HIGH THROUGHPUT SCREENING FOR MODULATORS OF APOPTOSIS

高通量筛选细胞凋亡调节剂

• 批准号: 2784248
• 负责人: JAIME F. MODIANO
• 金额: $ 10万
• 依托单位: DIAGNOSTIC SYSTEMS LABORATORIES
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-04-23 至 2000-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2784248
• 关键词: apoptosis; cell line; combinatorial chemistry; drug design /synthesis /production; drug screening /evaluation; inhibitor /antagonist; luminescence; method development

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.

描述：(改编自申请者的摘要)细胞凋亡是一种细胞自杀的机制，固定在每个细胞的遗传程序中。在癌症和心脏病等多种疾病的发病机制中，对促进或阻止细胞凋亡的途径进行不适当的控制是重要的，这些疾病在我们的社会中造成了相当大的发病率和死亡率。从鉴定选择性诱导或抑制细胞凋亡的化合物中可以获得切实的临床益处。然而，现有的评估细胞凋亡的方法并不能很好地从大型化合物文库中鉴定这样的促凋亡或抗凋亡药物，因为那些可以有效地进行的分析缺乏敏感性和特异性，而且那些敏感和特异的分析也是繁琐和劳动强度大的。这个第一阶段的STTR项目建议验证一种高通量分析，以确定在一组小的有机化合物中启动或阻止细胞凋亡的试剂。该项目有两个里程碑：(I)设计、开发和优化一种灵敏和特异的96孔板格式化学发光高通量筛选(HTS)方法，以检测DNA片断作为细胞凋亡的指标。(2)验证HTS试验的性能和格式，用于多重筛选和检测能激活或抑制细胞凋亡的有机化合物。建议的商业应用：药物筛选-评估化合物库中调节细胞凋亡的化合物。职业选手。凋亡化合物(或类似物)可进一步筛选为癌症或免疫药物疾病的治疗剂。抗细胞凋亡化合物可被筛选用于冠心病、中风或神经退行性疾病的高危患者。