Central Prolyl Carboxypeptidase (PRCP) in the regulation of metabolism

 描述（由申请人提供）：脂质和葡萄糖稳态代谢控制的改变使个体容易患上心脏代谢疾病，例如肥胖、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发挥着关键作用。在中枢神经系统内，黑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 个组件组成：1) 表达神经肽 Y/Agouti 相关肽 (NPY/AgRP) 的神经元，2) 表达阿片黑皮质素原 (POMC) 的神经元和 3) 表达黑皮质素受体（包括 MC3R 和 MC4R）的神经元。 POMC 基因编码多种肽，这些肽是复杂翻译后过程的产物。在这些肽中，α-黑素细胞刺激激素 (α-MSH) 已被证明在新陈代谢中发挥着重要作用。尽管对其生产进行了大量研究，但其降解过程长期以来一直未知。 2009年，我们证明脯氨酰羧肽酶（PRCP）是一种负责降解α-MSH的肽酶。我们已经证明 α-MSH1-13 确实是 PRCP 的底物，它将 α-MSH1-13 裂解为无活性的 α-MSH1-12。通过解剖、生化、药理学和遗传学工具，我们已经证明中枢 PRCP 是黑皮质素作用的重要调节因子。在本申请中，我们的目的是进一步阐明PRCP在特定神经元群体中在心脏代谢调节中的作用以及神经元活动在PRCP释放和作用中的作用。提出了四个具体目标： 目标 1 将确定 NPY/AgRP 神经元中的 PRCP 表达是否是调节食物摄入所必需的。目标 2 将确定下丘脑背内侧核 (DMH) 中的 PRCP 在调节血压和能量消耗 (EE) 中是否必要。目标 3 将确定 PRCP 释放是否由神经元活动促进。由于 PRCP 通过调节中枢黑皮质素信号传导在体内平衡中发挥着关键作用，因此 PRCP 代表了治疗肥胖、2 型糖尿病和心血管功能障碍等心脏代谢疾病的潜在新治疗靶点。因此，这些研究的执行将进一步揭示中枢 PRCP 在代谢调节中的作用，并将帮助我们更好地开发新类别的组织特异性 PRCP 抑制剂，以转化 PRCP 遗传学和生物化学来治疗心脏代谢疾病。

 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.