Chemoproteomic Identification and Therapeutic Validation of Proteins of Metabolic Significance

摘要 需要开发具有不同于已建立的药剂的作用机制的糖尿病药物。 脂肪细胞功能缺陷会导致全身性胰岛素抵抗和肥胖相关糖尿病的发生。的 肥大脂肪细胞处理葡萄糖和脂质以及分泌胰岛素增敏脂肪因子的能力， 严重受损，这导致高血糖症、高脂血症、胰岛素抵抗、炎症， 以及脂质沉积在组织如肝脏中，在那里它抑制胰岛素作用。可以将这些 组织间天然脂质分配的缺陷和恢复在人体中是有用的胰岛素增敏剂。的 该项目解决的关键挑战是新分子的鉴定和治疗验证， 可以通过调节胰岛素途径来恢复脂肪细胞缺陷和恢复胰岛素信号传导， 肝脏和其他组织。 我们的多学科团队将通过结合尖端的表型筛选和 化学蛋白质组学技术，在脂肪组织和肝脏生物学和脂质代谢方面具有深厚的专业知识。 我们已经开发出创新的策略，将表型筛选与化学蛋白质组学相结合， 简化了生物活性小分子的蛋白质靶点的鉴定，我们最初将其应用于 丝氨酸水解酶家族的酶，但最近已扩展到蛋白质组范围的研究。 我们建议补充我们最初的丝氨酸水解酶为重点的方法与我们的新的强大的平台， 综合表型筛选和化学生物学，使快速，系统，和蛋白质组范围内， 发现代谢靶点。通过筛选独特的小分子文库中所需的表型， 脂肪细胞和肝细胞中的一个公正的方式，我们将确定在串联生理相关的蛋白质 和化学工具来扰乱这些蛋白质的功能，以加快其功能注释， 在糖尿病和NASH中的治疗验证。在这个过程中，我们将创造一流的化学探针， 遗传模型来研究关键的代谢途径，将分发给更大的研究社区。 我们的尖端化学生物学平台从根本上扩展了蛋白质组的目标部分 用小分子。将这些工具应用于驱动糖尿病的核心问题赋予了这个项目 在发现治疗糖尿病和相关疾病的新靶点方面具有无与伦比的潜力。

Abstract There is a need to develop diabetes drugs with a mechanism of action distinct from that of established agents. Defects in adipocyte function drive the onset of systemic insulin resistance and obesity-linked diabetes. The ability of hypertrophied adipocytes to dispose of glucose and lipids and secrete insulin-sensitizing adipokines is severely compromised and this contributes to hyperglycemia, hyperlipidemia, insulin resistance, inflammation, and lipid deposition in tissues such as liver where it dampens insulin action. Agents that can revert these defects and restore natural lipid partitioning amongst tissues are useful insulin sensitizers in humans. The critical challenge that this project addresses is the identification and therapeutic validation of new molecular pathways that can be pharmacologically modulated to revert adipocyte defects and restore insulin signaling in liver and other tissues. Our multidisciplinary team will achieve this goal by combining cutting-edge phenotypic screening and chemoproteomic technologies, with deep expertise in adipose tissue and liver biology and lipid metabolism. We have developed innovative strategies that integrate phenotypic screening with chemoproteomics to streamline the identification of protein targets of bioactive small molecules, which we initially applied to enzymes of the serine hydrolase family, but have more recently extended for proteome-wide investigations. We propose to complement our initial serine hydrolase-focused approach with our new powerful platforms for integrated phenotypic screening and chemical biology to enable the rapid, systematic, and proteome-wide discovery of metabolism targets. By screening unique libraries of small-molecules for desirable phenotypes in adipocytes and hepatocytes in an unbiased manner, we will identify in tandem physiologically relevant proteins and chemical tools to perturb the function of these proteins to expedite their functional annotation and therapeutic validation in diabetes and NASH. In the process, we will create first-in-class chemical probes and genetic models to study key metabolic pathways that will be distributed to the larger research community. Our cutting-edge chemical biology platforms radically expand the portion of the proteome that can be targeted with small molecules. Application of these tools to the central problem that drives diabetes endows this project with unparalleled potential to discover new targets to treat diabetes and associated conditions.