NOT-NS-04-005: CALL FOR ASSAY PROPOSALS FOR THE NINDS HIGH THROUGHPUT DRUG SCREENING SERVICE FACILITY

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CALL FOR ASSAY PROPOSALS FOR THE NINDS HIGH THROUGHPUT DRUG SCREENING SERVICE FACILITY RELEASE DATE: March 05, 2004 NOTICE: NOT-NS-04-005 National Institute of Neurological Disorders and Stroke (NINDS) (http://www.ninds.nih.gov/) The National Institute of Neurological Disorders and Stroke established a high throughput drug screening (HTS) facility at Southern Research Institute in Birmingham, Alabama in 2002. This facility was established to provide an opportunity for neurodegeneration researchers with robust and reproducible assays to have their assays tested against a collection of 100,000 compounds in a high throughput setting. Working closely with investigators, the facility adapts these assays into high throughput formats and uses them to screen a collection of chemically diverse compounds. The data from the screens is returned to the contributing investigators for further evaluation. More information is available at: http://www.ninds.nih.gov/funding/areas/technology_development/HTS_Facility.htm. The NINDS is now accepting proposals for new neurodegeneration-related assays to be adapted and screened at the HTS facility. The types of assays sought and instructions for applying to the program follow. SCOPE Assays proposed for this service should be relevant to mechanisms associated with neurodegenerative diseases such as ALS, Parkinson’s disease, Spinal Muscular Atrophy, Alzheimer’s disease or Huntington’s disease and other triplet repeat disorders. Many of the in vitro biological and disease assays currently used to study the effects of specific compounds or genetic perturbations can be adapted to high throughput formats. There are a number of characteristics that make an assay suitable for high throughput approaches. The assay must be robust, reproducible and have a readout that is amenable to automated analysis. In addition, it must be possible to miniaturize the assay to a 96-well or higher density format. These features can be met by a broad range of assay types, including enzymatic and biochemical assays, and assays in intact cells or simple model organisms such as yeast or C. elegans. This announcement seeks innovative assays for use in both mechanistic studies and drug discovery programs, with an emphasis on biological novelty and relevance to neurodegeneration. Appropriate assays include: o Biochemical or cell-based assays of activity, behavior or interaction of proteins and other molecules of interest. o Assays of cellular or molecular phenotypes, viability or apoptosis. o Assays using model organisms such as yeast or C. elegans. o Assays involving mutant proteins linked to neurodegeneration or neuroprotection. o Modulation of expression of genes of interest, including effects on transcription, translation or RNA splicing. PROPOSAL CONTENT Proposals should demonstrate reproducibility of the proposed assay in a low-to-moderate throughput setting (e.g., 24-well format) and should be feasible for adaptation to an automated, high-throughput screening approach. For example, it should be possible to reduce the assay to a 96-well format and the assay should have a simple readout. Demonstration of feasibility for HTS must include: o Use of reagents and readouts that can be used in an automated HTS environment. However, please note that the NINDS HTS facility does not currently have high throughput imaging capability. o Demonstration of highly predictable and reproducible responses to pharmacological standards or other control conditions, including acceptable signal-to-noise and signal-to-background ratios, and a favorable Z value in a 96-well or higher density format. In addition, it is desirable to demonstrate the selectivity and reproducibility of response of the assay to a small but diverse collection of a few hundred compounds, such a collection of FDA approved drugs or other bioactive molecules. There must also be a clear plan for confirming, evaluating the significance of, and prioritizing the hits obtained in a primary high throughput screen. This plan should be feasible for the evaluation of a few hundred hit compounds that may be identified in a primary HTS effort. This plan should include feasible counter screens and secondary screens for confirming hits and eliminating artifacts. The overall goals of the screening project should be well defined and clearly presented. This discussion should include the expected use of the compounds in a follow-up research program, either in the context of biological research or therapeutics development. Plans for achieving these goals, such as evaluating and optimizing the compounds for in vivo testing, should be presented with enough detail to allow an evaluation of overall feasibility and completeness. ASSAY AUTOMATION AND SCREENING AT SOUTHERN RESEARCH Assays accepted for screening at Southern Research will be developed for automated screening in close collaboration with scientists at the facility. Investigators will be required to visit the facility to transfer the assay technique and to oversee pilot screens and interpretation of pilot data. These activities are likely to require at least two visits to the facility in Birmingham for at least one week at a time. Assays will be screened against a collection of approximately 100,000 public domain compounds. This collection consists of the 50,000 compound CNS-Set from Chembridge (http://www.chembridge.com), the MicroSource Discovery Systems (http://www.msdiscovery.com) Spectrum Collection of 2000 FDA approved and bioactive compounds and natural products, and a set of 50,000 compounds selected for chemical diversity from Tripos (http://www.tripos.com). Assays will be screened against this collection and the hits will be subjected to reproducibility and dose-response testing. Investigators will be given access to the entire data set from the screens as well as the names and sources of the reproducibly active compounds that are identified. Unless otherwise negotiated before screening is begun, all intellectual property that results from the assay development and screening will reside with the contributing investigator. The Material Transfer Agreement can be viewed at http://www.ninds.nih.gov/funding/technology_development/HTS_Facility.htm. COST ESTIMATION It is NOT necessary to provide a detailed estimation of the cost of developing and screening the assay. However, you must list the cost of any non-standard reagents that must be purchased to conduct the specific assay, such as antibodies, unusual media additives, viral preparations, etc. These costs should be calculated for a single well of a 96-well plate assuming a reaction volume of 200ul. You do NOT need to calculate the cost of standard buffers, media, serum, etc., or the cost of plates or other materials associated with cell culture or screening. MECHANISM OF SUPPORT NINDS will cover the costs of assay automation and screening through a contract with Southern Research. This will include the cost of travel of investigators to the facility to convey specifics of assay design and interpretation to scientists at Southern Research. Investigators will receive no additional support through this mechanism. Investigators are encouraged to apply for support for characterizing the results of their screens through alternative NIH funding mechanisms. Early stage characterization of hit compounds may be appropriate for the R21 Exploratory/Developmental Grants Mechanism (http://grants.nih.gov/grants/guide/pa-files/PA-03-107.html) or, for therapeutically directed projects, PAR-02-138, NINDS Exploratory/Developmental Projects in Translational Research (http://grants.nih.gov/grants/guide/pa-files/PAR-02-138.html). ELIGIBLE INSTITUTIONS You may submit a proposal if your institution has any of the following characteristics: o For-profit or non-profit organizations o Public or private institutions, such as universities, colleges, hospitals, and laboratories o Units of State and local governments o Eligible agencies of the Federal government o Domestic institutions/organizations HOW TO APPLY Submission of proposals should be made electronically. Send an Email message to HTSassays@ninds.nih.gov with the PI’s name (last name, first name) on the Subject line. Include the following sections in an attached file in MSWord, WordPerfect of PDF format: o A cover page citing this NOTICE and including the title of the assay, PI name, and address, phone and email information for the PI. o An abstract. o A proposal, limited to 5 pages, describing the assay, feasibility for adaptation to HTS, mechanisms for validating hits from screening and plans for use of the screening results. REVIEW PROCEDURE Applications appropriate to this solicitation will be reviewed by the NINDS HTS Facility Steering Committee. This committee includes scientists from academia, industry and the NINDS. Review criteria will include: o significance of the disease model for neurodegeneration o novelty of the assay approach and research plan for use of the compounds o technical merit of the approach o feasibility of adapting the assay to HTS format o quality of the plan for evaluating the compounds identified by HTS o quality of the statement of goals for use of identified compounds either as research tools or for drug discovery SELECTION CRITERIA NINDS will select three to five assays per year to be screened at the NINDS facility. Criteria for the selection of individual assays will include: o Scientific merit (as determined by the Steering Committee) o Programmatic Priorities of NINDS o Capacity of NINDS Facility Receipt deadlines: April 2, 2004 June 1, 2004 Future deadlines will be announced in separate notices. INQUIRIES Dr. Jill Heemskerk Program Director, Technology Development National Institute of Neurological Disorders and Stroke, NIH 6001 Executive Boulevard, Room 2229 Bethesda, MD 20892 Phone: 301-496-1779 Email (preferred): jill_heemskerk@ninds.nih.gov

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