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（由申请人提供）：多发性硬化症（MS）中的中枢神经系统炎性脱髓鞘病变中的少突胶质细胞及其连接的髓鞘通常受到损伤。多发性硬化症中少突胶质细胞和髓磷脂的靶向被认为是由对髓磷脂抗原和/或髓磷脂的自身免疫引发的。对特异性感染少突胶质细胞的病毒的炎症性免疫反应，无论起始方式如何，都是白质损伤的共同特征。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 白质细胞的氧化变化通常归因于炎症性脱髓鞘内或附近的炎症巨噬细胞、小胶质细胞和星形胶质细胞产生活性氧 (ROS)。然而，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，我们还发现蛋白质酪氨酸磷酸酶。 SHP-1 是少突胶质细胞中 ROS 产生和髓磷脂氧化损伤的关键调节因子，因此，我们认为 SHP-1 是脱髓鞘疾病易感性的关键因素，其途径通常涉及疾病活跃期的 ROS 产生。后一个命题源于我们对 SHP-1 缺陷小鼠和 SHP-1 缺陷小鼠对脱髓鞘疾病的易感性增加的相关观察。 MS 大脑中的少突胶质细胞（Gruber 等人，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，第一个是确定 SHP-1 如何调节组成型和 TNF-¿ -少突胶质细胞中诱导的 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，包括由 SHP-1 控制的位于早期核内体和线粒体内的 ROS 产生复合物。 SHP-1 缺陷型少突胶质细胞的脂质过氧化、蛋白质氧化和抗炎 PTP 氧化的分析。最后，第三个具体目标涉及一种新方法，通过在任一成熟少突胶质细胞中定向条件性删除 SHP-1 基因来确定 SHP-1 的体内功能。这些研究对于确定 SHP-1 在控制少突胶质细胞中 ROS 产生以及由此产生的体内脱髓鞘过程中的自主活性至关重要。