MINIATURIZATION OF ASSAYS FOR PHENOTYPING SMALL ANIMAL MODELS SBIR/STTR) Release Date: February 14, 2000 NOTICE: DK-00-002 National Institute of Diabetes and Digestive and Kidney Diseases PURPOSE The purpose of this Notice, relating to the SBIR/STTR program, is to emphasize and encourage the development of miniaturized assays that can be used to measure metabolites, ions, hormones and other signals in very small volumes of tissue. Microassays developed pursuant to this Notice should be useful for longitudinal metabolic or physiologic studies in small animal (mouse) models of disease, or in human subjects. This research topic is of special interest to the NIDDK and is identified in the NIH Omnibus Solicitation for SBIR Grant Applications found at http://grants.nih.gov/grants/funding/sbirsttr1/index.htm A collaborative approach among academic and industry leaders is strongly encouraged in order to facilitate development and distribution of important technology. Through the Small Business Innovative Research (SBIR) and Small Business Technology Transfer (STTR) mechanisms (R41/R43/R42/R44), small businesses can receive funding for early phase development of innovative technologies and proof of principle studies leading toward commercialization of these technologies. The solicitations are available electronically through the NIH, Office of Extramural Research "Small Business Funding Opportunities" home page located at http://grants.nih.gov/grants/funding/sbir.htm Background New chip and similar technologies will soon allow high-throughput screening of the genetic code, the expressed genes and their protein products, both in the laboratory and in the clinic. Transgenic methodologies have already resulted in the production of an enormous variety of new mouse strains engineered specifically to study particular genes or diseases. We can look forward to an enhanced ability to produce an even larger range of mice, and to identify a large number of genetic variants in people. In order to take full advantage of these new genetic tools to study metabolic diseases such as diabetes and obesity, it is important to improve the methodologies used to determine the metabolic and physiologic phenotypes of these animals and the metabolic outcome of genetic variation in people. New assays should be noninvasive or require very small volumes of tissue or employ implantable devices for continuous monitoring. This Notice calls for SBIR and STTR applications to develop assays for standard markers of metabolic and physiologic function that use minute volumes of tissue or body fluids and can be easily used in a variety of clinical and laboratory settings. A large number of techniques are currently used to characterize metabolism and physiology in people and in larger animals. These include the measurement in plasma of other body fluids of metabolites such as glucose and fatty acids, hormones such as insulin and glucagon, ions like calcium and sodium, cytokines and other signaling molecules, and various proteins. These measurements are used alone or in combination with infused radioactive or stable isotopes. We can also measure an enormous number of signaling and storage molecules, enzyme activities, etc., in biopsied tissue. Noninvasive imaging and spectroscopic techniques are used to monitor physiologic phenomena like blood flow and oxygenation, and other parameters of organ function. PET, NMR, absorption and fluorescence spectroscopy are increasingly used to measure metabolic parameters in living animals and people, and can now be used to interrogate brain function. Many of the existing techniques for characterizing metabolism and physiology can also be used in transgenic mouse models, but must be scaled down for use in tiny animals or small volumes of tissue. These techniques should use a minimum of blood or other tissues or be as noninvasive as possible so that repeated measures can be made over the life of a single animal. Appropriate reagents, such as mouse antibodies, must be used. In order to meet a need for widespread use by researchers from many different disciplines, the techniques should be inexpensive, easy to use, robust, and allow for the rapid screening of a large number of animals. Many of the same considerations apply to the production of microassays that can be used in the clinical setting. For instance, time and money could be saved and risk to the patient reduced if a hormone profile, viral or other pathogen load, or metabolite or ion concentrations could be easily measured using a drop of blood from a finger stick instead of many ml drawn from a vein. Scope The objective of this initiative is to support small companies and partnerships between companies and academic institutions in the development of commercially available miniaturized assays for use in the clinic, in metabolic research on humans, or in metabolic and physiologic characterization of transgenic mouse models. These assays should ideally be inexpensive, reproducible, and either automated or easily implemented in a variety of disease models and laboratory settings. A very broad range of metabolic products, signaling molecules, hormones, pathogens, enzymes and other proteins, and physiologic measurements of blood flow, metabolic fluxes, or other indices of organ function are appropriate research goals. Although it is impossible to foresee all assays that will be needed to phenotype very specialized animal models, it is possible to establish a set of standardized assays that can be used in a very large variety of mouse models. Examples are: ? Glucose, lactate, common fatty acids and amino acids, ions such as calcium, potassium, and sodium, and oxygen and carbon dioxide partial pressures measured in very small plasma volumes; ? Measurement of many hormone concentrations simultaneously in the same tissue sample; ? Easy measurement of cytokine profiles; ? Miniaturization of assays for enzyme activity for use in small tissue samples; ? Imaging or spectroscopic techniques for high-throughput or noninvasive measures of tissue composition, blood flow, oxygenation, metabolic flux, substrate uptake, or organ function in mice. Especially important would be miniaturized, inexpensive equipment for imaging in mice; ? Miniaturization of currently available, widely used automated assays for use in mice, or standardization of currently used specialized assays in forms that are inexpensive and easily implemented; ? Miniaturization of currently available assays for use in human needle biopsy tissue specimens. Mechanism of Support The mechanism of support will be SBIR/STTR grants. Although the average Phase I award for SBIR/STTR grants is approximately $100,000 in total costs for a 6-month project period, NIDDK recognizes that applications responsive to this Notice might require more funds and a somewhat longer duration to accomplish the objectives of a Phase I project. Applications should fully justify all proposed budgets and project periods. Applicants are encouraged to use the Fast-Track mechanism, which allows Phase I and II applications to be submitted and reviewed together. This eliminates the chance of a funding gap between the two phases of the project http://grants.nih.gov/grants/funding/sbirsttr1/6method.htm INQUIRIES Inquiries are encouraged. The opportunity to clarify any issues or questions from potential applicants is welcome. Direct inquiries regarding programmatic issues to: Maren R. Laughlin, Ph.D. Director, Metabolism Program Division of Diabetes, Endocrinology and Metabolic Diseases NIDDK Building 45, Room 5AN-24J 45 Center Drive, MSC 6600 Bethesda, MD 20892-6600 (301) 594-8802 phone (301) 480-3503 FAX maren.laughlin@nih.gov Direct inquiries regarding fiscal matters to: Mary Kay Rosenberg Grants Management Specialist NIDDK Building 45, Room 6AS-49D 45 Center Drive, MSC 6600 Bethesda, MD 20892-6600 (301) 594-8891 phone (301) 480-3504 RosenbergM@extra.niddk.nih.gov
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