Chemical Biology of Diabetes

描述(由申请人提供)： 线粒体在细胞和完好无损的动物的能量平衡中起着关键作用。线粒体氧化脂质和葡萄糖等底物，从而成为人类2型糖尿病中调节失调的燃料的中央控制点。最近的数据表明，人类2型糖尿病与肌肉中线粒体OXPHOS系统及其调节因子PGC-1共激活因子的低表达有关。我们最近未发表的遗传数据清楚地表明，肌肉中PGC-1a水平降低会导致糖耐量异常，即使在杂合子KO状态下也是如此。在这里，我们提出了一种综合的方法来开发能够调节细胞和动物中的PGC-1共激活子和/或线粒体功能的化合物。其目标是建立概念证据，证明这些系统的化学操作可以在肥胖和2型糖尿病中受益。我们将利用包括大量FDA批准的药物和类药物化合物的化学库，以及布罗德研究所生产的新型化学库。我们还将使用一种涉及重组酵母菌株的新方法，研究目标未知的新化合物的分子靶标。特定目标1将利用基于线粒体的筛选来寻找能够控制线粒体数量、膜电位和ATP合成的化合物。特定目标2将进行筛选，以识别调节PGC-1a和PGC-1β表达的化合物，以及它们在线粒体生物学中的功能。特殊目标3将利用一种使用重组酵母菌株的新方法来识别被目标1和目标2产生的新化学物质改变的靶标。在所有情况下，我们都将使用基于细胞的线粒体功能和胰岛素抵抗筛选。此外，我们将在肥胖症、胰岛素抵抗和2型糖尿病的动物模型中测试从这些筛查中产生的化合物。所有这些项目都将利用布罗德研究所的化学筛选和DFCI的动物资源。总而言之，这一高度整合和协作的项目很有可能为肥胖症和糖尿病的治疗提供一种新的途径的概念证明。

DESCRIPTION (provided by applicant): Mitochondria play a critical role in the energy homeostasis of the cell and the intact animal. Mitochondria oxidize substrates such as lipids and glucose, thereby serving as a central control point for fuels which are dysregulated in human type 2 diabetes. Recent data suggests that human type-2 diabetes is associated with lower expression of the mitochondrial OXPHOS system and their regulators, the PGC-1 coactivators, in muscle. Our recent unpublished genetic data clearly indicate that reduced PGC-1a levels in muscle can cause abnormal glucose tolerance, even in the heterozygous KO state. We propose here an integrated approach to develop chemical compounds that can modulate the PGC-1 coactivators and/or mitochondrial function in both cells and animals. The goal is to establish proof of concept that chemical manipulations of these systems can have a benefit in obesity and type-2 diabetes. We will utilize chemical libraries that include a large number of FDA-approved drugs and drug-like compounds, as well as novel chemical libraries produced at the Broad Institute. We will also investigate molecular targets of novel compounds where the target is not known, using a novel method involving the use of recombinant yeast strains. Specific Aim 1 will utilize mitochondrial-based screens to find compounds that can control mitochondria number, membrane potential and ATP synthesis. Specific Aim 2 will perform screens that will identify compounds that modulate the expression of PGC-1a and PGC-1beta, and their function in mitochondrial biology. Specific Aim 3 will utilize a novel method using recombinant yeast strain to identify targets that are being altered by novel chemical matter arising from Aims 1 and 2. In all cases, we will use cell-based screens of mitochondrial function and insulin-resistance. In addition, we will test the compounds arising from these screens in well-established animal models of obesity, insulin resistance and type-2 diabetes. All of these projects will make use of chemical screening at the Broad Institute and the animal resources at the DFCI. Together, this highly integrated and collaborative project has a high likelihood of providing proof of concept for a novel avenue to the therapeutics of obesity and diabetes.