Chemical Biology of Mitochondria and Diabetes

描述（由申请人提供）：我们正处于2型糖尿病（T2 D）的全球流行之中，日益保守的制药行业加剧了这种流行，现在迫切需要新的目标。越来越多的证据表明线粒体功能改变与T2 D和肥胖症的发病机制有关。例如，线粒体代谢在控制葡萄糖刺激的胰岛素分泌、肝细胞再生和外周燃料氧化中是关键的。二甲双胍是治疗T2 D最有用的药物之一，其唯一已知的直接靶点是线粒体复合物。在患有肥胖症和T2 D的人的骨骼肌中，以及在衰老期间，已经记录了线粒体质量/功能降低，并且通过运动可逆。棕色脂肪通过线粒体解偶联消耗化学能，最近已成为人类肥胖症的可能治疗靶点。总的来说，这些观察结果提出了一个令人兴奋的假设，即调节线粒体生理学可能有助于预防或逆转T2 D和肥胖的病理生理学。这个R24项目的目标是发现一种具有理想药理学特性的小分子的机械多样性集合，其可以通过靶向转录程序、翻译程序和直接线粒体生理学来调节体内线粒体能量学。我们高度集成的项目汇集了线粒体生物发生、生物能量学、化学筛选和药物化学领域的专家，以建立和追求这一大胆的治疗假设。在Aim 1中，我们将跟进令人兴奋的初步数据，这些数据揭示了一种新的小分子及其靶点，一种通过转录机制控制线粒体生物合成的质膜离子通道。使用这种有效的筛选策略，我们将筛选通过转录机制促进棕色脂肪分化的其他新型小分子。在目标2中，我们将跟踪一个大规模的化学筛选，旨在发现在翻译后修饰水平上影响线粒体生物发生的小分子。在目标3中，我们将利用最近发现的线粒体钙通道亚基，通过该资助的前一个资助期，并筛选通过靶向线粒体钙通量直接靶向线粒体生理学和能量学的新药。对于这三个目标，我们将与Broad Institute和Scripps的领先化学家密切合作，进行深入的铅优化和配方，并在培养细胞和啮齿动物模型中评估新药。如果成功的话，这个合作项目可能会导致发现机制多样的小分子，这将促进我们对线粒体代谢对T2 D发展的贡献的基本理解，同时也有助于为这种日益增长的流行病推出一种潜在的全新疗法。

DESCRIPTION (provided by applicant): We are in the midst of a worldwide epidemic in type 2 diabetes (T2D) that is exacerbated by an increasingly conservative pharmaceutical industry that is now desperate for new targets. A growing body of evidence implicates altered mitochondrial function in the pathogenesis of T2D and obesity. For example, mitochondrial metabolism is critical in the control of glucose stimulated insulin secretion, hepatic gluconeogenesis, and peripheral fuel oxidation. The only known direct target of metformin, one of the most useful agents for treating T2D, is a mitochondrial complex. Reduced mitochondrial mass/function have been documented in the skeletal muscle of humans with obesity and T2D, and during aging, and reversible with exercise. Brown fat, which expends chemical energy through mitochondrial uncoupling, has recently emerged as a possible therapeutic target for human obesity. Collectively, these observations raise the exciting hypothesis that modulating mitochondrial physiology may help prevent or reverse the pathophysiology of T2D and obesity. The goal of this R24 project is to discover a mechanistically diverse collection of small molecules with desirable pharmacologic properties that can modulate mitochondrial energetics in vivo by targeting transcriptional programs, translational programs, and direct mitochondrial physiology. Our highly integrated project brings together experts in mitochondrial biogenesis, bioenergetics, chemical screening, and medicinal chemistry, to build and pursue this bold therapeutic hypothesis. In Aim 1 we will follow-up on exciting preliminary data that has revealed a novel small molecule and its target, a plasma membrane ion channel that controls mitochondrial biogenesis via a transcriptional mechanism. Using this validated screening strategy, we will screen for additional novel small molecules acting via transcriptional mechanisms that promote brown fat differentiation. In Aim 2 we will follow-up on a large-scale chemical screen that is designed to discover small molecules that work at the level of post-translational modifications to influence mitochondrial biogenesis. In Aim 3 we will capitalize on the recent discovery of mitochondrial calcium channel subunits, enabled by the previous funding period of this grant, and screen for novel drugs that directly target mitochondrial physiology and energetics through targeting mitochondrial calcium flux. For all three aims we will collaborate closely with leading chemists at Broad Institute and Scripps to perform in-depth lead optimization and formulation and evaluate the novel drugs both in cultured cells as well as in rodent models. If successful, this collaborative project could result in the discovery of mechanistically diverse small molecules that will advance our fundamental understanding of the contribution of mitochondrial metabolism to the development of T2D, while also helping to launch a potentially brand new class of therapeutics for this growing epidemic.