Satellite Glial Cells

卫星胶质细胞

基本信息

批准号：
7922556
负责人：
LUC JASMIN
金额：
$ 33.44万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-06-01 至 2013-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7922556
关键词：
Adenosine Triphosphate Adult Afferent Neurons American Animals Behavior Behavioral Calcium Calcium-Activated Potassium Channel Cell Communication Chronic Code Connexin 43 Double-Stranded RNA Environment Enzymes Esthesia Exhibits Face Gap Junctions Gene Expression Gene Silencing Genes Genetic Glial Fibrillary Acidic Protein Glutamates Guanylate Cyclase Individual Injury Intractable Pain Ion Channel Ion Transport Life Location Long-Term Effects Mediating Medical center Modeling Nerve Neuroglia Neurons Neurosurgeon Neurotransmitter Receptor Neurotransmitters Nitric Oxide Pain Patients Perception Peripheral Persistent pain Phenotype Physiological Play Population Potassium Potassium Channel Principal Investigator Purinoceptor RNA Interference Rattus Regulation Research Research Institute Research Personnel Role Sensory Sensory Ganglia Series Signal Transduction Structure of trigeminal ganglion Symptoms Testing Therapeutic Human Experimentation Time Trigeminal nerve structure Up-Regulation Work behavior test cell type chronic pain constriction ganglion cell improved injured member nerve injury neuronal cell body neuronal excitability neurotransmitter release painful neuropathy protein expression public health relevance purinoceptor P2Y4 research study response therapy development

项目摘要

DESCRIPTION (provided by applicant): Approximately 6% of the American population suffers from intractable pain following nerve injury; yet available treatment options are only marginally effective. Persistent pain was previously attributed exclusively to sensory neuron functions; however, recent discoveries indicate that glial cells also contribute to chronic pain. Activation of satellite glial cells (SGCs), the type of glial cell surrounding primary sensory neurons, correlates with increased sensory neuron excitability. A better understanding of this glia-induced hyper-excitability is likely to open the door to new therapies for nerve-injured patients. Until recently, means of studying the role of glial cells in nerve injury were limited. By using stereotactically targeted RNA interference (RNAi) to inhibit gene expression, we can now silence specific genes in single sensory ganglia of adult rats. Here, we have chosen to study a series of SGC-specific genes involved in neuronal excitability including genes that code for a neurotransmitter receptor (P2Y4), an enzyme (guanylyl cyclase), a calcium-activated potassium channel (SK3), and a component of the gap junction (connexin 43). These genes are likely to play key roles in neuropathic pain since they regulate neuron-SGC communication and control neuronal excitability following injury. Our preliminary experiments utilizing RNAi-mediated gene silencing at the trigeminal ganglion, where SGCs surround the cell bodies of primary sensory neurons innervating the face, show that this approach selectively and reversibly silences SGC genes in freely behaving rats. We can quantify the effects of gene silencing in these animals through several behavioral tests, as well as by anatomical and physiological analyses. This proposal aims to elucidate the contribution of SGC-specific genes to the control of neuronal excitability and sensory behavior following trigeminal nerve injury. With these results we hope to define genetic targets for the development of therapies that could improve the lives of individuals suffering from the long-term effects of nerve injury. The Principal Investigator of this proposed study directs, and serves as the neurosurgeon for, the Interdepartmental Pain Group at Cedars-Sinai Medical Center and is a member of the Cedars-Sinai Gene Therapeutics Research Institute, where this work will be completed. Fifty percent of the Principle Investigator's time is protected to pursue research. PUBLIC HEALTH RELEVANCE Approximately 6% of the American population suffers from intractable pain following nerve injury; yet available treatment options are only marginally effective. Persistent pain was previously attributed exclusively to sensory neuron functions; however, recent discoveries indicate that glial cells also contribute to chronic pain. Activation of satellite glial cells (SGCs), the type of glial cell surrounding primary sensory neurons, correlates with increased sensory neuron excitability. A better understanding of this glia-induced hyper-excitability is likely to open the door to new therapies for nerve-injured patients.

描述（由申请人提供）：大约 6% 的美国人患有神经损伤后的顽固性疼痛；然而现有的治疗方案效果有限。以前，持续性疼痛仅归因于感觉神经元功能；然而，最近的发现表明神经胶质细胞也会导致慢性疼痛。卫星胶质细胞（SGC）是一种围绕初级感觉神经元的胶质细胞，其激活与感觉神经元兴奋性的增加相关。更好地了解这种神经胶质细胞引起的过度兴奋可能为神经损伤患者的新疗法打开大门。直到最近，研究神经胶质细胞在神经损伤中的作用的方法仍然有限。通过使用立体定向RNA干扰（RNAi）来抑制基因表达，我们现在可以沉默成年大鼠单个感觉神经节中的特定基因。在这里，我们选择研究一系列与神经元兴奋性相关的 SGC 特异性基因，包括编码神经递质受体 (P2Y4)、酶（鸟苷酸环化酶）、钙激活钾通道 (SK3) 和成分的基因间隙连接（连接蛋白 43）。这些基因可能在神经病理性疼痛中发挥关键作用，因为它们调节神经元-SGC 通讯并控制损伤后的神经元兴奋性。我们在三叉神经节（SGC 围绕着支配面部的初级感觉神经元的细胞体）利用 RNAi 介导的基因沉默进行了初步实验，表明这种方法选择性地、可逆地沉默了自由行为大鼠的 SGC 基因。我们可以通过一些行为测试以及解剖学和生理学分析来量化基因沉默对这些动物的影响。该提案旨在阐明 SGC 特异性基因对三叉神经损伤后神经元兴奋性和感觉行为控制的贡献。通过这些结果，我们希望确定开发治疗方法的遗传靶点，从而改善遭受神经损伤长期影响的个体的生活。这项拟议研究的首席研究员指导并担任雪松-西奈医疗中心跨部门疼痛小组的神经外科医生，并且是雪松-西奈基因治疗研究所的成员，这项工作将在该研究所完成。首席研究员百分之五十的时间被用来进行研究。公共卫生相关性大约 6% 的美国人患有神经损伤后的顽固性疼痛；然而现有的治疗方案效果有限。以前，持续性疼痛仅归因于感觉神经元功能；然而，最近的发现表明神经胶质细胞也会导致慢性疼痛。卫星神经胶质细胞（SGC）是一种围绕初级感觉神经元的神经胶质细胞，其激活与感觉神经元兴奋性的增加相关。更好地了解这种神经胶质细胞引起的过度兴奋可能为神经损伤患者的新疗法打开大门。