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、脂肪细胞脂解增加和脂肪以外组织的脂质增加密切相关。在肥胖中，肥大的脂肪细胞不能适当地储存多余的脂肪酸，脂肪分解的速度增加，这些脂质沉积在其他组织中，阻碍胰岛素的作用。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很重要，但大多数丝氨酸水解酶尚未被研究过。丝氨酸水解酶（SHs）是参与代谢和脂肪细胞功能的关键酶家族，在这里它们有助于脂肪分解，脂肪生成和脂质

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.