FULL CODING SEQUENCES OF GENES TO FACILITATE CANCER RESEARCH NIH Guide, Volume 26, Number 39, December 5, 1997 RFA: CA-98-004 P.T. National Cancer Institute Letter of Intent Receipt Date: February 5, 1998 Application Receipt Date: March 12, 1998 PURPOSE The Technology Development Branch of the Cancer Diagnosis Program, Division of Cancer Treatment and Diagnosis at the National Cancer Institute (NCI) invites applications proposing strategies for the cost-effective generation of full coding sequences of genes that may be useful for cancer research. This RFA is intended to support sequencing efforts which will provide high quality full coding sequences of genes to the research community in a systematic and timely way. Full coding sequences are defined as the assembled complete sequence of all the exons for a given gene (or any naturally occurring splice variant). Full coding sequences may be derived from single full length cDNA clones or they may be sequences assembled from partial clones which span the entire coding sequence of a gene. Investigators applying for this RFA must provide a plan to scale up and modify their current sequencing strategies to retrieve, prioritize and sequence cDNA clones in a high throughput manner. Proposed sequencing strategies must include mechanisms to assure that the final sequences are of high quality and methods to determine that the final sequences contain the full coding sequence of the genes. Investigators must also include a rationale for selecting genes to be sequenced based on their potential relevance to cancer research. While long-range gene selection strategies are being devised and tested, it is expected that initial sequencing efforts will focus on genes which have been previously identified as potentially relevant to cancer. Grants will be awarded using the R01 funding mechanism. A total of $2.5 million per year will be available to support approximately five awards. This RFA will support projects for up to three years to develop high throughput, cost effective systems for sequencing selected genes. At or before the end of three years, program staff will convene a review to evaluate project progress. Based on this review, the NCI will consider mechanisms to support further large scale cDNA sequencing efforts. Such support will be contingent on successful demonstration by the grantees of the cost effective production of high quality sequences coupled with a long range plan for selecting genes to be sequenced. 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), Full Coding sequences of Genes to Facilitate Cancer Research, is related to the priority area of cancer. 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 for this program will be through the National Institutes of Health (NIH) research project grant (R01) mechanism. The total project period for an application submitted in response to this RFA may not exceed three years. The anticipated award date is July 1, 1998. This RFA is a one-time solicitation. However, if there is sufficient continuing program need, NCI will invite recipients of awards under this RFA to submit competing continuation applications for review as described in REVIEW CONSIDERATIONS. Unsolicited competing continuation applications will compete with all investigator-initiated applications and will be reviewed according to the customary peer review procedures. Awards will be administered under PHS grants policy as stated in the Public Health Service Grants Policy Statement, DHHS Publications No. (OASH) 94-50,000, revised April 1, 1994. FUNDS AVAILABLE It is anticipated that a total of $2.5 million (total costs per year) will be available. Approximately five awards are expected to be made from the pool of applications received. The number of awards made will be contingent upon the quality of the applications received and the availability of funds. RESEARCH OBJECTIVES Background The rapid increase in our understanding of tumor biology coupled with the technology and data emerging from the human genome project offer the opportunity for a change in the way cancer research is done. It is becoming clear that cancer is not a single disease but many, and that cancers arise from the gradual accumulation of genetic changes in single cells. It is not clear which changes and how many changes are required to cause an invasive cancer. Defining which genes are involved in the initiation and progression of cancer remains a challenge. The NCI has established the Cancer Genome Anatomy Project (CGAP) to capitalize on the technology and data emerging from the human genome project and to direct them toward cancer research. One initial focus of CGAP has been the establishment of the Tumor Gene Index: a collection of expressed sequence tags (ESTs) from genes expressed in normal, precancerous, and cancerous tissues. ESTs are valuable in that they allow a rapid preliminary identification of a large number of expressed genes. They are limited in that the sequence, and sometimes the clones, represent only partial genes. Currently, individual investigators who have identified a potentially useful gene, often from an EST, must spend considerable time and funds to isolate, sequence and assemble clones containing the full coding sequence before they can proceed with the biological evaluation of the gene. An organized system to rapidly provide investigators with full length sequences and clones will facilitate the rapid analysis and characterization of these potentially useful genes. The initial issuance of this RFA (CA-97-012) was focused on the development of technology to generate full length, representational cDNA libraries from which full length sequences could be obtained. The development of such libraries is technically challenging and significant barriers must be overcome before these libraries become available. This reissuance takes advantage of a complementary, immediate opportunity to generate high quality sequences for use by the cancer community from existing libraries. The projects supported by this RFA will provide important reagents to the research community while the technologies for generating more comprehensive full length cDNA libraries progress. Research Objectives This RFA is intended to support the cost-effective generation of full coding sequences from genes that may be important in cancer biology. Investigators should devise a long term strategy for selecting genes to be sequenced based on their potential usefulness to cancer research. Applicants may choose, for example, to focus on genes expressed in tumors from specific sites or on members of specific gene pathways or gene families that may be involved in cancer biology (e.g. cell cycle genes). Applicants may also propose selection strategies that utilize emerging technologies such as expression arrays or differential display to identify genes which are differently regulated during cancer progression. While long-term gene selection strategies are being devised and tested, applicants should focus their efforts on sequencing genes which have been previously identified as potentially relevant to cancer. Initial gene targets could include but are not limited to genes identified by ESTs or other partial sequences for which there is a rationale to assume cancer relevance (e.g. strong sequence homology to an identified tumor suppressor gene). Although some unintentional duplication may be unavoidable, applicants should not knowingly sequence genes for which a complete, high quality sequence already exists. In an attempt to reduce redundancy between sequencing efforts, NCI will facilitate the coordination of these efforts. Applicants should also propose strategies for improving the efficiency of current technologies for generating full coding sequences of genes. Strategies could include but are not limited to selecting full length clones from cDNA libraries, devising more efficient sequencing strategies or improving sequence assembly. Applicants are required to define criteria they will use to demonstrate that they are obtaining the complete, fully assembled, coding sequence of the genes. They are also asked to define criteria they will use for assessing final sequence quality. Finished sequence quality should have an error rate not higher than one error in 10,000 bases. Finally, applicants will be required to make available the full assembled sequence and clones from which the sequences are derived in a timely manner. Clones already publicly available need not be made available in a separate way but should be clearly identified. Clones which are developed specifically for this project or which are not otherwise available, will be made available through the CGAP distribution network. Final assembled sequences should be submitted to Genbank on a regular basis: every two weeks or in batches of ten clones, which ever comes first. Finally, all projects must show the potential for effectively scaling up the sequencing effort. Early stages of the projects may require applicants to spend time devising selection strategies and thus fewer sequences may be produced. As projects progress, sequencing efforts should be able to produce sequences at a rate of several hundred finished sequences per year. 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 policy results from the NIH Revitalization Act of 1993. 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 also 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 February 5, 1998, 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 NCI staff to estimate the potential review workload and avoid conflict of interest in the review. The letter of intent is to be sent to: Jennifer Couch, Ph.D. Division of Cancer Treatment and Diagnosis National Cancer Institute 6130 Executive Boulevard, Room 700, MSC 7388 Bethesda, MD 20892 Telephone: (301) 402 4185 FAX: (301) 402 7819 Email: jc332a@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 301/710-0267, email: ASKNIH@od.nih.gov. 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: CENTER FOR SCIENTIFIC REVIEW (formerly 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: Ms. Toby Friedberg Division of Extramural Activities National Cancer Institute 6130 Executive Boulevard, Room 636 Bethesda, MD 20892-7399 Rockville, MD 20850 (for express/courier service) Applications must be received by March 12, 1998. 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 the NCI. Incomplete applications will be returned to the applicant without further consideration. If the application is not responsive to the RFA, CSR staff may 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. 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 NCI in accordance with the review criteria stated below. 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 methods? 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? Additional Review Criteria Specific for this RFA: 1. The adequacy of the plan for generating high quality sequence and for assessing sequence quality. 2. The validity of the criteria for determining that the final sequences are the complete coding sequence of the expressed gene. 3. The feasibility and merit of the strategy for choosing clones to be sequenced based on their potential relevance to cancer. 4. The potential of the proposed project to rapidly scale up to high throughput and cost effective sequencing of full coding sequences. The initial review group will also examine: the appropriateness of proposed project budget and duration; the adequacy of plans to include both genders and minorities and their subgroups 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 Selection of applications for award will be based on their scientific and technical merit reflected in the priority score as determined by peer review, the degree to which it meets the goals of the RFA, other programmatic considerations and the availability of funds. Schedule Letter of Intent Receipt Date: February 5, 1998 Application Receipt Date: March 12, 1998 Review by National Cancer Advisory Board: May 1998 Anticipated Award Date: July 1, 1998 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: Jennifer Couch, Ph.D. Division of Cancer Treatment and Diagnosis National Cancer Institute 6130 Executive Boulevard, Suite 700, MSC 7388 Bethesda, MD 20892 Telephone: (301) 402 4185 FAX: (301) 402 4185 Email: jc332a@nih.gov Direct inquiries regarding fiscal matters to: Ms. Teresa Mercogliano Grants Administration Branch National Cancer Institute 6120 Executive Boulevard, Room 243, MSC 7150 Bethesda, MD 20892 Telephone: (301) 496 7800, ext. 243 FAX: (301) 496 8601 Email: mercoglt@gab.nci.nih.gov AUTHORITY AND REGULATIONS This program is described in the Catalog of Federal Domestic Assistance No. 93.394. 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 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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