Function of SHP-1 in oligodendrocytes

SHP-1 在少突胶质细胞中的功能

基本信息

批准号：
8820945
负责人：
Paul T Massa
金额：
$ 27.91万
依托单位：
UPSTATE MEDICAL UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-04-01 至 2017-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8820945
关键词：
Anti-Inflammatory Agents Anti-inflammatory Antigens Astrocytes Autoimmunity Brain Cells Cellular biology Central Nervous System Diseases Complex Demyelinating Diseases Demyelinations Disease Disease Pathway Early Endosome Experimental Designs Generations Genes Genetic Human Immune response Immune system In Vitro Inflammatory Knock-out Lesion Lipid Peroxidation Lipids Mediating Metabolic Microglia Mitochondria Multiple Sclerosis Multiple Sclerosis Lesions Mus Myelin Nerve Neuraxis Neurologic Oligodendroglia Oxidative Stress PTPN6 gene Pathology Pathway interactions Phase Predisposition Process Production Protein Tyrosine Phosphatase Proteins Reactive Oxygen Species Role Source Structure Superoxides TNF gene Virus Virus Diseases Wild Type Mouse central nervous system demyelinating disorder cytokine in vivo interest macrophage novel novel strategies oxidation oxidative damage stem white matter white matter damage

项目摘要

DESCRIPTION (provided by applicant): Oligodendrocytes and their connected myelin sheathes are extensively damaged in CNS inflammatory demyelinating lesions in multiple sclerosis (MS). Targeting of oligodendrocytes and myelin in MS is thought to be initiated by either autoimmunity to myelin antigens and/or to inflammatory immune responses to viruses that specifically infect oligodendrocytes. Irrespective of the mode of initiation, common features of white matter damage are oxidative stress of the oligodendrocytes and oxidation of myelin lipids and proteins. The source of oxidative changes in MS white matter is typically assigned to production of reactive oxygen species (ROS) by inflammatory macrophages, microglia, and astrocytes within or near to inflammatory demyelinating lesions. However, we have evidence that major cells responsible for ROS production are oligodendrocytes. Further, we have identified that the protein tyrosine phosphatase SHP-1 is a critical regulator of ROS production in oligodendrocytes and oxidative damage to myelin. As such, we believe that SHP-1 is a key factor in susceptibility to demyelinating disease by pathways that commonly involve ROS generation in the active phase of disease when inflammatory lesions are produced. The latter proposition stems from our related observations of increased susceptibility to demyelinating disease in SHP-1-deficient mice and SHP-1- deficiency in oligodendrocytes in MS brain (Gruber et al, 2011, submitted). The present project is focused on elucidating the mechanisms of ROS production in oligodendrocytes exposed to proinflammatory cytokines that exist in MS lesions and how SHP-1 controls production of ROS in these cells. To do this, we propose 3 specific aims. The first is to determine how SHP-1 regulates constitutive and TNF-¿-inducible ROS production in oligodendrocytes. These studies will identify the sources of superoxide production in oligodendrocytes including ROS-producing complexes localized within early endosomes and mitochondria that are controlled by SHP-1. The second aim is to determine the consequences of increased ROS production in SHP-1-deficient oligodendrocytes. Analysis of lipid peroxidation, protein oxidation, and oxidation of anti-inflammatory PTP in SHP-1-deficient and wild type oligodendrocytes and myelin will be performed using both in vivo and in vitro approaches. Finally, the third specific aim involves a novel approach to ascertain the function of SHP-1 in vivo using targeted conditional deletion of the SHP-1 gene in either mature oligodendrocytes or in macrophages/microglia. These studies will be critical to defining the autonomous activity of SHP-1 in controlling ROS production in oligodendrocytes and resulting demyelinating processes in vivo.

描述（由适用提供）：在多发性硬化症（MS）中，中枢神经系统炎症性脱髓鞘病变（MS），少突胶质细胞及其连接的髓鞘被广泛损害。靶向MS中的少突胶质细胞和髓磷脂的靶向是通过自身免疫性到髓磷脂抗原和/或炎症性免疫呼吸引发的，对特异性感染少突胶质细胞的病毒。无论起始模式如何，白质损伤的共同特征是少突胶质细胞的氧化应激以及髓磷脂脂质和蛋白质的氧化。 MS白质中氧化变化的来源通常由炎症性巨噬细胞，小胶质细胞和星形胶质细胞内或附近炎症性脱髓鞘病变分配给活性氧（ROS）。但是，我们有证据表明负责ROS产生的主要细胞是少突胶质细胞。此外，我们已经确定蛋白质酪氨酸磷酸酶SHP-1是少突胶质细胞中ROS产生的关键调节剂和对髓磷脂的氧化损伤。因此，我们认为SHP-1是通过途径敏感的敏感性的关键因素，该途径通常涉及在产生炎症水平时在疾病的活动阶段产生ROS的疾病。后者的提议步骤从我们对SHP-1缺陷小鼠中脱髓鞘疾病的易感性增加的相关观察结果以及MS脑中少突胶质细胞中SHP-1缺陷的敏感性增加（Gruber等，2011，2011年，提交）。本项目的重点是阐明暴露于MS病变中存在的促炎细胞因子的少突胶质细胞中ROS产生的机制，以及SHP-1如何控制这些细胞中ROS的产生。为此，我们提出了3个具体目标。首先是确定SHP-1如何调节少突胶质细胞中的宪法和TNF-tnf-¿诱导ROS产生。这些研究将确定少突胶质细胞中超氧化物产生的来源，包括局部内体内体内的ROS产生复合物和由SHP-1控制的线粒体。第二个目的是确定SHP-1缺陷少突胶质细胞中ROS产生增加的后果。分析脂质过氧化，蛋白质氧化以及SHP-1缺乏症和野生型少突胶质细胞和髓磷脂中抗炎性PTP的氧化，将使用体内和体外方法进行。最后，第三个特定的目的涉及一种新的方法来确定SHP-1基因在成熟的少突胶质细胞或巨噬细胞/小胶质细胞中的SHP-1基因的靶向条件缺失。这些研究对于定义SHP-1在控制少突胶质细胞中的ROS产生和体内脱髓鞘过程中的自主活动至关重要。