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易于发生心脏代谢疾病，如肥胖症、2型糖尿病（T2 D）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成分。该系统由3个部分组成：1）表达神经肽Y/AgRP相关肽（NPY/AgRP）的神经元，2）表达前阿黑皮素（POMC）的神经元和3）表达黑皮质素受体（包括MC 3R和MC 4 R）的神经元。POMC基因编码几种肽，这些肽是复杂的翻译后过程的产物。在这些肽中，α-黑素细胞刺激激素（α-MSH）已被证明在代谢中发挥重要作用。虽然它的生产已被大量研究，但其降解过程一直是未知的。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-MSH 1 -13确实是PRCP的底物，PRCP将α-MSH 1 -13切割成无活性的α-MSH 1 -12。通过解剖学，生物化学，药理学和遗传学的工具，我们已经证明，中央PRCP是一个重要的调节黑皮质素行动。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调节心脏代谢的作用以及PRCP释放和作用中神经元活性的作用。提出了四个具体的目标：目标1将确定是否PRCP在NPY/AgRP神经元的表达是必要的，以调节食物的摄入。目的2：研究下丘脑背内侧核（DMH）的PRCP是否参与血压和能量消耗的调节。目的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在体内平衡中起着关键作用，因此PRCP代表了治疗心脏代谢疾病如肥胖、2型糖尿病和心血管功能障碍的潜在新治疗靶点。因此，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类型的组织特异性PRCP抑制剂，以转化PRCP遗传学和生物化学用于治疗心脏代谢疾病。

 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.