HIGH THROUGHPUT SCREENING FOR MODULATORS OF APOPTOSIS

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DESCRIPTION: (Adapted from the applicant's abstract) Apoptosis is a mechanism of cell suicide hard-wired into the genetic program of every cell. Inappropriate control of the pathways that promote or prevent apoptosis are important in the pathogenesis of diverse conditions such as cancer and heart disease, which account for substantial morbidity and mortality in our society. Tangible clinical benefits could be derived from the identification of compounds that selectively induce or inhibit apoptosis. However, available assays to evaluate apoptosis are not well suited to identify such pro-apoptotic or anti-apoptotic agents from large compound libraries, as those assays that can be performed efficiently lack sensitivity and specificity, and those assays that are sensitive and specific are also tedious and labor intensive. This phase I STTR project proposes to validate a high through-put assay to identify agents that initiate or prevent apoptosis within a combinatorial set of small organic compounds. The project has two milestones: (i) Design, develop and optimize a sensitive and specific 96-well plate format chemiluminescent High Throughput Screening (HTS) assay to detect DNA fragmentation as an indicator of apoptosis. (ii) Validate the performance and format of the HTS assay for multiple screening and detection of organic compounds that activate or inhibit apoptosis. PROPOSED COMMERCIAL APPLICATION: Drug Screening - Evaluating compound libraries for compounds that modulate apoptosis. Pro. apoptotic compounds (or analogues) can be further screened as therapeutic agents for cancer or immune- medicated disease. Anti-apoptotic compounds can be screened for use in high risk patients with coronary disease, stroke, or neurodegenerative disorders.