RFA-RR-99-003: INTEGRATED GENOMICS TECHNOLOGIES

Department of Health
and Human Services (HHS)

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INTEGRATED GENOMICS TECHNOLOGIES Release Date: December 23, 1998 RFA: RR-99-003 P.T. National Center for Research Resources National Human Genome Research Institute National Institute of General Medical Sciences Application Receipt Date: February 23, 1999 PURPOSE This Request for Applications (RFA) targets new, innovative, multidisciplinary efforts to develop integrated genomics technologies, which will lead to the biologists" tools of five or more years hence. The resulting highly integrated technologies will be capable of high-speed serial or highly parallel analyses at a sensitivity level capable of single-cell genomics analysis. Such technologies will enable new levels of understanding of cellular processes and will, for example, permit development of highly specific drugs through screening against in vivo cellular processes. Development of new ex vivo analytical capabilities will permit high throughput analysis of cellular/organelle constituents, single- cell protein and nucleic acid sequencing, including characterization of phosphorylation and methylation states, and single-cell genome expression analysis. Similarly, new in vivo analytical and methodological capabilities will permit: characterization of protein interactions, including protein-protein, protein-nucleic acid, protein-ligand interactions in single cells, in vivo protein and nucleic acid sequencing, the biosynthetic production and self- assembly of intracellular sensors and probes, and single-molecule detection in single cells. 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, Integrated Genomics Technologies, is related to several of the 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 and foreign, for-profit and nonprofit organizations, public or 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 RFA is through the NIH Research Project Grant (R01) mechanism. Applicants for R01 awards must receive permission from the NCRR prior to the submission of an application requesting more than $500,000 in direct costs per year for any year of the proposed study. Awards will be administered under NIH grants policy as stated in the NIH Grants Policy Statement, issued October 1, 1998 (http://grants.nih.gov/grants/policy/nihgps/). FUNDS AVAILABLE It is expected that four to eight awards will be made in FY99, and $4 million will be designated for this purpose. The number of awards will be dependent upon receipt of a sufficient number and diversity of applications with high scientific merit. RESEARCH OBJECTIVES A recent Integrated Genomics Technologies Workshop (October 15 and 16, 1998, the workshop report will soon be uploaded to http://www.ncrr.nih.gov), sponsored by the NCRR with the involvement of other NIH Institutes, the Department of Energy, and the National Science Foundation, identified the grand challenge of fully characterizing the genomics/proteomics of the intact living cell as the basis for the identification of critical enabling technology development needs in this area. Contemporary genome sequencing and expression studies have suggested the feasibility of our understanding the information encoded in the genome in the context of the cell"s protein world. At the same time these studies have indicated large gaps in our understanding of the protein constituents of the cell, their local environment, and the quantitative details of the intracellular protein-protein, protein-macromolecule, and protein-small molecule interactions-- which together define the material, energetic, and informational flows of the living cell. Recent developments in optical imaging, particularly quantitative fluorescence microscopy, ultra-small volume sampling and analysis, incorporation of optically useful probes, such as green fluorescent protein into cellular constituents, combinations of photobleaching and imaging, and optical approaches to determining the rates and equilibria of intracellular processes clearly indicate the enormous potential of in vivo single cell studies for our understanding of cell physiology, as well as the remaining substantial difficulties. Biologists need tools capable of analyzing the genomic and proteomic information of the living single cell. The quantitation, localization, and identification of proteins within the cell, as well as full characterization of intracellular interactions involving proteins in their structural, catalytic, and control roles, will be essential for development of a comprehensive and integrative view of cell physiology. Furthermore, development of highly specific drugs must ultimately involve screening against in vivo cellular processes. Thus, the envisioned technology development will enable the application of profoundly powerful combinatorial approaches to understanding and regulating the interior world of the cell, as well as characterizing the cell-physiological consequences of rare phenotypes--particularly those associated with disease. New ex vivo and in vivo measurement capabilities are needed for the quantitative study of the intact cell"s physiology. Ex vivo analytical needs include single- cell, high-throughput characterization of proteins, including their identification, local concentration, and sequence, as well as characterization of protein-protein and protein-small molecule interactions. Such needs may be approached through the development of new or significantly enhanced broad-based integrated analytical platforms (MS, micro-NMR, and micro/nanofabricated high sensitivity, high throughput devices). No limitation on the nature of such integrated devices should be construed from the examples provided. In vivo single-cell analytical needs include: approaches to single-molecule detection, quantitation of rates and equilibria of protein-protein interactions, nucleic acid and protein sequencing and identification, intracellular sensing, and measures of whole cell and regional dynamical processes, including diffusion, transport, and trafficking. Specific examples of technology development related to these analytical needs may include: new screens, extensions of photon correlation spectroscopy, new near-field and surface plasmon resonance approaches to subcellular spectroscopy, continued development of non-linear spectroscopy/microscopy, achievement of single-cell NMR, approaches to the analysis of the propagation of small perturbations from equilibrium, and evanescent wave approaches to localization. Many of the analytical needs have no obvious current technology upon which to draw, suggesting that entirely new technologies must be developed. It is expected that such long-term systematic technology development efforts will involve interdisciplinary teams engaging expertise in such areas as nano- and microfabrication, engineering, laser applications, optics, molecular biology, separation science, chemistry, physics, mathematics, and sensors. The resulting highly integrated technologies will be capable of high-speed serial or highly parallel analyses at a sensitivity level capable of single-cell genomics analysis. Applications responsive to this RFA will propose development of new innovative technologies in the context of genomics analysis. This RFA does not seek incremental improvements in specific analytical methods. Instead, it seeks broadly conceived multidisciplinary approaches to clearly defined genomics analytical needs. To be useful to the biologist of the future, devices must be highly integrated, involving cell selection, separations methods, analysis/detection, and output. While an application need not involve all aspects of an integrated high throughput device, it is necessary to utilize this context in describing the significance and innovation of the proposed research. 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 has been published in the Federal Register of March 20, 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. 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 clear and compelling 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. 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, email: GrantsInfo@nih.gov. The RFA label available in the PHS 398 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. The completed original application and three 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) Two additional copies of the application must also be sent to: Office of Review National Center for Research Resources 6705 Rockledge Drive, Room 6018 MSC 7965 Bethesda, MD 20892-7965 Bethesda, MD 20817 (for express/courier service) Applications must be received by the application receipt date listed in the heading of this RFA. If an application is received after the application receipt 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 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 by the CSR for completeness and by NCRR for responsiveness. Incomplete and/or non-responsive applications will be returned to the applicant without review. Applications that are complete and responsive will be reviewed for scientific and technical merit and the documented ability of the investigators to meet the RESEARCH OBJECTIVES of this RFA by an initial review group convened by the NCRR Office of Review, in accordance with the standard NIH peer review procedures. As part of the initial merit review, all applications will receive a written critique and may 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 Advisory Research Resources Council. REVIEW CRITERIA Any response to this RFA must place the proposed integrated genomics technology development into the broader context of genomics research. o Significance: Does this study address an important problem? Does the proposed technology development have the potential of initiating paradigm shifts in analysis of biological systems? o Innovative aspects of the technology development plan: Does the project employ novel concepts, approaches, or methods? Are the aims original and innovative? Does the project challenge existing paradigms in developing new methodologies or techniques? It is not a requirement that the proposed studies be hypothesis driven. o Approach: Are the conceptual framework, design, methods, and analyses adequately developed, well integrated, and appropriate to the aims of the project? Is the approach multi-disciplinary? Does the applicant acknowledge potential problem areas and consider alternative tactics? o 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 investigator and other researchers (if any)? For programs involving integrating multidisciplinary efforts, the review committee will consider the care with which the overall program is integrated and the detailed plans for implementation of a comprehensive program. o 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? o For those applications that propose collaborative efforts between several applicants, additional factors to be considered during review would include the efficacy of the collaboration, the commitment of the participants to the collaboration, the design and responsibilities of the coordinating center and the cost effectiveness of the collaborative effort. o Where appropriate, the adequacy of assurances detailing the proposed means for (a) safeguarding human or animal subjects and/or (b) protecting against or minimizing any adverse effect on the environment. o Adequacy of plans to include both genders, minorities, and children and their subgroups as appropriate for the scientific goals of the research. In addition, the review committee will evaluate the appropriateness of the proposed budget and duration in relation to the proposed research. Schedule Application Receipt Date: February 23, 1999 NCRR Committee Review: June/July 1999 Council Review: September 1999 Earliest Funding: September 1999 AWARD CRITERIA The anticipated date of award is September 30, 1999. The factors that will be used to make award decisions include: o Scientific and technical merit as determined by peer review, o Availability of funds, and o Programmatic priorities, such as balance among scientific areas. 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: Karl A. Koehler, Ph.D. Biomedical Technology National Center for Research Resources 6705 Rockledge Drive, Room 6160, MSC 7965 Bethesda, MD 20892-7965 Telephone: (301) 435-0755 FAX: (301) 480-3659 Email: Karlk@ep.ncrr.nih.gov Or send an email inquiry to: BTAdir@ep.ncrr.nih.gov Jeffery A. Schloss, Ph.D. Technology Development Coordination National Human Genome Research Institute Building 38A, Room 614 Bethesda, MD 20892-6050 Telephone: (301) 496-7531 FAX: (301) 480-2770 Email: jeff_schloss@nih.gov James Cassatt, Ph.D. CCB Division National Institute of General Medical Sciences 45 Center Drive Bethesda, MD 20892-6200 Telephone: (301) 594-0533 FAX: (301) 480-2004 Email: Jc12b@NIH.GOV Direct inquiries regarding fiscal matters to: Ms. Judith Musgrave Office of Grants Management National Center for Research Resources 6705 Rockledge Drive, Room 6086, MSC 7965 Bethesda, MD 20892-7965 Telephone: (301) 435-0844 FAX: (301) 435-3777 Email: jm133b@NIH.GOV Ms. Jean M. Cahill Grants Management Officer National Human Genome Research Institute 38A Library Drive, MSC 6050 Bethesda, MD 20892-6050 Telephone: (301) 402-0733 Email: Jean_Cahill@nih.gov Ms. Phyllis Finch Grants Management Office National Institute of General Medical Sciences 45 Center Drive Bethesda, MD 20892-6200 Telephone: (301) 594-5135 Email: pf21m@nih.gov AUTHORITY AND REGULATIONS This program is described in the Catalog of Federal Domestic Assistance No. 93.371. Awards are made under authorization of the Public Health Service Act, Title III, 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 74 or 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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