Full Text CA-97-012 IMPROVED TECHNOLOGIES FOR PRODUCTION OF FULL-LENGTH HUMAN cDNA NIH GUIDE, Volume 26, Number 1, January 10, 1997 RFA: CA-97-012 P.T. 34 Keywords: Biology, Molecular Nucleic Acids Gene Cloning National Cancer Institute Letter of Intent Receipt Date: February 15, 1997 Application Receipt Date: April 29, 1997 PURPOSE The Technology Development Branch of the Cancer Diagnosis Program, Division of Cancer Diagnosis, Treatment, and Centers at the National Cancer Institute (NCI) invites applications for the development and application of innovative technologies for efficiently generating representational, full length cDNA libraries. Full length cDNAs are those clones that contain a copy of the entire mRNA sequence from which they were derived. Representational libraries are those libraries that contain at least one cDNA for every mRNA species present in the starting tissue. Ultimately, this new technology must provide an efficient, cost-effective method for generating full length, representational cDNA libraries from tissue samples. These libraries will provide access to full length clones for those investigators who have previously identified important partial clones in other libraries. In addition the clones from these libraries will provide new gene sequences which will aid in gene discovery and gene function assessment. Therefore, investigators may propose to develop novel technologies initially on a small scale or they may propose to further develop existing efficient technologies into a high-throughput system. The most desirable technologies will be those that are easily exportable to the research community. In order to encourage applications proposing innovative, high-risk projects, exploratory/experimental research grant (R21s) will be used to support meritorious applications. A total of $2.5 million will be available to support approximately 10 awards. 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) Improved Technologies for Production of Full-Length Human cDNA, 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 nonprofit organizations, public and private, such as universities, colleges, hospitals, laboratories, units of State and local governments, and eligible agencies of the Federal government. Applications may be from single institutions but collaborative studies are also encouraged. 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) exploratory/experimental research grant (R21) awards. The total project period for applications submitted in response to the present RFA may not exceed three years. The anticipated award date is September 1, 1997. This RFA is a one-time solicitation. Future unsolicited competing continuation applications will compete with all investigator-initiated applications and will be reviewed according to the customary peer review procedures. Except as otherwise noted in this RFA, 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) will be available. Approximately 10 awards are expected to be made from the total pool of applications received. The number of awards made will be contingent upon the quality of 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. An immediate benefit from the human genome project has been the large scale generation and sequencing of over 500,000 human expressed sequence tags (EST). EST are valuable in that they allow a rapid preliminary identification of a large number of expressed genes. They are limited in that the clones themselves often represent only partial genes. Often the partial clone is not adequate to assess the gene's biological function. In addition, few of the libraries currently being sequenced are from tumor or other cancer related tissues. Cost-effective, representational full length cDNA libraries are necessary to facilitate the identification of genes involved in cancer initiation and progression. The NCI has established the Cancer Genome Anatomy Project (CGAP) to capitalize on the technology and data emerging from the human genome project and refocus it in the direction of cancer research. CGAP has two main foci: first, the development of a complete index of genes expressed in tumors and second, the development of new technologies that will facilitate high throughput analysis of molecular alterations in cancer cells and dissemination of these technologies to basic and clinical researchers. The initial effort of CGAP is to generate and sequence cDNA libraries from four targeted tumor sites: breast, prostate, colon and lung. Though these libraries will be useful in identifying genes involved in cancer, they rely on current technology which does not guarantee complete representation or full length clones. Current technology allows the production of representational libraries of partial genes or production of more limited libraries of full length clones, which are generally enriched for shorter genes. In addition, technology exists to create normalized (reduced redundancy) cDNA libraries. However, it is not currently possible to efficiently generate representational libraries of full length cDNAs. In order to derive the maximum benefit from libraries currently being developed and to find expressed genes not present in the initial libraries, new technologies for generating full length representational cDNA libraries are necessary. Objectives This RFA is intended to support the development and/or the implementation of technologies that generate representational libraries of full length cDNAs from tissues that will contribute to the understanding of cancer at the molecular level. Investigators may propose to create novel technologies or adapt existing technologies for the generation of representational libraries of full length cDNA clones. They may also propose feasibility studies designed to generate libraries from appropriate tissues using the developed technologies. Preferred technologies will be those that are efficient (including, but not limited to, normalization techniques), scalable for high-throughput and easily transferred to other cancer researchers. A primary goal of CGAP is the compilation of a complete index of all genes expressed in tumors. In order to understand the significance of individual genes or gene expression levels, it will be necessary to have libraries from cancerous and nonneoplastic tissue from the same organs for comparison. Therefore, investigators may propose to generate individual libraries or to generate libraries that are enriched for genes differentially expressed from appropriate tissues after successful completion of the technology development phase of the project. Appropriate tissues are those that will provide information about the initiation and/or progression of cancers, including but not limited to tumors of different stages, tumor vs. nonneoplastic tissue, etc. In all cases, approaches must be described for demonstrating that the clones in the libraries encode the entire sequence of the mRNA from which they were derived and contain a representative sample of the original mRNA population of the selected tissue. In addition, the NCI is interested in stimulating the development of innovative technologies that may be supported by limited preliminary data. In order to judge the feasibility of the proposed studies, it is necessary to establish criteria for scientific progress. Therefore, in their applications, investigators must propose specific, quantifiable milestones which can be used to measure the progress of the studies. Although the details are left to the investigator, the milestones proposed must consist of clear, well defined criteria for measuring progress. They must be appropriate for the proposed studies and as specific as possible. Investigators should also propose a clear time line for successfully completing the proposed milestones. 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 new policy results from the NIH Revitalization Act of 1993 (Section 492B of Public Law 103-43) and supersedes and strengthens the previous policies (Concerning the Inclusion of Women in Study Populations, and Concerning the Inclusion of Minorities in Study Populations), which have been in effect since 1990. The new policy contains some provisions that are substantially different from the 1990 policies. All investigators proposing research involving human subjects should read the "NIH Guidelines for Inclusion of Women and Minorities as Subjects in Clinical Research," which have been published in the Federal Register of March 20, 1994 (FR 59 14508-14513) and reprinted in the NIH Guide for Grants and Contracts, Volume 23, Number 11, March 18, 1994. Investigators also may obtain copies of the policy from the program staff listed under INQUIRIES. Program staff may also provide additional relevant information concerning the policy. LETTER OF INTENT Due to the specialized nature of this program, it is strongly recommended that prospective applicants contact NCI staff to discuss research objectives. Prospective applicants are asked to submit, by February 15, 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. 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, Diagnosis and Centers National Cancer Institute 6130 Executive Boulevard, Room 513, MSC 7388 Bethesda, MD 20892-7388 Telephone: (301) 496-1591 FAX: (301) 402-1037 Email: couchj@dcbdcep.nci.nih.gov APPLICATION PROCEDURES The research grant application form PHS 398 (rev. 5/95) is to be used in applying for these grants. These forms are available at most institutional offices of sponsored research; 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: 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 might 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) To expedite the review process, at the time of submission, send two additional copies of the application to: MS. TOBY FRIEDBERG REFERRAL OFFICER NATIONAL CANCER INSTITUTE 6130 EXECUTIVE BOULEVARD, ROOM 636A, MSC 7405 BETHESDA, MD 20892-7405 ROCKVILLE, MD 20852 (for overnight/courier service) Telephone: (301) 496-3428 FAX: (301) 402-0275 Applications must be received by April 29, 1997. If an application is not received by this 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 a substantially revised application, but such applications must include an introduction addressing the previous critique. REVIEW CONSIDERATIONS Upon receipt, applications will be reviewed for completeness by the DRG and for responsiveness by the NCI program staff. Incomplete applications will be returned to the applicant without further consideration. If the application is not responsive to the RFA, DRG 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 proposing the use of currently available technologies for the generation of cDNA libraries form tumor tissues will not be responsive to this RFA. Applications that fail to include the description of appropriate mileposts will also not be responsive. 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. 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 will be assigned a priority score. All applicants will receive a summary statement consisting of the reviewer's written comments. 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 Cancer Advisory Board. Review criteria for RFAs are essentially the same as those for unsolicited research grant applications and include the following: o scientific and technical merit of research plans and novelty of proposed research o appropriateness and adequacy of the experimental approach and methodology proposed to carry out the research o qualifications and research experience of the Principal investigator and staff, particularly but not exclusively, in the area of the proposed research o appropriateness of the proposed budget and duration in relation to the proposed research o availability of the resources necessary to perform the research The initial review group will also examine the provisions for the protection of human and animal subjects, the safety of the research environment, and conformance with the NIH Guidelines for the Inclusion of Women and Minorities as Subjects in Clinical Research. Additional considerations specific to this RFA include the following: o the degree to which the technology meets the ultimate objective of creating representational libraries of full length cDNA clones from appropriate tissues o efficiency and cost-effectiveness of the proposed technology. o the appropriateness of the time-frame and mile posts proposed by the investigator to evaluate the progress of the technology development and/or implementation AWARD CRITERIA The anticipated date of award is September 30, 1997. The following criteria will be considered in making funding decisions: the quality of the proposed project as determined by peer review; the responsiveness of the proposed project to the goals of this RFA; and the availability of funds. INQUIRIES Written and telephone inquiries concerning this RFA are encouraged. The opportunity to clarify any issues or questions from potential applicants are welcome. Direct inquiries regarding programmatic issues to: Jennifer Couch, Ph.D. Division of Cancer Treatment, Diagnosis and Centers National Cancer Institute 6130 Executive Boulevard, Room 513, MSC 7388 Bethesda, MD 20892-7388 Telephone: (301) 496-1591 FAX: (301) 402-1037 Email: couchj@dcbdcep.nci.nih.gov Direct inquiries regarding fiscal matters to: Ms. Theresa Mercogliano Grants Administration Branch National Cancer Institute 6120 Executive Boulevard, Room 243, MSC 7150 Bethesda, MD 20892-7150 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, Cancer Detection and Diagnostic Research. 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 Part 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 recipients to provide a smoke-free workplace and promote the non-use of all tobacco products. This is consistent with the PHS mission to protect and advance the physical and mental health of the American people. 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. .
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