Identification and Therapeutic Valiation of Adipocyte Serine Hydrolases of Metab

描述(由申请人提供)：肥胖相关的胰岛素抵抗和2型糖尿病与脂肪细胞功能障碍、脂肪细胞脂解增加以及脂肪以外组织中的脂质堆积密切相关。在肥胖症中，肥大的脂肪细胞不能大量储存多余的脂肪酸，脂解率增加，这些脂类沉积在其他组织中，在那里它们阻碍了胰岛素的作用。抑制肥胖相关的脂肪细胞脂解可以改善胰岛素敏感性。所有参与脂肪细胞脂肪分解的酶都属于丝氨酸水解酶家族。尽管丝氨酸水解酶在脂肪细胞生理学中具有重要作用，但大多数丝氨酸水解酶还没有被研究过。丝氨酸水解酶(SHS)是参与新陈代谢和脂肪细胞功能的关键酶家族，参与脂肪分解、脂肪生成和脂肪生成 领悟。然而，超过50%的120+人类丝氨酸水解酶，包括一些与人类疾病有关的基因，仍然没有注释，没有已知的功能或生理底物，而且大多数缺乏有助于其表征和治疗验证的抑制剂。由于个别SHS已经构成了治疗代谢性疾病的药物的靶点，因此有理由假设在众多仍未确定特征的SHS中将发现重要的额外药物靶点。辨别这些未加注释的SHS中哪些与脂肪细胞功能相关，哪些可能作为肥胖-糖尿病的治疗靶点是一个非常复杂的问题。这个项目解决的至关重要的研究挑战是识别和治疗验证贫穷的注释代谢性丝氨酸水解酶，这些酶在脂肪细胞功能中发挥关键作用。我们的多学科团队将实现这一目标 目的通过将尖端的化学蛋白质组学和代谢组学方法与肥胖症和2型糖尿病的深厚生物学专业知识相结合。具体地说，我们打算在全球范围内识别和评估未注释的SHS的治疗潜力，这些SHS活性存在于脂肪细胞中，其活性在生理条件和肥胖-糖尿病中受到调节。其中一些酶可能成为代谢性疾病的新靶点。在此过程中，我们将创建一流的化学探针和遗传模型来研究脂肪细胞SHS，并将其分发给更大的研究社区。

DESCRIPTION (provided by applicant): Obesity-linked insulin resistance and type 2 diabetes are intimately linked to adipocyte dysfunction, increased adipocyte lipolysis, and lipid accretion in tissues other than adipose. In obesity, the hypertrophied adipocyte is not able to properiy store excess fatty acids, the rate of lipolysis is increased, and these lipids deposit in other tissues where they hamper insulin action. Inhibiting obesity-linked adipocyte lipolysis can improve insulin sensitivity. All enzymes involved in adipocyte lipolysis belong to the serine hydrolase family. Despite their importance in fat cell physiology, the majority of serine hydrolases have not been studied. Serine hydrolases (SHs) are a key enzyme family involved in metabolism and adipocyte function, v\/here they contribute to lipolysis, lipogenesis, and lipid uptake. Yet, more than 50% ofthe 120+ human serine hydrolases, including some that have been genetically linked to human disease, remain unannotated, have no known function or physiological substrates, and most lack inhibitors to aid in their characterization and therapeuti validation. Because individual SHs already constitute targets for drugs that treat metabolic disease, it is reasonable to hypothesize that important additional drug targets will be found among the numerous SHs that remain uncharacterized. Discerning which of these unannotated SHs are relevant in adipocyte function and which may serve as therapeutic targets for obesity-diabetes is a very complex problem. The critically important research challenge that this project addresses is the identification and therapeutic validation of pooriy annotated metabolic serine hydrolases that play key roles in adipocyte function. Our multidisciplinary team will achieve this goal by combining cutting-edge chemoproteomic and metabolomics methods with deep biological expertise in obesity and type 2 diabetes. Specifically, we intend to globally identify and assess the therapeutic potential of unannotated SHs active in adipocytes and whose activity is modulated in physiologic conditions and in obesity-diabetes. Some of these enzymes may be new targets for metabolic disease. In the process, we will create first-in-class chemical probes and genetic models to study adipocyte SHs that will be distributed to the larger research community.