetic factors are likely to modulate the severity of SCD, but the genetic factors are more amenable to study. There have been two case reports of undefined, non-genetic factors affecting the course of SCD in identical twins; however, a large twin study has not yet been done. On the genetic side, statistically significant correlations have been reported between beta-globin gene cluster polymorphisms (haplotypes), or co-inheritance of alpha-thalassemia, and SCD morbidity. Further support for the existence of genetic modifiers of SCD severity has come from investigations of various additional genetic factors, but especially those which determine fetal hemoglobin (Hb F) levels. In addition to this evidence for indirect genetic modifiers associated with Hb F levels, recent studies in progress have implicated other genetic factors, including polymorphisms in HLA genes related to stroke, and in MTHFR (5,10- methylene-tetrahydrofolate reductase) genes related to avascular necrosis. Thus, both genetic and non-genetic modifiers of SCD have been reported, and the relative importance of the two is presently unclear. However, if additional genetic modifiers could be identified with certainty, their ability to predict benign versus severe disease would clearly improve patient care. Hemochromatosis is a common inherited disease of iron overload that results from mutations in the HFE gene. Increased iron storage, particularly in the liver, leads to the clinical course of the disease, but the iron accumulation and the associated clinical presentation can be highly variable, even within one family. A recent population study found that only half of those who were homozygous for the major HFE mutation had clinical features of hemochromatosis, and others have reported an even smaller proportion of affected individuals with clinical signs of the disease. It appears most likely that genetic factors are involved in modifying the expression of the gene, although some environmental factors may have a role. Examples in Mediterranean populations of iron overload in which HFE coding sequences are normal indicate that genes other than HFE and/or HFE mutations may be responsible. A single mutation (C282Y) in HFE has been found to be responsible for the vast majority of clinical disease, so mutations in other genes must be involved, resulting in differences in iron loading. There is recent clinical evidence for hemochromatosis-modifying genes, but the identity of these genes is not known. The obvious candidate genes are those encoding proteins known to be important in iron transport, but it is not known to what degree variations in the iron transport genes contribute to the clinical presentation of hemochromatosis and other iron disorders. Although several important genes of iron transport have been identified in recent years, there may be others not yet discovered that impact on the expression of the HFE gene. Reportedly monogenic cardiovascular disorders (such as inheritable forms of hypertension, dilated and hypertrophic cardiomyopathies, arrhythmogenic dysplasias, atrial arrhythmias, and arrhythmias that contribute to Sudden Cardiac Death), show large differences in phenotypic expression and penetrance. Such conditions affect thousands of cardiac patients as well as many apparently asymptomatic individuals. In the case of mutations associated with familial hypertension, many of the primary defects occur in genes involved in the regulation of renal Na transport and in its hormonal regulators (aldosterone, vasopressin, angiotensin, etc.). Modifying factors or genes that define vulnerability to the primary defect in these conditions may be particularly important in mediating end-organ injury. Similarly, many of the genetically variable forms of hypertrophic and dilated cardiomyopathies are associated with primary defects in at least eight different genes which code for sarcomeric contractile proteins, but modifier genes alter clinical outcome here as well. Although the genes for arrhythmogenic dysplasia and atrial arrhythmias have not been identified, many of those cases that map to single chromosomal sites have widely disparate degrees of penetrance. Hundreds of mutations in the coding regions for at least six genes determining structural subunits for Na and K ion channels have been implicated in causing inherited ventricular arrhythmias, such as the congenital Long QT Syndromes, and the impact of many of these on channel function has been examined at a molecular level and in transgenic mice. Despite functional similarity at these levels, there is considerable divergence in how these mutations affect in vivo cardiac electrophysiology in affected individuals within the same family, and differing degrees of penetrance between different affected families with the same identical mutation. For example, different mutations within the same exon and domain of one gene (i.e., the SCN5A Na channel alpha subunit), have been linked to three quite distinct cardiac disorders (i.e., LQT-3 Syndrome, idiopathic ventricular fibrillation and primary cardiac conduction disease or Lev’s syndrome), each of which results in a different electrical phenotype. This degree of allelic and genetic heterogeneity is likely to involve a number of as yet unidentified genetic and environmental modifiers and interactions (e.g., in pathways of autonomic renal control), subject to independent variation. The genes responsible for a variety of inherited heart, lung and blood disorders have been identified using functional and positional approaches. Now the difficult process of finding the modifier genes and their relevant mutations must be undertaken. The number of biologically plausible candidate genes may be very large. As such, the search for genetic modifiers of Mendelian disorders will be similar to studies of complex genetic disorders such as asthma or hypertension. Association studies utilizing reasonable candidate genes or candidate loci offer valuable approaches to facilitate efforts to find the genes. The completion of the human genome project and the development of high-throughput technologies such as "gene chip" and streamlined SNP (single nucleotide polymorphism) analyses should greatly facilitate the search for genes that contribute to disease variability. The identification and characterization of modifier genes will clarify the process of pathophysiology, enable more accurate prognosis, early diagnosis, and may provide novel, and possibly, more accessible therapeutic targets, that are more useful than the gene primarily involved in causing the disease. Research Scope This initiative is intended to solicit applications to identify the modifier gene or genes responsible for variation in the clinical progression and outcome of heart, lung, and blood diseases known to be due to single gene defects (using state-of-the-art approaches including, but not limited to, genetic mapping, positional candidate cloning, positional cloning to narrow the region, computer cloning, and genomic technologies), to characterize the allelic variants of the gene(s) identified, and to demonstrate that the variation in the gene(s) is responsible for phenotype variation. Applicants must be able to demonstrate the availability of well-characterized families and/or well-defined genetic animal models of single gene disorders in whom some aspect of phenotype variability has been demonstrated to be inherited independent of the disease-causing gene. Some research topics that will be responsive to this program are listed below. These are only examples; applicants are encouraged to propose other topics that address the overall goals of this initiative. The following are examples of research areas relevant to the objectives of this RFA: o Loci containing a modifier gene or genes have been mapped to multiple regions of the genomes of humans and animal models. Studies are now needed to identify specific polymorphisms in candidate genes that lie within these linkage regions. Although it will likely be prudent to begin examining intuitive candidates within linkage regions, this approach can greatly bias the results and potentially lead to exclusion of important genes. Thus investigators should consider combining new high throughput technologies such as "gene chip" approaches and rapid SNP analyses with the more traditional approaches. Recent advances in molecular techniques such as "gene chip technology" have provided considerable power and speed in identification of differentially expressed genes. Functional genomic approaches (using cDNA and oligonucleotide arrays) to identify differentially expressed genes, combined with classic genetic analysis and positional candidate approaches, can significantly enhance gene discovery efforts. o A variety of animal models have advanced our understanding of the pathogenesis of single gene disorders. As genetic studies of animal models have yielded important insight into the mechanisms underlying these disease states, it is likely that they will be equally useful in the identification and characterization of modifier genes. Numerous murine strains, with well- defined genomes that exhibit a high degree of homology with the human genome, have considerable potential to provide insights into the presence and location of modifier genes. Thus, studies that explore the genetic basis of phenotype variation in animal models of monogenic human diseases are needed. o Identification of genetic modifiers in humans can be facilitated by detailed study of genetically related individuals. Analysis of concordant and discordant traits among affected family members can point to genetically determined aspects of phenotype variability. Studies of this type require the collection and characterization of sufficient numbers to afford statistical power. Thus, collaborative arrangements that facilitate the formation or extension of patient registries for the purpose of modifier gene identification are needed. o Variation in proteins involved in molecular pathways affected by the dysfunction of a disease-causing gene are likely to influence pathogenesis. Critical members of a particular pathway may be excellent candidate modifier genes. The identification of naturally occurring and biologically relevant variants in these candidates, and demonstration of their contribution to alteration in pathways affected in a monogenic disease would support their candidacy as modifier genes. Thus, in addition to human studies, in vitro and/or animal studies could be used to explore the functional contribution of various candidate genes to phenotype variation in monogenic disorders. o Even in the case of monogenic diseases, evidence suggests that the interactions of multiple genes result in expression of specific disease traits. Once polymorphisms relevant to phenotype have been identified in a modifier gene or genes, efforts should be directed at assessing interactions between the disease-causing gene and the modifiers. o Genotype/phenotype studies reveal the degree to which disease severity can be attributed to allelic differences. In certain monogenic disorders, the strength of the correlation between presentation and mutation varies by organ system, suggesting that gene-environment interactions may play a significant role in predisposition to this disease. Thus, studies to assess these gene- environment interactions are also needed. THESE ARE EXAMPLES ONLY. INVESTIGATORS SHOULD NOT FEEL LIMITED TO THE SUBJECTS MENTIONED ABOVE AND ARE ENCOURAGED TO SUBMIT OTHER TOPICS PERTINENT TO THE OBJECTIVES OF THE RFA. SPECIAL REQUIREMENTS To be responsive to this RFA, applications must demonstrate the availability of well-characterized families and/or well-defined animal models with a monogenic disorder where the correlation between genotype at the disease locus and phenotype has been explored in depth. Studies of the genetic basis of phenotype variation in animal models are responsive to this RFA; however, applicants who propose to conduct genetic studies using animal models must demonstrate their usefulness in gaining insights into modifiers of the human phenotype. Additional studies designed to extend and validate findings in human disorders are particularly encouraged. Human studies are especially solicited, but must be designed with sufficient statistical power to address the hypothesis being tested. The use of existing registries and /or repositories of biological samples from well-characterized patients is encouraged. Applicants wishing to pursue studies related to rare diseases are encouraged to form consortium arrangements with collaborating institutions, in order to have adequate statistical power for their studies. Focused clinical and epidemiologic studies that address a specific aspect of phenotype variability, and facilitate the identification of modifier genes of Mendelian disorders relevant to heart, lung, and blood diseases, are within the scope of this RFA. Upon initiation of the program, the NHLBI 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 the same patient population or animal models to avoid unnecessary duplication and to expedite modifier gene discovery efforts. Travel funds should be included in the modules for two people (the Principal Investigator and one co- investigator from the grant) to attend a one day meeting two times 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 genetic 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 the NIH that children (i.e., individuals under the age of 21) must be included in all human subjects research, conducted or supported by the NIH, unless there are scientific and ethical reasons not to include them. This policy applies to all initial (Type 1) applications submitted for receipt dates after October 1, 1998. All investigators proposing research involving human subjects should read the "NIH Policy and Guidelines on the Inclusion of Children as Participants in Research Involving Human Subjects" that was published in the NIH Guide for Grants and Contracts, March 6, 1998, and is available at the following URL address: 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. 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 a letter of intent that includes a descriptive title of the proposed research, the name, address, and telephone number of the Principal Investigator, the identities of other key personnel and participating institutions, and the number and title of the RFA in response to which the application may be submitted. Although a letter of intent is not required, is not binding, and does not enter into the review of subsequent applications, the information that it contains allows NHLBI staff to estimate the potential review workload and plan the review. The letter of intent is to be faxed or mailed to Dr. Deborah Beebe at the address listed under INQUIRIES by January 18, 2001. 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, e-mail:GrantsInfo@nih.gov. The RFA label found 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 CSR and responsiveness by NHLBI. Incomplete and/or non-responsive applications will be returned to the applicant without further consideration. Applications that are complete and responsive to 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 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 the research 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 that may be adversely affected by the project proposed in the application. The initial review group will also examine the provisions for the protection of human subjects and the safety of the research environment. The personnel category will be reviewed for appropriate staffing based on the requested percent effort and justification provided. The direct costs budget request will be reviewed for consistency with the proposed methods and specific aims. The duration of support will be reviewed to determine if it is appropriate to ensure successful completion of the requested scope of the project. Schedule Letter of Intent Receipt Date: January 18, 2001 Application Receipt Date: February 20, 2001 Peer Review Date: June/July 2001 Council Review: September 6-7, 2001 Earliest 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 encouraged. The opportunity to clarify any issues or questions from potential applicants is welcome. Direct inquiries regarding programmatic issues to: Pulmonary: Susan Banks-Schlegel, Ph.D. Division of Lung Diseases National Heart, Lung, and Blood Institute 6701 Rockledge Drive, Room10018, MSC 7952 Bethesda, Maryland 20892-7952 Telephone: (301) 435-0202 FAX: (301) 480-3557 E-mail: SchlegeS@ nih.gov Extrapulmonary CF: Catherine McKeon, Ph.D. Division of Diabetes, Endocrinology and Metabolic Diseases National Institute of Diabetes and Digestive and Kidney Diseases 6707 Democracy Blvd Room 6103, MSC 5460 Bethesda, Maryland 20892-5460 Telephone: (301) 594-8810 FAX: (301) 480-3503 E-mail: Catherine.McKeon@nih.gov Hematology: 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 Cardiovascular: Peter Spooner, Ph.D. Division of Heart and Vascular Diseases National Heart, Lung, and Blood Institute 6701 Rockledge Drive, Room 9192, MSC 7940 Bethesda, Maryland 20892-7940 Telephone: (301) 435-0504 FAX: (301) 480-1454 E-mail: SpoonerP@ nih.gov Direct inquiries regarding review matters and address the letter of intent to: Deborah Beebe, Ph.D. Division of Extramural Affairs National Heart, Lung, and Blood Institute 6701 Rockledge Drive, Room , 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: Tanya McCoy Division of Extramural Affairs National Heart, Lung, and Blood Institute 6701 Rockledge Drive, Room 7154, MSC 7926 Bethesda, MD 20892-7926 Telephone: (301) 435-0171 FAX: (301) 480-3310 E-mail: McCoyT@ nhlbi.nih.gov AUTHORITY AND REGULATIONS This program is described in the Catalog of Federal Domestic Assistance, No. 93.838, 93.847, and 93.849. 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 and 92. This program is not subject to the intergovernmental review requirements of Executive Order 12372 or a Health Systems Agency Review. The PHS strongly encourages all grant 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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