DEVELOPMENTAL PROCESSES IN DIFFERENTIAL EXPRESSION OF GLOBIN GENES Release Date: April 30, 1998 PA NUMBER: PAS-98-060 P.T. National Institute of Diabetes and Digestive and Kidney Diseases National Heart, Lung, and Blood Institute PURPOSE The National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) and the National Heart, Lung and Blood Institute (NHLBI) invite investigators to submit research grant applications to pursue basic investigations into the developmental processes involved in the differential expression of globin genes. Applications from new investigators and investigators in training are particularly encouraged. HEALTHY PEOPLE 2000 The Public Health Service (PHS) is committed to achieving the health promotion and disease prevention objectives of "Healthy People 2000," a PHS-led national activity for setting priority areas. This PA, Developmental Processes In Differential Expression Of Globin Genes, is related to the priority area of chronic disabling diseases. 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 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 Support of this program will be through the National Institutes of Health (NIH) research project grant (R01) and exploratory/developmental grant (R21) support mechanisms. The direct costs per year for each R21 application must not exceed $75,000. The total project period for an R21 application funded in response to this PA may not exceed two years and is not renewable. The Exploratory/Developmental (R21) research grant program provides limited funds for short-term research projects. These R21 grants provide an opportunity for initiating studies that may be preliminary in nature. Research investigators in relevant fields are invited to apply for R21 grants in order to develop preliminary data that could form the basis of future research project grant (R01) applications. Applications 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 from either the GCRC program director or principal investigator should be included with the application. FUNDS AVAILABLE A total of $2.0 million in total cost will be committed by each of the participating Institutes to fund applications of high scientific merit submitted in response to this Program Announcement. Because the nature and scope of the research proposed in response to this PA may vary, it is anticipated that the size of an award will vary also; however, the support of requests exceeding the NIH average size of $160,000 direct cost for R01 grants would be unusual and would require ample justification. Although this program is provided for in the financial plans of the NIDDK and the NHLBI, the award of grants pursuant to this PA is contingent upon the availability of funds for this purpose. RESEARCH OBJECTIVES Background Mutations in the globin gene cluster are among the most common inherited diseases in humans, leading to disorders that affect many individuals in the U.S. and around the world, such as sickle cell anemia and thalassemia (Cooley's anemia). Treatment for these disorders eventually may include both pharmaceutical agents and gene therapy. Some therapeutic approaches currently being studied are based on the fact that a number of naturally occurring mutations, such as HPFH and delta beta-thalassemia, are associated with significantly elevated levels of fetal hemoglobin (Hb F) in adult RBC. This increase in Hb F can be therapeutically beneficial, and modifies the clinical severity of hemoglobinopathies associated with abnormal or deficient beta globin chains. A number of experimental drugs have been used successfully in some patients to increase the level of fetal hemoglobin in adults and some children. These studies have established the feasibility of this therapeutic approach to diseases with abnormal beta-globin production including sickle cell anemia and beta- thalassemia. However, not all patients respond to these treatments, their applicability to other disorders is not established, and the molecular and cellular basis for their mode of action remains unclear. Hence further advances are needed to broaden the range of possible therapeutic strategies for disorders of globin synthesis. The elucidation of precise molecular mechanisms responsible for increased Hb F production in these disorders could lead to the development of novel future therapeutic approaches to treat hemoglobinopathies. In addition, studies of the developmental- and tissue-specific control of the globin gene cluster are important for optimizing gene transfer, via viral or chemical vectors, for gene replacement therapy. In the last decade, the DNA of the human alpha- and beta-globin gene clusters have been fully mapped and sequenced. Similar work has been done for a number of other species that serve as model systems. The basic control of globin gene expression at the transcriptional level, as controlled by proximal promoters, and at post-transcriptional levels has partially been elucidated. In addition, a number of important trans-acting factors and the cis-acting DNA sequences with which they interact have been described. These include the GATA family, EKLF, and other DNA-binding proteins. Studies using transfection assays and transgenic and knockout methods have partially clarified mechanisms of transcriptional control, including reciprocal gamma- and beta-globin gene interactions. Other mechanisms including RNA splicing processes, mRNA stabilizing elements and other post- transcriptional mechanisms also have been studied. Recent studies have shown that the locus control region (LCR) is a dominant regulator of many aspects of globin gene expression. LCRs are key genetic regulators that place large sub-elements of chromosomes under a common control, and hence allow chromosomal regions with distinct functions to be differentially regulated. There is a fundamental need to clarify fully the elements involved in the regulation of the expression of globin genes through its LCR. In addition to the benefits of this knowledge to disorders of hemoglobin production, this system may serve as a model for advances in understanding the coordinate regulation of other chromosomal gene clusters, and to answer fundamental questions about chromatin structure and regulation of gene expression. Research into the globin LCR is anticipated to expand our understanding of large-scale chromosomal regulatory mechanisms operational over much of the genome. The nature and extent of interactions between the cis-acting sequences in the proximal promoter and their trans-acting factors of the individual globin genes and distal elements including the LCR remain controversial. Mechanisms for interaction or communication between distal elements and these promoters have not been established definitively, nor has the mechanism of interaction of these control regions with the transcription initiation complex been studied in any detail. The way in which cell cycle control, erythroid cell differentiation and pharmacological agents, such as hydroxyurea, affect globin gene expressions also are poorly understood. In addition to its fundamental importance, studies in this area are anticipated to contribute to design of approaches to expand the erythroid compartment in bone marrow or to expand erythroid precursors in vitro and to promote their appropriate differentiation. The linkage between erythroid cell differentiation and globin gene control needs further study. The temporal processes dictating globin gene expression and the mechanisms for the developmental timetable are important unresolved issues in erythropoiesis of relevance to this initiative. Research Goals and Scope The purpose of this program announcement is to stimulate new avenues of research into the developmental processes involved in the differential expression of globin genes. Applications from new investigators and investigators with relevant expertise in other fields are encouraged. The areas of research within this program announcement include, but are not restricted to: (1) Determine the chromatin structure associated with the active and repressed (or silenced) states of the globin genes; (2) Study the interaction of the LCR and other distal elements with the promoter and transcription initiation complex of the individual globin genes; (3) Determine the enzymatic activities needed for the structural transitions of the chromatin associated with the active and repressed states of the globin genes, and the proteins needed to maintain those states; (4) Identify and characterize trans-acting factors and other proteins involved in the developmental regulation of the globin genes; (5) Characterize post-transcriptional mechanisms that may control developmental control of globin genes; (6) Examine the relevance of cell cycle control in erythroid differentiation and globin gene expression; (7) Study molecular and cellular mechanisms, operative in various high HbF syndromes, that can modulate the production of HbF in all cells or increase the number of circulating red cells that contain HbF (so-called F-cells); (8) Determine the mechanism of action of drugs, such as hydroxyurea and butyrate, that affect HbF levels; (9) Develop new technological approaches to examine the mechanism of globin gene regulation, especially with regard to the LCR, and new in vivo and in vitro assays; (10) Identify non-globin-linked genes that may affect the expression of the gamma gene; (11) Study the linkage between erythroid cell differentiation and the developmental control of the globin genes; (12) Develop new model systems to study globin gene regulation. In applying for support under this announcement, investigators are encouraged to present other research ideas not suggested above. 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 is provided that inclusion is inappropriate with respect to the health of the subjects or the purpose of the research. This policy results from the NIH Revitalization Act of 1993 (Section 492B of Public Law 103-43). All investigators proposing research involving human subjects should read the "NIH Guidelines For Inclusion of Women and Minorities as Subjects in Clinical Research," which have been published in the Federal Register of March 28, 1994 (FR 59 14508-14513) and in the NIH Guide for Grants and Contracts, Volume 23, Number 11, March 18, 1994. Investigators may obtain copies of the policy from the program staff listed under INQUIRIES. Program staff also may provide additional relevant information concerning the policy. NIH POLICY AND GUIDELINES ON THE 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://www.nih.gov/grants/guide/notice-files/not98-024.html APPLICATION PROCEDURES Applications are to be submitted on the grant application form PHS 398 (rev. 5/95) and will be accepted at the standard application deadlines as indicated in the application kit. Application kits are available at most institutional offices of sponsored research and may be obtained 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: asknih@od.nih.gov. The program announcement 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 completed original application and five legible copies must be sent or delivered 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) REVIEW CONSIDERATIONS Applications will be assigned on the basis of established Public Health Service referral guidelines. Applications that are complete 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 appropriate national advisory council or board. Review Criteria The goals of NIH-supported research are to advance our understanding of biological systems, improve the control of disease, and enhance health. The reviewers will comment on the following aspects of the application in their written critiques 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 by the reviewers 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 a 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? The initial review group also will examine: the appropriateness of proposed project budget and duration; the adequacy of plans to include both genders, minorities and their subgroups, and children as appropriate for the scientific goals of the research and plans for the recruitment and retention of subjects; 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: o Quality of the proposed project as determined by peer review o Availability of funds o Program priority. INQUIRIES Inquiries concerning this PA are encouraged. The opportunity to clarify any issues or questions from potential applicants is welcome. Inquiries regarding programmatic issues may be directed to: David G. Badman, Ph.D. Division of Kidney, Urologic and Hematologic Diseases National Institute of Diabetes and Digestive and Kidney Diseases 45 Center Drive, Room 6AS-13C MSC 6600 Bethesda, MD 20892-6600 Telephone: (301) 594-7717 FAX: (301) 480-3510 Email: David_Badman@nih.gov Helena O. Mishoe, Ph.D. Division of Blood Diseases and Resources National Heart, Lung and Blood Institute 6701 Rockledge Drive, Room 10156 Bethesda, MD 20892-7950 Telephone: (301) 435-0050 FAX: (301) 480-0868 Email: hm31y@nih.gov Inquiries regarding fiscal and administrative matters may be directed to: Aretina D. Perry-Jones Division of Extramural Activities National Institute of Diabetes and Digestive and Kidney Diseases 45 Center Drive, Room 6AN-38 - MSC 6600 Bethesda, MD 20892-6600 Telephone: (301) 594-8862 FAX: (301) 480-3504 Email: PerryA@extra.niddk.nih.gov Ms. Jane R. Davis Grants Management Office National Heart, Lung and Blood Institute 6701 Rockledge Drive, MSC 7926 Bethesda, MD 20892-7926 Telephone: (301) 435-0166 FAX: (301) 480-3310 Email: jane_davis@nih.gov AUTHORITY AND REGULATIONS This program is described in the Catalog of Federal Domestic Assistance Nos. 93.849 and 93.839. Awards will be made under authority 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.
Return to NIH Guide Main Index
Office of Extramural Research (OER) |
National Institutes of Health (NIH) 9000 Rockville Pike Bethesda, Maryland 20892 |
Department of Health and Human Services (HHS) |
||||||||
Note: For help accessing PDF, RTF, MS Word, Excel, PowerPoint, Audio or Video files, see Help Downloading Files. |