Chemical Biology of Mitochondria and Diabetes

描述(由申请人提供)：我们正处于2型糖尿病(T2D)的全球流行之中，日益保守的制药业现在迫切需要新的靶点，这加剧了这一流行病。越来越多的证据表明线粒体功能改变与T2D和肥胖的发病机制有关。例如，线粒体代谢在控制葡萄糖刺激的胰岛素分泌、肝脏糖异生和外周燃料氧化方面起着关键作用。二甲双胍是治疗T2D最有用的药物之一，其唯一已知的直接靶点是线粒体复合体。在肥胖和T2D患者的骨骼肌中，以及在衰老过程中，线粒体质量/功能降低已被证明，并在运动中可逆。棕色脂肪通过线粒体解偶联来消耗化学能量，最近已成为人类肥胖的可能治疗靶点。总而言之，这些观察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T2D和肥胖的病理生理学。该R24项目的目标是发现具有理想药理学特性的小分子的机械多样性集合，这些小分子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的线粒体能量。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方面的专家，以建立和追求这一大胆的治疗假说。在目标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标，即通过转录机制控制线粒体生物发生的质膜离子通道。使用这一经过验证的筛选策略，我们将筛选通过促进棕色脂肪分化的转录机制发挥作用的其他新的小分子。在目标2中，我们将跟进一个大规模的化学筛选，该筛选旨在发现在翻译后修饰水平上工作的小分子，以影响线粒体的生物发生。在目标3中，我们将利用最近发现的线粒体钙通道亚单位，并通过靶向线粒体钙通量来筛选直接针对线粒体生理学和能量学的新药。对于所有这三个目标，我们将与布罗德研究所和斯克里普斯的领先化学家密切合作，进行深入的领先优化和配方，并在培养细胞和啮齿动物模型中对新药进行评估。如果成功，这个合作项目可能会发现机械上不同的小分子，这将促进我们对线粒体代谢对T2D发展的贡献的基本理解，同时也有助于推出一种潜在的全新类别的疗法来治疗这种日益增长的流行病。

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.