Schwann Cell Control of Chronic Nerve Injury

雪旺细胞对慢性神经损伤的控制

基本信息

批准号：
7887698
负责人：
Ranjan Gupta
金额：
$ 32.08万
依托单位：
UNIVERSITY OF CALIFORNIA-IRVINE
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：
2010-01-19 至 2014-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7887698
关键词：
American Basal lamina Bioreactors Carpal Tunnel Syndrome Cell Proliferation Cell physiology Cells Chondroitin Sulfate Proteoglycan Chronic Clinical Coculture Techniques Collagen Complex Cubital Tunnel Syndrome Custom Demyelinations Disease Doppler Echocardiography Dystroglycan Environment Erinaceidae Esthesia Event Experimental Models Extracellular Matrix Fibroblasts Fibrosis Functional disorder Glucose Transporter Goals Hypoxia In Vitro Inflammation Inflammatory Injury Integrins Ischemia Knowledge Laminin Lasers Measures Mechanical Stress Mechanics Mediating Mediator of activation protein Modeling Molecular Morbidity - disease rate Mus Muscular Atrophy Myelin Nerve compression syndrome Orthopedics Oxygen measurement, partial pressure, arterial Pain Pathogenesis Pathway interactions Pattern Peripheral Nerves Peripheral Nervous System Diseases Phase Phosphotransferases Physicians Predisposition Process Proteins Research Reverse Transcriptase Polymerase Chain Reaction Schwann Cells Scientist Secondary to Signal Transduction Source Spinal Ganglia Spinal nerve root structure Stenosis Surgeon Symptoms System Testing Time To specify Transgenic Organisms Translating Vascular Endothelial Growth Factors Wallerian Degeneration Western Blotting Work axonal degeneration clinical care design extracellular improved in vitro Model in vivo myelination nerve injury novel null mutation public health relevance relating to nervous system response transcription factor

项目摘要

DESCRIPTION (provided by applicant): Each year, millions of Americans suffer from chronic nerve compression (CNC) injuries such as carpal tunnel syndrome, cubital tunnel syndrome, and spinal nerve root stenosis. These peripheral neuropathies produce substantial morbidity secondary to symptoms of pain, altered sensation, and muscle atrophy because treatment options are very limited. As an orthopaedic surgeon specializing in peripheral nerve dysfunction, my goals as a physician-scientist are to improve our basic knowledge of the underlying pathophysiology and to identify approaches for translating these scientific discoveries into clinical care. As such, this project builds upon our prior work in defining the underlying molecular pathways involved in the pathogenesis of CNC injury. Previously, we established an experimental model for CNC injuries that demonstrated massive Schwann cell proliferation accompanied by demyelination without axonal degeneration in the early injury phase. Interestingly, this appears to occur in the absence of inflammatory cell activation. Additional work is needed to specify the signals triggering this cascade of events. In this project, we will test our primary hypothesis that CNC injury is an acquired basal lamina-associated disease. We will examine whether Schwann cells mediate the mechanical and ischemic effects of CNC injury by activating secondary messenger systems via alteration of the extracellular matrix (ECM) CM). A secondary hypothesis is that integrins serve as the critical intermediaries for the transduction of extracellular signals from CNC injury into intracellular molecular pathways; possible signals include mechanical stress and ischemia contributing independently or synergistically. The specific aims of this project are (1) to determine if CNC injury induces the fibroproliferative response by altering Schwann cell basal lamina constituents (2) to test if Schwann cell integrins are key regulators of mechanotransduction after CNC injury via functional linkage to the ECM, and (3) to determine whether ischemia modulates Schwann cell mechanotransduction by lowering the threshold for mechanically induced demyelination. The present application seeks to define the signals that alter the ECM and trigger the injury-related responses, using our experimental models of CNC injury. In accomplishing these goals, we will have the potential to design novel new therapies by targeting these specific pathways. PUBLIC HEALTH RELEVANCE: Millions of Americans suffer from chronic nerve compression (CNC) injuries such as carpal tunnel syndrome, cubital tunnel syndrome and spinal nerve root stenosis. Over the past eight years our research described for the first time that CNC injuries are a distinct entity characterized by the loss of myelin without axonal injury, the proliferation of Schwann cells and a lack of inflammation. The goal of this application is to build upon our previous research in the hopes of identifying the key molecular pathways involved in the disease process so that we will have the potential to design novel new therapies by targeting these specific pathways.

描述（由申请人提供）：每年，数百万美国人遭受慢性神经压迫（CNC）损伤，例如腕管综合征、肘管综合征和脊神经根狭窄。由于治疗选择非常有限，这些周围神经病会导致继发于疼痛、感觉改变和肌肉萎缩症状的大量发病率。作为一名专门研究周围神经功能障碍的骨科医生，作为一名医师科学家，我的目标是提高我们对潜在病理生理学的基础知识，并确定将这些科学发现转化为临床护理的方法。因此，该项目建立在我们之前定义 CNC 损伤发病机制相关分子途径的工作基础上。此前，我们建立了 CNC 损伤的实验模型，该模型表明在损伤早期，雪旺细胞大量增殖并伴有脱髓鞘，但没有轴突变性。有趣的是，这似乎是在没有炎症细胞激活的情况下发生的。需要进行额外的工作来指定触发这一系列事件的信号。在这个项目中，我们将检验我们的主要假设，即 CNC 损伤是一种获得性基底层相关疾病。我们将检查雪旺细胞是否通过改变细胞外基质 (ECM) CM) 激活第二信使系统来介导 CNC 损伤的机械和缺血效应。第二个假设是整合素是细胞外信号从 CNC 损伤转导到细胞内分子途径的关键中介。可能的信号包括独立或协同作用的机械应力和缺血。该项目的具体目标是 (1) 确定 CNC 损伤是否通过改变施万细胞基底层成分来诱导纤维增殖反应 (2) 测试施万细胞整合素是否通过与 ECM 的功能连接成为 CNC 损伤后机械转导的关键调节因子， (3)确定缺血是否通过降低机械诱导脱髓鞘的阈值来调节雪旺细胞机械转导。本申请旨在使用我们的 CNC 损伤实验模型来定义改变 ECM 并触发损伤相关反应的信号。在实现这些目标的过程中，我们将有可能通过针对这些特定途径来设计新颖的疗法。公众健康相关性：数百万美国人患有慢性神经压迫 (CNC) 损伤，例如腕管综合征、肘管综合征和脊神经根狭窄。在过去的八年里，我们的研究首次描述了 CNC 损伤是一个独特的实体，其特征是髓磷脂缺失但没有轴突损伤、雪旺细胞增殖和缺乏炎症。该应用的目标是建立在我们之前的研究基础上，希望能够确定疾病过程中涉及的关键分子途径，以便我们有可能通过针对这些特定途径来设计新颖的疗法。