Central Prolyl Carboxypeptidase (PRCP) in the regulation of metabolism

 描述(由申请人提供)：脂肪和葡萄糖稳态代谢控制的改变使个人易患心脏代谢疾病，如肥胖、2型糖尿病(T2D)和心血管功能障碍。中枢神经系统(CNS)在心脏代谢动态平衡的调节中起着关键作用。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成分。该系统由3部分组成：1)表达神经肽Y/Agti相关肽(NPY/AgRP)的神经元；2)表达阿片黑素皮质素原(POMC)的神经元；3)表达黑素皮质素受体的神经元，包括MC3R和MC4R。POMC基因编码几个多肽，这些多肽是复杂的翻译后过程的产物。在这些多肽中，α-黑素细胞刺激素(α-MSH)已被证明在新陈代谢中起着基础作用。虽然人们对其产品进行了大量的研究，但其降解过程长期以来一直不为人所知。2009年，我们证明了Pro-羧基肽酶(PrCP)是一种负责降解α-MSH的多肽酶。我们已经证明α-msh1-13确实是PrCP的底物，它将α-msh1-13裂解成失活的α-msh1-12。通过解剖学、生化、药理学和遗传学工具，我们已经证明中央PRCP是黑素皮质素作用的重要调节因子。在这一应用中，我们旨在进一步阐明特定神经元群体中PRCP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。提出了四个特定的目标：目标1将确定NPY/AgRP神经元中PRCP的表达是否是调节食物摄入所必需的。目的2确定下丘脑背内侧核(DMH)内的PRCP是否在调节血压和能量消耗(EE)中是必需的。目的3将确定PRCP的释放是否受到神经元活动的促进。由于PRCP通过调节中枢黑素皮质素信号在体内稳态中起关键作用，因此PRCP有望成为治疗肥胖、2型糖尿病和心血管功能障碍等心脏代谢紊乱的新靶点。因此，这些研究的实施将进一步揭示中央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，这些抑制剂需要转化PRCP遗传学和生物化学来治疗心脏代谢性疾病。

 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.