Full Text HL-97-004 RAT GENE CATALOG AND EXPRESSED SEQUENCE TAG (EST) MAP NIH Guide, Volume 26, Number 5, February 14, 1997 RFA: HL-97-004 P.T. 34 Keywords: Aging/Gerontology Behavioral/Social Studies/Service National Heart, Lung and Blood Institute National Human Genome Research Institute National Cancer Institute National Institute of Mental Health National Institute of Child Health and Human Development National Institute of Diabetes and Digestive and Kidney Diseases National Institute on Drug Abuse National Institute on Alcohol Abuse and Alcoholism National Institute on Deafness and Other Communication Disorders National Institute of Dental Research National Institute of Environmental Health Sciences National Institute of Neurological Disorders and Stroke Letter of Intent Receipt Date: March 28, 1997 Application Receipt Date: April 23, 1997 PURPOSE The purpose of this Request for Applications (RFA) is to expand the Rat Genome Project by soliciting applications for research projects to accomplish three objectives: 1) arraying and distributing existing rat cDNA libraries, 2) developing Expressed Sequence Tags (ESTs) from those libraries, and 3) mapping a subset of those ESTs. The overall goal of this effort is to construct a rat gene catalog and an EST map that will facilitate the mapping of genes in the rat and increase the value of the rat as a biomedical research model. 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 RFA, Rat Gene Catalog And Expressed Sequence Tag (EST) Map, is related to many priority areas. 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 for-profit and non-profit organizations, public and private, such as universities, colleges, companies, hospitals, laboratories, units of State and local governments, and eligible agencies of the Federal Government. Applications from social/ethnic minority individuals, women, and persons with disabilities are encouraged. Applications from foreign institutions will not be accepted. However, subcontracts to foreign institutions are allowable, with sufficient justification. MECHANISM OF SUPPORT This RFA will use the National Institutes of Health (NIH) individual research project grant (R01) mechanism. Applications that address any one or all of the objectives listed above are encouraged. Because the NIH wishes to retain maximum flexibility in organizing the best possible overall program, it is possible that, in the case of an application proposing to accomplish more than one objective, only one component would be funded. Therefore, applicants who propose to address more than one of the objectives should organize the application in individual sections, each of which describes the approach proposed for a single objective; individual budgets should also be proposed for each objective. A summary budget for the entire application must also be included and the cover page should state the total funds requested (direct and total costs). All investigators funded under this initiative will be expected to work together cooperatively so that resources developed will be of maximum usefulness to the community. This RFA is an initiative of the Institutes listed above. However, the awards will be made by the National Heart, Lung, and Blood Institute (NHLBI) and will be managed by the NHLBI with the National Human Genome Research Institute (NHGRI) and the other participating Institutes. FUNDS AVAILABLE $3.5 million (including direct and indirect costs) is available for year -01. Anticipated funds available for year -02 are between $1.2 and $2.5 million. An exact dollar figure will be provide to those applicants that submit a letter of intent. It is anticipated that three to six awards may be made. Proposed funding levels are subject to change due to budgetary, administrative, and/or scientific considerations. RESEARCH OBJECTIVES Background The rat is an important experimental model for studying many human diseases, such as hypertension, cancer, behavioral disorders, diabetes, drug abuse, alcoholism, cranio-facial and dental disorders, and obesity. As a result, the existing body of knowledge about physiological mechanisms in this animal is large and the advantages include the ease of breeding, and the ability to generate inbred congenic rat strains. Because of its large size, the rat is preferred to the mouse for studies of anatomy, physiology and pharmacology. Examples include studies of the chemical senses and of intricate neuronal pathways in the brain. In 1995, a consortium of NIH Institutes and Centers funded a four- year Rat Genome Project, the purpose of which is to construct genomic resources that will enhance genetic studies of the rat. The goals of the Rat Genome Project are 1) to construct a 6,000 marker genetic map of the rat genome, 2) to produce physical mapping reagents that will be useful for both isolating rat genes and for constructing a physical map of the rat genome, and 3) to construct cDNA libraries from different rat tissues. This project has made significant progress to date. An early-stage genetic map has been constructed (the first 1,250 markers and a framework map will be released by the Whitehead Institute Genome Science and Technology Center in March, 1997), rat YAC and PAC libraries have been constructed, and twelve normalized cDNA libraries are nearing completion. In addition to these resources, a radiation hybrid panel for the rat has been prepared by a European consortium and is also available commercially. While the genetic and physical map resources currently being constructed will be extremely useful to investigators using the rat as a model to study human diseases, isolating rat genes of relevance to a particular disease is still not routine and investigators pursuing such efforts would benefit from additional resources. As there are no current plans to sequence the entire rat genome, constructing an index of a significant number of genes, and determining the map positions of as many as possible, would greatly increase the usefulness of the rat as a model system for studying human disease, health and behavior. A useful approach to constructing such a gene catalog and map has been demonstrated for the human genome. Schuler et al., (Science 274:540 (1996)) recently used a catalog of human genes to construct a map of more than 16,000 of them. These genes were identified using short sequences called Expressed Sequence Tags (ESTs) from cDNA clones. The present RFA seeks to support a similar project in the rat. Not only will sequencing rat ESTs lead to the identification of a significant number of new genes from this organism, but because of the synteny between the rat genome and both the human and the mouse genomes (a mouse EST project has also recently begun), comparisons of the gene maps from all three organisms will add to the usefulness of the information on each. Objectives and Scope There are three objectives of this RFA. The first is to array and distribute, rapidly, efficiently and at low cost, the twelve normalized cDNA libraries that have been produced by the Rat Genome Project. The second is to produce ESTs from rat cDNA, and the third is to construct a gene EST map, including a framework of existing genetic markers. Arraying and distribution of cDNA libraries Twelve normalized rat cDNA libraries are being prepared by Dr. Bento Soares at Columbia University. In order to increase the usefulness of these libraries to the research community and to readily provide the cDNAs to EST sequencing and mapping projects, the cDNA clones need to be arrayed and distributed. Applications are sought to array the cDNA clones and to establish a distribution mechanism to provide unrestricted access to both individual clones and to the arrayed libraries. Applicants may contact Dr. Soares (e-mail: cuc@cuccfa.ccc.columbia.edu or (212)960-2313) regarding access to the existing libraries. Rat EST Sequencing The strategy of sequencing short sequences from cDNAs in order to identify human genes was first demonstrated by Venter and his colleagues (Adams et al., Science 252:1651 (1991)). A large collection of human ESTs has now been deposited in public databases. cDNAs in current libraries are not full-length, but as a rule represent only a portion of the gene from which they were derived. As a result, multiple clones in a library can be derived from the same gene. Therefore, the sequence fragments in the existing EST collection have to be analyzed to identify clusters or distinct genes. The product of this effort is the unique set or human gene catalog (Schuler et al., Science 274:540 (1996)). Sequence from the 3' end of each cDNA to be mapped was converted to a gene-specific sequenced tagged site (STSs) for mapping. As EST projects in other organisms have begun, there has been discussion about the value of using a combination of sequencing strategies, i.e., sequencing more 5' than 3' ends of clones or sequencing complete clone inserts, in order to most efficiently identify as many genes as possible. To create a gene catalog for the rat, applicants are free to propose the sequencing of 5' ends of clones only, 3' ends of clones only, both 5' and 3' ends of clones, full-length inserts or any combination of these elements of clones from the rat cDNA libraries. Rationale should be offered for the choice of strategy. Applicants are encouraged to propose the most efficient and cost-effective strategy that will contribute the largest number of genes to the rat gene catalog. Rat EST Map As stated above, a rat genetic map is currently under construction at the Whitehead Institute GESTEC Center (http:\\www-genome.wi.mit.edu). A rat YAC library has been constructed and is available from Research Genetics, Inc. (http:\\www.resgen.com), a rat PAC library is available from Pieter De Jong at Roswell Park Cancer Institute (e- mail: pieter@dejong.med.buffalo.edu or (716) 845-8449). Additionally, DNA from cells in a radiation hybrid panel will shortly be available from Research Genetics, Inc. Applications are sought for projects that will use these, or other physical mapping resources, to construct a gene map of the rat genome. In order for the map to be cross-referenced to the emerging genetic map, and to provide markers in regions of low gene density, it is desirable for applicants to build the gene map on a framework of rat genetic markers. Efficient, cost-effective strategies for constructing the most useful physical map, which need not include mapping all of the ESTs, are sought. This RFA does not specify the number of ESTs that should be sequenced or mapped or the strategy for EST/cDNA sequencing. Rather, the investigator should propose a strategy that will balance the sequencing and mapping objectives with the funds available to produce the most useful resource for the community of researchers using the rat as a model organism. As mentioned above, a proposal may address one or more than one of the objectives of this RFA, e.g., only sequencing or both sequencing and mapping. In each case, the level of sequencing and/or mapping proposed must be justified in terms of the usefulness of the resource it will provide for researchers. Each objective of this RFA will be considered individually by the NIH, which will select for funding those applications that, as a group, will have the greatest potential to yield the best, most efficient and most cost-effective strategy for accomplishing the aim of each objective and to work together to meet the overall objectives of the Rat Genome Program. In the rapidly advancing field of genomic research, it is prudent to anticipate that improved technology might greatly decrease the costs of either sequencing or mapping (or both) during the course of the effort. Applicants should address the impact that changes in technology might have on the throughput and costs proposed. Data and Resource Sharing The sharing of materials and data in a timely manner has been an essential element in the rapid progress made in construction and use of the human, mouse and rat genetic maps. Public Health Service (PHS) policy requires that investigators make the results and accomplishments of funded activities publicly available. The advisors to the NIH and the DOE genome programs have developed a set of "NIH-DOE Guidelines for Access to Mapping and Sequencing Data and Material Resources" (available at http:\\www.nchgr.nih.gov/grants_info/funding/statements/ data_release.html) that address the special needs of genome research. Those guidelines call for material and information from genome research to be made available within six months of the time the data or materials are generated; more rapid sharing is encouraged and has become the norm in the genome community. Applications submitted in response to this RFA should include detailed plans for sharing data and materials generated through the grant. Where appropriate, grantees may work with the private sector in making unique resources available to the larger biomedical research community at a reasonable cost. The plans proposed for sharing and data release will be reviewed for adequacy by NIH staff prior to award of the grant and the proposed sharing plan will be made a condition of the award. Investigators may request funds to defray the costs of sharing materials or submitting data in their application. Such requests must be adequately justified. POST-AWARD MANAGEMENT During the course of the grant period, technologies will improve, genomic technologies will evolve, and the rate of progress and focus of work supported by the grant(s) may change. It is expected that the Principal Investigator(s) will make any necessary adjustment in scientific direction to accommodate the changing environment. In order to ensure that the project(s) remains focused on appropriate goals, maintains excellent coordination with the other projects funded under this RFA, incorporates new technological advances and makes sufficient progress, scientific and programmatic visits to the grantees will be conducted at a frequency to be negotiated with the awardees. In addition, applications should include travel funds for the P.I. and the other key investigators in the grant to meet annually with NIH staff in the Washington D.C. area. LETTER OF INTENT Prospective applicants are asked to submit, by March 28, 1997, 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. Any applicant planning to submit an application for more than $500,000 direct cost in any one year must contact the NHLBI staff listed under the INQUIRIES section in order for the application to be accepted by NIH. 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 Institute 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: James C. Scheirer, Ph.D. Division of Extramural Affairs National Heart, Lung, and Blood Institute 6701 Rockledge Drive, Room 7220 - MSC 7924 Bethesda, MD 20892-7924 Telephone: (301) 435-0266 FAX: (301) 480-3460 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. Applications 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 301/435-0714, email: ASKNIH@odrockm1.od.nih.gov; and from the program administrator listed under INQUIRIES. The RFA label available in the PHS 398 (rev. 5/95) 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. Submit a signed, typewritten original of the application, including the Checklist, and three signed, photocopies, in one package to: DIVISION OF RESEARCH GRANTS NATIONAL INSTITUTES OF HEALTH 6701 ROCKLEDGE DRIVE, SUITE 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 also be sent to Dr. James Scheirer, as listed under the LETTER OF INTENT section. Applications must be received by April 23, 1997. 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 Upon receipt, applications will be reviewed for completeness by DRG and for responsiveness to the RFA by NIH program staff. Incomplete applications will be returned to the applicant without further consideration. If the application is not responsive to the RFA, NIH staff will contact the applicant to determine whether to return the application to the applicant or submit it for review in competition with unsolicited applications at the next review cycle. Those applications that are complete and responsive will be evaluated in accordance with the criteria stated below for scientific/technical merit by an appropriate peer review group convened by the NHLBI and the NHGRI. As part of the initial merit review, a process may be used by the initial review group in which applications will be determined to be competitive or non-competitive based on their scientific merit relative to other applications received in response to the RFA. Applications judged to be competitive will be discussed and be assigned a priority score. All applicants will receive a summary statement consisting of the reviewer's written comments essentially unedited. Summary Statements for competitive applications will also contain a summary of the review committee's discussion. The second level of review will be provided by the National Heart, Lung, and Blood Advisory Council and by the National Advisory Councils/Boards of the other Institutes involved. Review criteria will include the following: o scientific and technical merit of the research proposed to meet the objectives of this RFA; o the value of the proposed resource to the scientific community; 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 and technology necessary to perform the research; o adequacy of facilities and resources and the level of institutional commitment; o appropriateness of the proposed budget and duration in relation to the proposed research. AWARD CRITERIA The anticipated date of award is September 30, 1997. Factors that will be used to make award decisions are as follows: o Quality of the proposed project as determined by peer review; o Promise of the proposed program to accomplish the goals of this RFA and address the need of the participating Institutes as regards their interest in the rat as a model organism; o Cost effectiveness of the proposed strategy; o Quality of the plans to cooperate with other projects that may be funded under this RFA; o Nature and extent of the plans for sharing and distributing data and resources in a timely manner; o Availability of funds. 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: Stephen C. Mockrin, Ph.D. or Susan E. Old, Ph.D. Division of Heart and Vascular Diseases National Heart, Lung, and Blood Institute 6701 Rockledge Drive, MSC 7940 Bethesda, MD 20892-7940 Telephone: (301) 435-0477 FAX: (301) 480-1336 Email: sm60d@nih.gov or so40y@nih.gov Jane L. Peterson, Ph.D. Large Scale Sequencing National Human Genome Research Institute Building 38A, Room 610 - MSC 6050 Bethesda, MD 20892-6050 Telephone: (301) 496-7531 FAX: (301) 480-2770 Email: petersoj@odder.nchgr.nih.gov Grace L. Shen, Ph.D, Hematology and Oncology for Extramural Program National Cancer Institute 6130 Executive Boulevard, Room 501, MSC 7381 Rockville, MD 20892-7531 Telephone: (301) 496-7815 FAX: (301) 496-8656 Email: gs35r@nih.gov Ljubisa Vitkovic, Ph.D. Division of Neuroscience and Behavioral Science National Institute of Mental Health 5600 Fishers Lane, Room 11C-06 Rockville, MD 20857 Telephone: (301) 443-5288 FAX: (301) 443-4822 Email: vitkovic@helix.nih.gov Steven L. Klein, Ph.D. Developmental Biology, Genetics and Teratology Branch National Institute of Child Health and Human Development 6100 Executive Boulevard, Room 4B01, (MSC 7510) Bethesda, MD 20892-7510 Telephone: (301) 496-5541 FAX: (301) 402-4083 Email: kleins@hd01.nichd.nih.gov Joan T. Harmon, Ph.D. Division of Diabetes, Endocrinology and Metabolic Diseases National Institute of Diabetes and Digestive and Kidney Diseases Building 45, Room 5AN-18G, MSC 6600 Bethesda, MD 20892-6600 Telephone: (301) 594-8813 FAX: (301) 480-3503 Email: joan_harmon@nih.gov Thomas P. Jacobs, Ph.D. Division of Stroke, Trauma and Neurodegenerative Disorders National Institute of Neurological Disorders and Stroke 7750 Wisconsin Avenue, Room 8A13 Bethesda, MD 20892-9155 Telephone: (301) 496-4226 FAX: (301) 480-1080 Email: tj12g@nih.gov Theresa Lee, Ph.D. Division of Basic Research National Institute on Drug Abuse 5600 Fishers Lane, Room 10A-19 Rockville, MD 20857 Telephone: (301) 443-6300 FAX: (301) 594-6043 Email: tl37h@nih.gov Robert Karp, Ph.D. Division of Basic Research National Institute on Alcohol Abuse and Alcoholism 6000 Executive Boulevard, Suite 402, MSC 7003 Bethesda, MD 20892-7003 Telephone: (301) 443-2239 FAX: (301) 594-0673 Email: rkarp@willco.niaaa.nih.gov Kenneth A. Gruber, Ph.D. Division of Human Communication National Institute on Deafness and Other Communication Disorders 6120 Executive Boulevard, Suite 400C, MSC 7180 Rockville, MD 20892-7180 Telephone: (301) 402-3458 FAX: (301) 402-6251 Email: kenneth_gruber@nih.gov Eleni Kousvelari, Ph.D. Division of Extramural Research National Institute of Dental Research Natcher Building, Room 4AN 18A Bethesda, MD 20892-6402 Telephone: (301) 594-2427 FAX: (301)480-8318 Email: kousvelari@de45.nidr.nih.gov William A. Suk, Ph.D., M.P.H. Division of Extramural Research and Training National Institute of Environmental Health Sciences P.O. Box 12233 Research Triangle Park, NC 27709 Telephone: (919) 541-0797 FAX: (919) 541-2843 Email: suk@niehs.nih.gov AUTHORITY AND REGULATIONS This program is described in the Catalog of Federal Domestic Assistance No. 93.837, Heart and Vascular Diseases. 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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