PA-99-007: PROBES AND INSTRUMENTS FOR MICRO-IMAGING THE BRAIN

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PROBES AND INSTRUMENTS FOR MICRO-IMAGING THE BRAIN Release Date: October 23, 1998 PA NUMBER: PA-99-007 P.T. National Institute of Mental Health National Institute on Deafness and Other Communication Disorders PURPOSE The National Institute of Mental Health (NIMH) and the National Institute on Deafness and Other Communication Disorders (NIDCD) issue this Program Announcement (PA) to invite grant applications for Small Business Innovation Research (SBIR) projects on micro-imaging the brain and other parts of the nervous system, with award duration and amounts greater than those routinely allowed under the SBIR program. The NIMH and NIDCD encourage applications from teams of investigators from commercial, academic and other sectors of the research community. Non-commercial partners, including those at colleges and universities, may play important roles in SBIR-supported research, and may receive substantial support for their efforts. More specifically, this PA solicits SBIR grant applications that propose research and development of tools and approaches to better image the structure and function of molecules and subcellular elements of neurons and other cells of the nervous system. Of special interest are applications that propose research and development of wholly novel approaches and tools, although significant enhancements of those which already exist are also solicited. This initiative has two thrusts: novel probes to generate signals reflecting processes and structures, and novel instruments (including software) with which to detect and analyze those signals. An individual application may propose to focus on both probes and instruments, or on just one of these areas. It is expected that this initiative will require expertise from a variety of disciplines, including neuroscience, biology, chemistry, physics, engineering, biotechnology, and bioengineering. Moreover, it is anticipated that these types of expertise will be brought together in various combinations in individual proposed projects. This PA must be read in conjunction with the Omnibus Solicitation of the Public Health Service (Omnibus Solicitation) for Phase I SBIR Grant Applications (PHS 98-2) and the instructions for Phase II Grant Applications revised March 1998. All instructions and information in these documents also apply to applications submitted in response to this PA except where otherwise noted, below. 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, PROBES AND INSTRUMENTS FOR MICRO-IMAGING THE BRAIN, is related to the priority area of mental health and mental disorders and chronic 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 Eligibility requirements are described in the Omnibus Solicitation. MECHANISM OF SUPPORT - PHASE I Phase I applications in response to this PA will be funded as Phase I SBIR Grants (R43) with modifications as described below. Responsibility for the planning, direction, and execution of the proposed research will be solely that of the applicant. Applications for Phase I grants should be prepared following the directions for Phase I SBIR applications as described in the Omnibus Solicitation. The Omnibus Solicitation is available on the Internet at: http://www.nih.gov/grants/funding/sbir1/sbir.htm A limited number of hard copies of the Omnibus Solicitation are available from: PHS SBIR/STTR Solicitation Office 13685 Baltimore Avenue Laurel, MD 20707-5096 Telephone: (301) 206-9385 FAX: (301) 206-9722 Email: a2y@cu.nih.gov o Project Period and Amount of Award Because the duration and cost of research developing novel agents and/or instruments for studying cellular physiology and structure often exceeds that routinely awarded for SBIR grants, NIMH and NIDCD will consider well-justified Phase I applications under this PA with a project period up to two years and a budget not to exceed a total cost of $400,000 (an average of $200,000 per year). o Consultant and contractual costs The total amount of all consultant costs and contractual costs normally may not exceed 33% of the total costs requested for Phase I SBIR applications. Nevertheless, NIMH and NIDCD will consider well-justified Phase I applications under this PA with greater than 33% contractual costs when additional costs are necessary to support collaborative activities with academic institutions or with other partners. o Page Limitations The 25-page limitation for Phase I applications applies (see Omnibus Solicitation). MECHANISM OF SUPPORT - PHASE II Phase II applications in response to this PA will be awarded as Phase II SBIR grants (R44) with modifications as described below. Phase II applications in response to this PA will only be accepted as competing continuations of previously funded NIH Phase I SBIR awards. The previously funded Phase I award need not have been awarded under this PA, but the Phase II proposal must be a logical extension of the Phase I research. Applications for Phase II awards should be prepared following the instructions for NIH Phase II SBIR applications in the Omnibus Solicitation. o Project Period and Amount of Award Because the duration and cost of research developing novel agents and/or instruments for studying cellular physiology and structure often exceeds that routinely awarded for SBIR grants, NIMH and NIDCD will consider well-justified Phase II applications under this PA with a project period up to three years and a budget not to exceed $450,000 per year total cost. o Consultant and Contractual Costs The total amount of all consultant costs and contractual costs normally may not exceed 50% of the total costs requested for Phase II SBIR applications. Nevertheless, NIMH and NIDCD will consider well-justified Phase II applications under this PA with greater than 50% contractual costs when additional costs are necessary to support collaborative activities with academic institutions or with other partners. MECHANISM OF SUPPORT - FAST TRACK The Fast Track initiative (described in the Omnibus Solicitation) is designed to expedite the decision and award of SBIR Phase II funding for scientifically meritorious applications for projects that have a high potential for commercialization. Fast Track is a parallel review option available to those small business concerns (applicant organizations) whose applications satisfy additional criteria which enhance the probability of the project’s commercial success, those criteria are described in the Omnibus Solicitation. Applications that do not meet these criteria may be redirected for review through the standard review procedures described in the Omnibus Solicitation. Fast Track offers two major advantages: 1) concurrent submission and peer review of both Phase I and Phase II projects and 2) minimal or no funding gap between Phase I and Phase II. SBIR applications are eligible for the Fast Track review process upon meeting the criteria which are described in the Omnibus Solicitation. Special aspects of the Phase I and II components of applications submitted in response to this PA, as described above, also apply to Phase I and II components of Fast Track type applications submitted in response to this PA. MECHANISM OBJECTIVES The SBIR program consists of the following three phases: o Phase I The objective of Phase I is to establish the technical merit and feasibility of proposed research or research and development efforts and to determine the quality of performance of the small business grantee organization prior to providing further federal support in Phase II. o Phase II The objective of this phase is to continue the research or research and development efforts initiated in Phase I. o Phase III The objective of this phase, where appropriate, is for the small business concern to pursue the commercialization of the results of the research or research and development funded in Phases I and II. Phase III occurs without SBIR funding. RESEARCH OBJECTIVES Background This initiative has two thrusts: novel probes to generate signals reflecting processes and structures within cells of the nervous system, and novel instruments (including software) with which to detect and analyze those signals. An individual application may propose to focus on both probes and instruments, or on just one of these areas. NOVEL PROBES: An emerging area of scientific opportunity is the design and use of probes to study structure and function at the molecular and subcellular level in living cells. Approaches and tools such as labels that attach to specific peptide or nucleotide moieties, Fluorescent Resonance Energy Transfer, Green Fluorescent Protein (and mutant color variants), and genetically-engineered voltage or ion-sensitive fluorophores are making it possible to begin to visualize not only the distribution of molecular species in cells, but the manner in which they interact. Research and development of these, and other such, technologies hold the promise of providing scientists the capabilities to track the ebb and flow of signal transduction cascades, protein-protein interactions, protein-nucleotide interactions, movement of subcellular elements within cells, and other dynamic events. And, it appears that as such tools are elaborated and further studied, they will permit such observations to be quantitative and made in real time. Finally, bioengineering individual probes that are detectable by multiple modalities, e.g., electron microscopy, fluorescent microscopy and spectroscopy, magnetic resonance imaging) would add great value by allowing independent lines of scientific inquiry to converge on the same cellular process and/or structure as indicated by the multimodal probe. This area of science and technology is poised for major advances, and these advances would bring new levels of understanding of the molecular physiology of nervous system cells, as well as the manner in which this physiology is affected by disease, pharmacologic agents, development, etc. NOVEL INSTRUMENTS: The signals generated by existing probes as well as probes that are developed in response to this program announcement will, of course, need to be detected and analyzed. In the last several years, a range of technologies has been developed that permit better spatial resolution of signals generated intrinsically and by probes, better capabilities for understanding three dimensional structure, and better ways to following molecular and cellular processes in the fourth dimension, time. Imaging instruments at the cutting-edge of biology which are well positioned for advances include, but are not limited to: two/multi-photon laser microscopy (for benign analysis of fluorophores or autofluorescence), magnetic resonance micro-imaging (for cellular level imaging), magnetic resonance force imaging (molecular level imaging), electron energy-loss spectroscopic imaging (for analysis of elemental composition of specimens), cryoelectron microscopy (three dimensional structural analysis of non-crystallized macromolecules), and near field optical scanning microscopy (non-invasive "force" microscopy of living cells). An important aspect of such instrumentation is the software to facilitate the acquisition, analysis and visualization of data by these instruments. By taking these, and other, tools to the next level of sophistication, and by developing entirely new instruments and associated software, it should be possible to begin to fill in the spatial resolution gap between that afforded by X-ray crystallography and that possible with microscopy. Moreover, it should be possible to improve the ability to follow quantitatively changes and movement of probes over time. Research Topics Examples of general research topics that would be considered responsive to this PA are listed below. This is not meant to be an exhaustive, exclusive or delimiting set of topics, rather these merely represent illustrations of projects that would be considered relevant to this PA. o Bioengineering of very small, sterically benign probes that can be genetically linked to proteins that play important roles in cell function o Research, development and engineering of probes that can be detected with both fluorescent microscopy and near field optical scanning microscopy to report the rate of turnover of specific receptors or other membrane proteins o Research and development of probes that attach to specific sites on proteins which are observable through light microscopy and magnetic resonance micro-imaging. o Development of high speed multi-photon microscopy to track the movement, and quantitate the amount of probes reporting intracellular signal transduction processes o Research of instruments for spectral analyses of Fluorescent Resonance Energy Transfer data generated by intracellular processes o Development of electronics and software to improve signal to noise ratios in videomicroscopy o Design and development of software to analyze and compare datasets from imaging instruments. 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 are provided that inclusion is inappropriate with respect to the health of the subjects of 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 the NIH Guide for Grants and Contracts, Vol. 23, No. 11, March 18, 1994. Investigators may obtain copies from these sources or from the program staff listed under INQUIRIES. Program staff may also 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 is scientific or ethical reasons not to include them. This 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 Applicants should follow the instructions for SBIR Phase I, Phase II, or Fast Track submission with the modifications as noted in this PA. Potential applicants are strongly encouraged to contact program staff for pre- application guidance and/or for more specific information on the research topics described in this PA. Mailing Instructions For purposes of identification and processing, the title and number of this PA must be shown in item 2 on the face page of the SBIR Phase I applications and in item 1A of the face page of Phase II grant applications (i.e., "PROBES AND INSTRUMENTS FOR MICRO-IMAGING THE BRAIN," PA-99-007). Follow the mailing instructions in the Omnibus Solicitation for Phase I applications. Follow the mailing instructions in the Phase II application package for Phase II applications. REVIEW CONSIDERATIONS Review Procedures Applications will be assigned on the basis of established PHS referral guidelines. Upon receipt, applications will be reviewed for completeness by the NIH Center for Scientific Review. Incomplete applications will be returned to the applicant without further consideration. Applications will be reviewed for scientific and technical merit by study sections of the Center for Scientific Review, NIH, in accordance with the standard 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 the applications under review, will be discussed, assigned a priority score, and receive a second level review by the appropriate national advisory council. Review Criteria Review criteria are described in the Omnibus Solicitation. The Phase I application should specify clear, measurable goals (milestones) that should be achieved prior to initiating Phase II. Failure to provide clear, measurable goals may be sufficient reason for the study section to judge the application non-competitive. Release of Grant Application Review Information Following evaluation of grant applications by the study section but prior to National Advisory Council or Board action, summary statements will be sent automatically to principal investigators. A "summary statement" documents the evaluation of an application by the study section and conveys the group s recommendations to the awarding component and its Council or Board. No one other than the Principal Investigator may receive the summary statement and evaluation rating. AWARD CRITERIA The following will be considered when making funding decisions: quality of the proposed project as determined by peer review, program balance among research areas of the announcement, the availability of funds, and the commercialization status where the small business concern has received more than 15 Phase II awards in the prior five (5) fiscal years, if applicable (see this application requirement under "Prior SBIR Phase II Awards" found in the "Introduction and Application Instructions" portion of the Omnibus Solicitation). Applications will compete for available funds with all other favorably recommended SBIR applications. Note that applicants may achieve all Phase I goals and milestones and still not receive Phase II funding. INQUIRIES Written and telephone inquiries are encouraged. The opportunity to clarify any issues or questions from potential applicants is welcome. Inquiries regarding programmatic issues may be directed to: Michael F. Huerta, Ph.D. Division of Basic and Clinical Neuroscience Research National Institute of Mental Health 5600 Fishers Lane, Room 11-103 Rockville, MD 20857 Telephone: (301) 443-3563 FAX: (301) 423-1731 Email: mhuerta@helix.nih.gov Lynn E. Huerta, Ph.D. Division of Human Communication National Institute on Deafness and Other Communication Disorders 6120 Executive Boulevard, Room 400-C, MSC 7180 Bethesda, MD 20892-7180 Telephone: (301) 402-3458 FAX: (301) 402-6251 Email: lynn_huerta@nih.gov Direct inquiries regarding fiscal matters to: Ms. Melinda Nelson Grants Management Branch National Institute of Child Health and Human Development 6000 Executive Boulevard, Room 8A17 Bethesda, MD 20892-7510 Telephone: (301) 496-5481 FAX: (301) 402-0915 Email: nelsonm@hd01.nichd.nih.gov Sharon Hunt Grants Management Branch National Institute on Deafness and Other Communication Disorders 6120 Executive Boulevard, Room 400-B, MSC 7180 Bethesda, MD 20892-7180 Telephone: (301) 402-0909 FAX: (301) 402-1758 Email: sharon_hunt@nih.gov AUTHORITY AND REGULATIONS This program is described in the Catalog of Federal Domestic Assistance No. 93.242 (NIMH) and No. 93-173 (NIDCD). 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. Awards will be administered under PHS grants policy as stated in the Public Health Service Grants Policy Statement (April 1, 1994). PHS strongly encourages all grant and contract recipients to provide a smoke- free workplace and promote the nonuse 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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