Chemical Genetic Screens for Mitochondrial Division and Fusion Inhibitors

描述(由申请人提供)：我们建议在分子文库筛选中心网络中进行高通量筛选，与在较小的筛选规模上已经成功识别线粒体分裂和融合抑制剂的筛选相同。具体地说，我们将在酿酒酵母菌株中使用直接的基于生长的分析来监测线粒体的分裂和融合活性，以确定更多的小分子抑制剂。鉴于我们的成功，我们相信将会发现许多新的化合物。由线粒体膜动力学调节的事件的医学重要性，如细胞凋亡，表明化学遗传学方法也可能导致发现和开发治疗中风、心肌梗死、神经退行性疾病和癌症的新的治疗药物。我们相信，这些化合物的新的治疗潜力，我们在寻找目标方面的专业知识，以及我们利用它们更充分地了解机制的独特能力，证明我们有理由要求在这一资助机制下扩大我们的筛查范围。我们建议在分子文库筛选中心网络中进行高通量筛选，与在较小的筛选规模上已经成功识别线粒体分裂和融合抑制剂的筛选相同。具体地说，我们将在酿酒酵母菌株中使用直接的基于生长的分析来监测线粒体的分裂和融合活性，以确定更多的小分子抑制剂。鉴于我们的成功，我们有信心会发现许多新的化合物。由线粒体膜动力学调节的事件的医学重要性，如细胞凋亡，表明化学遗传学方法也可能导致发现和开发治疗中风、心肌梗死、神经退行性疾病和癌症的新的治疗药物。我们相信，这些化合物的新的治疗潜力，我们在寻找目标方面的专业知识，以及我们利用它们更充分地了解机制的独特能力，证明我们有理由要求在这一资助机制下扩大我们的筛查范围。

DESCRIPTION (provided by applicant): We propose to conduct a high through put screen in the Molecular Libraries Screening Centers Network identical to the one that, on a smaller screening scale, has already successfully identified mitochondrial fission and fusion inhibitors. Specifically, we will employ straightforward growth-based assays in S. cerevisiae strains that monitor mitochondrial fission and fusion activity to identify additional small molecule inhibitors. Given our success, we are confident that many novel compounds that will be found. The medical importance of events regulated by mitochondrial membrane dynamics, such as apoptosis, indicates that the chemical genetic approach may also lead to the identification and development of novel therapeutic agents for stroke, myocardial infarction, neurodegenerative diseases, and cancer. We believe that the novel therapeutic potential of these compounds, our expertise in finding their targets, and our unique ability to exploit them to more fully understand mechanism, justifies our request to expand our screen under this funding mechanism. We propose to conduct a high through put screen in the Molecular Libraries Screening Centers Network identical to the one that, on a smaller screening scale, has already successfully identified mitochondrial fission and fusion inhibitors. Specifically, we will employ straightforward growth-based assays in S. cerevisiae strains that monitor mitochondrial fission and fusion activity to identify additional small molecule inhibitors. Given our success, we are confident that many novel compounds will be found. The medical importance of events regulated by mitochondrial membrane dynamics, such as apoptosis, indicates that the chemical genetic approach may also lead to the identification and development of novel therapeutic agents for stroke, myocardial infarction, neurodegenerative diseases, and cancer. We believe that the novel therapeutic potential of these compounds, our expertise in finding their targets, and our unique ability to exploit them to more fully understand mechanism, justifies our request to expand our screen under this funding mechanism.