Central Prolyl Carboxypeptidase (PRCP) in the regulation of metabolism

中央脯氨酰羧肽酶 (PRCP) 在代谢调节中的作用

• 批准号: 10360810
• 负责人: Sabrina Diano
• 金额: $ 5.8万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-01 至 2021-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10360810
• 关键词: Central; Prolyl; Carboxypeptidase; PRCP; regulation

 DESCRIPTION (provided by applicant): Alterations in the metabolic control of lipid and glucose homeostasis predispose an individual to develop cardiometabolic diseases, such as obesity, type 2-diabetes (T2D) and cardiovascular dysfunction. The Central Nervous System (CNS) plays a critical role in regulating cardiometabolic homeostasis. Within the CNS, the melanocortin system has been shown to be a major component in modulating cardiometabolic homeostasis. This system consists of 3 components: 1) neurons expressing Neuropeptide Y/Agouti related peptide (NPY/AgRP), 2) neurons expressing pro-opiomelanocortin (POMC) and 3) neurons expressing melanocortin receptors, including MC3R and MC4R. The POMC gene encodes several peptides that are the products of a complex post-translational process. Among these peptides, alpha-melanocyte stimulating hormone (α-MSH) has been shown to play a fundamental role in metabolism. Although its production has been largely studied, its degradation process has been unknown for a long time. In 2009, we demonstrated that prolyl carboxypeptidase (PRCP) is a peptidase responsible for the degradation of α-MSH. We have showed that α-MSH1-13 is indeed a substrate of PRCP, which cleaves α-MSH1-13 to inactive α-MSH1-12. Through anatomical, biochemical, pharmacological and genetic tools, we have demonstrated that central PRCP is an important regulator of melanocortin action. In this application, we aim to further elucidate on the role of PRCP in specific neuronal populations in the regulation of cardiometabolism and on role of neuronal activity in PRCP release and action. Four specific aims are proposed: Aim 1 will determine whether PRCP expression in NPY/AgRP neurons is necessary to modulate food intake. Aim 2 will determine whether PRCP in the hypothalamic dorsomedial nucleus (DMH) is necessary in the regulation of blood pressure and energy expenditure (EE). Aim 3 will determine whether PRCP release is promoted by neuronal activity. Because PRCP plays a pivotal role in homeostasis by regulating central melanocortin signaling, PRCP represents a potential new therapeutic target to treat cardiometabolic disorders such as obesity, type 2 diabetes and cardiovascular dysfunction. Thus, the execution of these studies will further unmask the role of central PRCP in metabolism regulation and will help us to better develop new classes of tissue-specific PRCP inhibitors needed to translate PRCP genetics and biochemistry for treatments of cardiometabolic disorders.

 描述（通过应用程序提供）：脂质和葡萄糖稳态的代谢控制的改变，易于患者发展心脏代谢性疾病，例如肥胖，肥胖，2型糖尿病（T2D）和心血管功能障碍。中枢神经系统（CNS）在调节心脏代谢稳态中起着至关重要的作用。在中枢神经系统中，黑素皮质素系统已被证明是调节心脏代谢稳态的主要组成部分。该系统由3个组成部分组成：1）表达神经肽y/agouti相关肽（NPY/AGRP）的神经元，2）表达促蛋白质素的神经元（POMC）和3）表达黑色素皮质受体的神经元，包括MC3R和MC3R和MC4R。 POMC基因编码了几种宠物，这些宠物是复杂的翻译后过程的产物。在这些宠物中，α-甲状腺细胞刺激的马酮（α-MSH）的产生在很大程度上是研究的，但其降解过程已经很长一段时间了。在2009年，我们证明了丙酰羧肽酶（PRCP）是导致α-MSH降解的肽。我们已经表明，α-MSH1-13确实是PRCP的底物，它将α-MSH1-13切割至无效α-MSH1-12。通过解剖学，生化，药理学和遗传工具，我们证明了Central Prcp是黑色素性作用的重要调节剂。在此应用程序中，我们旨在进一步阐明PRCP在特定神经元种群中的作用，并在心脏代谢的调节中以及神经元活性在PRCP释放和作用中的作用。提出了四个具体目的：AIM 1将确定在调节食物摄入量中是否有必要使用NPY/AGRP神经元中的PRCP表达。 AIM 2将确定在血压和能量消耗（EE）的调节中，下丘脑背核（DMH）中的PRCP是否需要。 AIM 3将确定PRCP释放是否通过神经元活性促进。由于PRCP通过控制中央黑色皮质素信号传导在体内平衡中起关键作用，因此PRCP代表了治疗心脏代谢性疾病（例如肥胖，2型糖尿病和心血管功能障碍）的潜在新治疗靶标。这是这些研究的执行将进一步揭示中央PRCP在代谢调节中的作用，并将帮助我们更好地开发新的组织特异性PRCP抑制剂，以转化PRCP遗传学和生物化学用于心脏代谢疾病的治疗方法。