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：
8302064
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 2016-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8302064
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. PUBLIC HEALTH RELEVANCE: Oxidation of white matter is a main cause of myelin damage in CNS demyelinating diseases including multiple sclerosis (MS). Knowing the cause for this oxidation and how it is genetically controlled would help us understand how demyelination occurs in MS. Our studies will investigate the myelin-forming oligodendrocytes in the white matter as novel sources for CNS reactive oxygen species (ROS), the role for ROS in white matter oxidation, and the genetic control of both ROS production and myelin oxidation by the protein tyrosine phosphatase SHP-1.

描述（由申请人证明）：少突胶质细胞及其连接的髓鞘在多发性硬化症（MS）和/或对病毒的炎症性免疫反应中的大量损伤。髓磷脂脂质和蛋白质通常由炎症性巨噬细胞分配给反应性氧气（ROS），而在炎症性甲状腺素中或附近的星形胶质细胞则是如何有ROS产生的主要细胞。少突胶质细胞中的ROS产生的关键调节剂对髓磷脂的氧化性损害。 -1型NT小鼠和SHP-1缺陷在MS大脑中的少突胶质细胞中（Gruber等人，2011年，提交）。 1控制ROS的生产。 - 少突胶质细胞中的ROS产生。少突胶质细胞的脂质过氧化，蛋白质氧化和SHP-1缺陷的抗炎PTP的氧化，将使用体内和Intreactes进行确定的方法来进行SHP-1野生型野生型野生型。 1在成熟的ig胶细胞或巨噬细胞/小胶质细胞中使用靶向的SHP-1基因的靶向条件缺失。。公共卫生相关性：白质是中枢神经系统脱素损伤的主要原因（MS）。作为CNS活性氧（ROS）HITE物质氧化的来源，以及蛋白质酪氨酸磷酸SHP-1对ROS产生和髓磷脂氧化的遗传控制。