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Altered Sensibility Following Peripheral Nerve Damage

周围神经损伤后敏感性改变

基本信息

批准号：
7340107
负责人：
CLIFFORD J WOOLF
金额：
$ 43.58万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
1998
资助国家：
美国
起止时间：
1998-12-05 至 2008-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7340107
关键词：
Actins Adult Afferent Neurons Apoptosis Apoptotic Axon Axotomy Benzodiazepine Receptor Binding Binding Sites C Fiber Cell Death Cell Survival Cells Cessation of life Chickens Cluster Analysis Complementary DNA Consensus DNA Binding Databases Development Diazepam Binding Inhibitor Disruption Dominant-Negative Mutation Epithelial Essential Genes Gene Cluster Gene Expression Gene Expression Regulation Genes Genetic Transcription Genomics Grant Heat shock proteins Herpes zoster disease Human In Vitro Injury Intention Knockout Mice Lead Lesion Ligands MAPK14 gene Mitogen-Activated Protein Kinases Molecular Molecular Profiling Motor Motor Neurons Mus Neonatal Neuroglia Neurons Neuropathy Nociception Numbers Numbness Oligonucleotide Microarrays Peripheral Peripheral Nerves Peripheral nerve injury Phenotype Phospho-Specific Antibodies Phosphorylation Play Process Promoter Regions Protein Kinase Inhibitors Protein Overexpression Proteins Receptor Activation Research Personnel Role Schwann Cells Sensory Serine Signal Transduction Site Site-Directed Mutagenesis Sodium Channel Spinal Ganglia Techniques Testing Thinking Transgenic Mice Trauma Up-Regulation Work capsaicin receptor central sensitization chromatin immunoprecipitation density diabetic dorsal horn in vivo loss of function neonate nerve injury neuron apoptosis neuron loss neuronal survival novel prevent programs promoter protein expression protein kinase inhibitor receptor response to injury sciatic nerve tool transcription factor

项目摘要

DESCRIPTION (provided by applicant): Peripheral nerve lesions (e.g. trauma, Herpes Zoster, diabetic and AIDs neuropathy) can lead to a loss of sensation as a result of the degeneration or death of primary sensory neurons in the dorsal root ganglion. This grant proposes to examine factors responsible for the survival and the loss of dorsal root ganglion neurons after peripheral axonal injury and after disruption in Schwann cell-axon signaling. This will be investigated by examining the cell survival roles of two genes, the small heat shock protein Hsp27 (Hsp27) and the peripheral benzodiazepine receptor (PBR), and by identifying those transcription factors responsible for the regulation of these genes. Three Aims will be investigated: 1. Can Hsp 27 overexpression rescue DRG neurons from cell death after peripheral nerve injury in the neonate and adult mouse and does its survival role require its phosphorylation? 2. Does the upregulation of PBR after nerve injury play a role in sensory neuron survival in the mouse after injury or a disruption in Schwann cell-axon signaling? 3. What is the master molecular switch responsible for the induction of cell survival genes after nerve-injury? Gain and loss of function approaches in vivo and in vitro will be used to study the contribution of Hsp27 and PBR to sensory neuron survival and injury-induced death. A cluster analysis of gene expression profiles obtained from high-density oligonucleotide microarrays will be used to identify genes regulated coordinately with Hsp27 and PBR and common consensus sites on their promoter regions. The major hypothesis to be tested is that certain transcription factors control cell survival of DRG neurons after axonal injury by regulating the transcription of genes essential for neuronal survival. Absence of these intrinsic survival genes contributes to cell death after nerve injury/lesions.

描述(申请人提供)：周围神经病变(如创伤、带状疱疹、糖尿病和艾滋病神经病变)可导致背根神经节初级感觉神经元退化或死亡，从而导致感觉丧失。这项资助建议研究在外周轴突损伤和雪旺细胞-轴突信号中断后，背根神经节神经元存活和丢失的因素。这将通过检测两个基因，小热休克蛋白Hsp27(Hsp27)和外周苯二氮卓类受体(PBR)的细胞生存作用，并通过识别负责调节这些基因的转录因子来进行研究。我们将研究三个目标：1.热休克蛋白27的过表达能否挽救新生和成年小鼠周围神经损伤后DRG神经元的死亡，其生存作用是否需要其磷酸化？2.神经损伤后PBR的上调是否在小鼠损伤后的感觉神经元存活中起作用，或者雪旺细胞-轴突信号的中断？3.神经损伤后诱导细胞存活基因的主要分子开关是什么？体内和体外的功能获得和丧失方法将被用来研究Hsp27和PBR在感觉神经元存活和损伤诱导的死亡中的作用。从高密度寡核苷酸微阵列获得的基因表达谱的聚类分析将用于识别与Hsp27和PBR协同调控的基因及其启动子区域上的共同共识位点。有待检验的主要假设是，某些转录因子通过调节神经元存活所必需的基因的转录来控制轴突损伤后DRG神经元的细胞存活。这些固有生存基因的缺失导致了神经损伤/损伤后的细胞死亡。