Role of SHP-1 in monocyte-mediated demyelination

SHP-1 在单核细胞介导的脱髓鞘中的作用

基本信息

批准号：
8144300
负责人：
Paul T Massa
金额：
$ 27.35万
依托单位：
UPSTATE MEDICAL UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-09-15 至 2014-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8144300
关键词：
Address Anti-Inflammatory Agents Anti-inflammatory Area Attenuated Biology Blood Bone Marrow CCL2 gene Cell Communication Cell Lineage Cells Central Nervous System Diseases Complex Demyelinating Diseases Demyelinations Dendritic Cells Development Disease Effector Cell Event Gene Expression Genes Genetic Human ITGAM gene Immune response Immune system Infection Infiltration Inflammation Inflammatory Knowledge Laboratories Lead Lesion Mediating Meninges Microbe Modeling Movement Multiple Sclerosis Multiple Sclerosis Lesions Mus Myelin Neuraxis Neurologic Neurons Nitric Oxide Oligodendroglia PTPN6 gene Patients Peripheral Peritoneum Phase Phenotype Population Predisposition Production Research Role Site Spinal Cord Spleen Systemic infection TMEV Tissues Tropism Viral Viral Physiology Virus Virus Diseases Virus Replication Virus-Cell Membrane Interaction Wild Type Mouse bean chemokine cytokine design gray matter human NOS2A protein human disease in vivo interest intraperitoneal macrophage microbial monocyte monocyte chemoattractant protein 1 receptor mouse model novel novel strategies public health relevance theories trafficking white matter

项目摘要

DESCRIPTION (provided by applicant): Cells of the innate immune system such as macrophages express specific genes that control both virus replication and virus-induced inflammation. Dysregulation of these genes has been shown to result in increased susceptibility to either viral infections or inflammatory diseases. Our laboratory is focused on genes that control specific virus-cell interactions in monocyte-lineage cells including macrophages that cause virus- induced inflammatory demyelination in the central nervous system (CNS). These studies are particularly relevant to understanding the genetic mechanisms for initiation and sustained inflammatory demyelination mediated by monocyte-lineage cells in the human demyelinating disease multiple sclerosis (MS). Of particular importance is that we have discovered a deficiency in the key anti-inflammatory gene SHP-1 in macrophages of MS patients that results in high levels of inflammatory activity in these cells similar to that seen in MS lesions. To further define the role of SHP-1 deficiency in demyelinating disease, we are studying both anti- inflammatory and anti-viral activities in monocytes of mice that are genetically deficient in SHP-1. Recently, we have shown that SHP-1-deficient mice are profoundly susceptible to virus-induced demyelinating disease compared to wild type mice following a peripheral inoculation with relatively low amounts of Theiler's murine encephalomyelitis virus (TMEV). TMEV infection appears to predominant initially in the spleen and in inflammatory monocytes in the blood prior to entry of these cells and TMEV into the CNS. These new observations have posed important questions on how peripheral virus infection of monocytes may elicit a relatively specific targeting of monocyte-mediated inflammation in the CNS white matter. Thus, the specific aims are designed to address how TMEV infects and then stimulates monocytes in the periphery to enter the CNS in large numbers and subsequently mediate inflammatory demyelination. Specific aim 1 will characterize the initial infection and spreading of TMEV within monocyte populations following peripheral inoculation. Specific aim 2 will focus on the role for the chemokine MCP-1 and its receptor CCR2 in the spreading of TMEV to monocytes in peripheral tissues and eventual movement of these infected monocytes to the CNS. Specific aim 3 will determine whether infected inflammatory monocytes that enter the white matter following peripheral TMEV inoculation differentiate into either mature macrophages or dendritic cells within demyelinating lesions and function in demyelination. Finally, we will characterize the role for SHP-1 deficiency in allowing heightened infection and persistence of TMEV in monocyte-lineage cells that may be an essential condition for development of CNS disease. Together, the research plan presents novel approaches to further elucidate the importance of SHP-1 in monocyte-lineage cells in controlling multiple key events critical for virus-induced inflammatory diseases in the CNS. PUBLIC HEALTH RELEVANCE: An essential effector cell in the human demyelinating disease, multiple sclerosis (MS), is the macrophage. Macrophages in MS white matter lesions express multiple inflammatory cytokines, toxic molecules, and phagocytic activity that cause destruction of both myelin-forming oligodendrocytes and myelin sheathes. Yet, our knowledge of macrophage biology in demyelinating disease is incomplete. We have found that a key molecule SHP-1 stringently modulates inflammatory activities of macrophages in demyelinating disease. The present project is thus focused on defining the essential role of SHP-1 in macrophage-mediated demyelinating disease.

描述（由申请人提供）：巨噬细胞等先天免疫系统的细胞表达了控制病毒复制和病毒诱发的炎症的特定基因。这些基因的失调已被证明会增加对病毒感染或炎症性疾病的敏感性。我们的实验室集中于控制单核细胞细胞中特定病毒细胞相互作用的基因，包括引起病毒诱导的中枢神经系统（CNS）炎症性脱髓鞘的巨噬细胞。这些研究与理解引发的遗传机制和持续的炎症性脱髓鞘尤其相关。特别重要的是，我们发现在MS患者的巨噬细胞中，关键的抗炎基因SHP-1缺乏，这些细胞中类似于MS病变类似的细胞的炎症活性很高。为了进一步定义SHP-1缺乏症在脱髓鞘疾病中的作用，我们正在研究SHP-1遗传缺陷的小鼠的抗炎性和抗病毒活性。最近，我们已经表明，与野生型小鼠相比，SHP-1缺陷的小鼠对病毒诱导的脱髓鞘疾病非常容易受到外围接种，而野生型小鼠的疾病则相对较低，其含量相对较低，其含量相对较低。 TMEV感染最初在脾脏和血液中的炎症单核细胞中似乎占主导地位，然后再进入这些细胞和TMEV进入CNS。这些新观察结果提出了有关单核细胞外周病毒感染如何引起中枢神经系统白质中单核细胞介导的炎症的相对特异性靶向的重要问题。因此，特定的目的旨在解决TMEV感染并刺激外围单核细胞大量进入CNS的单核细胞，然后随后介导炎症性脱髓鞘。特定的目标1将表征周围接种后单核细胞种群中TMEV的初始感染和扩散。具体的目标2将重点关注趋化因子MCP-1及其受体CCR2在TMEV向周围组织中单核细胞扩散以及这些感染单核细胞向CNS的最终运动的作用。具体目标3将确定在周围TMEV接种后进入白质的感染炎症单核细胞是否在脱髓鞘病变中分化为成熟的巨噬细胞或树突状细胞。最后，我们将表征SHP-1缺乏症在允许增加感染和TMEV持续性的单核细胞细胞中的作用，这可能是CNS疾病发展的重要条件。研究计划共同提出了新的方法，以进一步阐明SHP-1在单核细胞细胞中控制CNS病毒诱导炎症性疾病至关重要的多个关键事件中的重要性。公共卫生相关性：人类脱髓鞘疾病的基本效应细胞，多发性硬化症（MS）是巨噬细胞。 MS白质病变中的巨噬细胞表达多种炎症细胞因子，毒性分子和吞噬活性，这些活性会导致髓磷脂形成的少突胶质细胞和髓磷脂的破坏。然而，我们对脱髓鞘疾病中巨噬细胞生物学的了解是不完整的。我们发现，一个关键的分子SHP-1严格调节巨噬细胞在脱髓鞘疾病中的炎症活性。因此，本项目的重点是定义SHP-1在巨噬细胞介导的脱髓鞘疾病中的重要作用。