Molecular basis of Scapuloperoneal SMA and Charcot-Marie-Tooth disease type 2C

肩胛腓骨 SMA 和 2C 型腓骨肌萎缩症的分子基础

基本信息

批准号：
8536406
负责人：
Han-Xiang Deng
金额：
$ 32.61万
依托单位：
NORTHWESTERN UNIVERSITY AT CHICAGO
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：
2012-09-01 至 2016-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8536406
关键词：
Address Affect Agonist Amyotrophic Lateral Sclerosis Axon Axonal Neuropathy Biochemical Biological Assay Biotinylation Calcium Calcium Channel Cations Cell Survival Cell surface Cells Charcot-Marie-Tooth Disease Chemicals Clinical Clinical Medicine Confocal Microscopy Data Development Disease Disease Outcome Family Genes Genetic Genotype Goals Hereditary Motor and Sensory Neuropathies Image In Vitro Link Molecular Motor Neuron Disease Motor Neurons Muscular Atrophy Mutation Nature Nerve Degeneration Neurodegenerative Disorders Neuromuscular Diseases Neuropathy Pathogenesis Pathology Peripheral Phenotype Prevalence Probability Property Role Spastic Paraplegia Spinal Spinal Muscular Atrophy Stimulus Transgenic Mice Tumor Cell Line Variant Work axonal degeneration base cell type design effective therapy in vivo insight member mouse model mutant nervous system disorder neurophysiology novel patch clamp receptor

项目摘要

DESCRIPTION (provided by applicant): Through collaborative work over the past 20 years, we have discovered that mutations in the TRPV4 gene cause two allelic neuromuscular disorders, scapuloperoneal spinal muscular atrophy (SPSMA) and Charcot- Marie-Tooth disease type 2C (CMT2C, also known as hereditary motor and sensory neuropathy type IIC (HMSN IIC)). Both SPSMA and CMT2C are characterized by peripheral axonal neuropathy. The pathogenesis of the axonal degeneration underlying these allelic disorders is not known. The TRPV4 gene encodes a transient receptor potential (TRP) cation channel, subfamily V, member 4 (TRPV4), a known Ca2+-permeable, non-selective cation channel. Our preliminary studies indicate that the SPSMA- and CMT2C-linked mutant TRPV4 channels have remarkably increased open probability to Ca2+, leading to an increased intracellular Ca2+ concentration when these channels are expressed in transfected tumor cell lines. These data suggest a potentially pathogenic role for abnormal changes in intracellular Ca2+ concentration in axonal degeneration. To date, 11 different mutations have been found in 24 unrelated families and isolated cases with variant forms of axonal neuropathies. Because the TRPV4-linked axonal neuropathies represent a newly identified group of neuromuscular disorders (TRPV4-channelopathies), many essential questions about their genetic and clinical features, and pathogenic mechanism remain to be addressed. In this application, we propose two closed related specific aims to address a few of the key unresolved issues, including (1) the overall picture of the genetics, clinical variants and potential genotype-phenotype correlation of the TRPV4-linked axonal neuropathies~ (II) the properties of mutant TRPV4 channels in motor neurons, the predominantly affected cell type in this group of disease. Successful completion of this project will provide much needed information for understanding not only the nature of these diseases, but also the molecular basis of the pathogenic mechanism, and therefore to provide a pathophysiological basis for rational therapies. This may be especially true when considering that the calcium channel activity of TRPV4 can be regulated by some known agonists and antagonists. Because TRPV4 can be activated by a wide range of physical and chemical stimuli, and increased Ca2+ influx has been associated with a number of other neurodegenerative diseases, the outcome of this project may also have important implications in the studies of other neurodegenerative diseases.

描述（由申请人提供）：通过过去20年的合作工作，我们发现TRPV4基因的突变引起了两种等位基因神经肌肉疾病，肩p骨脊髓肌肉肌肉萎缩（SPSMA）和Charcot-Marie-Tooth病疾病2C型2C（CMT2C）（CMT2C）（CMT2C），也已知AS HESEDIRE IINIC IIC（HMS）（HMS）（HMS）（HMS）（HMS）（HMS）（HMS）（HMS）（HMS）（HMS HASTY NEIROP）（HMS HASTY NEIROP）（HMS HASTY NEIROP）（HMS HASTY NEIROP）（HMS HASTY NEIROP）。 SPSMA和CMT2C均以周围轴突神经病变为特征。这些等位基因疾病的基础轴突变性的发病机理尚不清楚。 TRPV4基因编码瞬时受体电位（TRP）阳离子通道，亚家族V，成员4（TRPV4），一种已知的Ca2+可渗透性，非选择性阳离子通道。我们的初步研究表明，SPSMA和CMT2C连接的突变体TRPV4通道显着提高了对Ca2+的开放概率，当这些通道在转染的肿瘤细胞系中表达时，细胞内Ca2+浓度增加。这些数据表明，轴突变性中细胞内Ca2+浓度异常变化的潜在致病作用。迄今为止，在24个不相关的家族和具有轴突神经病形式的孤立病例中发现了11种不同的突变。由于TRPV4连接的轴突神经病代表了新鉴定的一组神经肌肉疾病（TRPV4-通道病），因此有关其遗传和临床特征的许多基本问题，并且致病机制仍有待解决。 In this application, we propose two closed related specific aims to address a few of the key unresolved issues, including (1) the overall picture of the genetics, clinical variants and potential genotype-phenotype correlation of the TRPV4-linked axonal neuropathies~ (II) the properties of mutant TRPV4 channels in motor neurons, the predominantly affected cell type in this group of disease. 该项目的成功完成将提供急需的信息，不仅了解这些疾病的性质，还可以理解致病机制的分子基础，因此为理性疗法提供了病理生理基础。考虑到一些已知的激动剂和拮抗剂可以调节TRPV4的钙通道活性时，这可能尤其如此。由于TRPV4可以通过广泛的物理和化学刺激激活，并且增加的Ca2+流入与许多其他神经退行性疾病有关，因此该项目的结果也可能在其他神经退行性疾病的研究中具有重要意义。