OPIOID METABOLISM BY IMMUNE SYSTEM PEPTIDASES

描述（申请人摘要）：驱动该项目的假设是， 免疫系统中的肽酶在调节局部阿片样物质 肽浓度和活性阿片肽的谱。调节 肽酶活性的表达是一种强大的机制， 终止或改变受体识别、信号转导和生理 免疫细胞对外源性阿片肽的反应。阿片肽是 据报道，作为调节信号之间的神经内分泌和免疫 系统以及免疫系统细胞之间。阿片肽（即， 脑啡肽和内啡肽）在体外影响许多免疫系统功能 (e.g.,抗体产生，细胞增殖，细胞毒性，淋巴因子 生产和趋化性）。一些免疫活性细胞类型合成并 释放脑啡肽和内啡肽来响应炎症刺激。阿片 已经报道调节严重受损的免疫系统（例如， 获得性免疫缺陷综合征和癌症）。我们最近的研究 β-内啡肽（B-EP）代谢表明，细胞内肽酶 称为胰岛素降解酶（IDE），也称为β-内啡肽 生成酶（EpGE）负责这种阿片样物质的代谢 免疫细胞中的肽。拟议的研究重点是监管 这种IDE/（EpGE）的表达和功能，因为它与B-EP代谢有关 并在免疫细胞中发挥作用。这些研究提出了一种独特的机制 包括刺激的巨噬细胞摄取B-EP， 通过IDE将B-EP内化为活性代谢物，并分泌 肽产品。基于这些新的观察，提出了三个目标：1） 为了确定IDE/EpGE的表达在激活过程中是如何调节的， 和巨噬细胞的成熟/刺激。2)阐明本 参与B-EP摄取和分泌的机制以及其他 巨噬细胞的B-EP代谢物。3)鉴定B-EP转运蛋白/受体。

DESCRIPTION (applicant's abstract): The hypothesis driving this project is that peptidases in the immune system are important in modulating both local opioid peptide concentrations and the spectrum of active opioid peptides. Regulated expression of peptidase activity is a powerful mechanism having potential to terminate or alter receptor recognition, signal transduction, and physiological responses of immune cells to exogenous opiate peptides. Opioid peptides are reported to serve as regulatory signals between the neuroendocrine and immune systems as well as among immune system cells. Opioid peptides (i.e., enkephalins and endorphins) affect a number of immune system functions in vitro (e.g., antibody production, cell proliferation, cytotoxicity, lymphokine production, and chemotaxis). Some immunocompetent cell types synthesize and release enkephalins and endorphins in response to inflammatory stimuli. Opioids have been reported to modulate severely compromised immune systems (e.g., acquired immunodeficiency syndrome and cancer). Our recent studies on beta-endorphin (B-EP) metabolism suggest that an intracellular peptidase referred to as insulin degrading enzyme (IDE), also known as beta-endorphin generating enzyme (EpGE), is responsible for the metabolism of this opioid peptide in immune cells. The proposed studies focus on the regulation of expression and function of this IDE/(EpGE as it is related to B-EP metabolism and function in immune cells. A unique mechanism is suggested by these studies involving the uptake of B-EP by stimulated macrophages, the conversion of the internalized B-EP to active metabolites by IDE, and the secretion of the peptide products. Based on these novel observations three aims are proposed: 1) To determine how the expression of IDE/EpGE is regulated during the activation of T cells and maturation / stimulation of macrophages. 2) To elucidate the mechanisms involved in the uptake of B-EP and the secretion of B-EP and other B-EP metabolites by macrophages. 3) To identify the B-EP transporter/receptor.