A model of TRPV4 channelopathy

TRPV4 通道病模型

• 批准号: 8684485
• 负责人: Charlotte Jane Sumner
• 金额: $ 26.38万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-02-15 至 2016-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8684485
• 关键词: Address; Affect; Age; Animal Model; Back; Behavioral Assay; Biological Assay; Biotinylation; Calcium; Calcium Channel; Cations; Cell membrane; Cell surface; Charcot-Marie-Tooth Disease; Conflict (Psychology); Data; Development; Disease; Distal Spinal Muscular Atrophy; Electrophysiology (science); Evolution; Functional disorder; Future; Genes; Health Care Costs; Image; Immunohistochemistry; Inherited; Investigation; Ion Channel; Knock-in Mouse; Measures; Mediating; Membrane; Modeling; Molecular; Motor; Mus; Muscle Weakness; Mutation; Nature; Nerve; Nerve Degeneration; Nerve Fibers; Neuronal Dysfunction; Neurons; Neuropathy; Outcome Measure; Pathology; Patients; Peripheral; Peripheral Nerves; Peripheral Nervous System Diseases; Physiology; Population; Publishing; Rodent Model; Role; Sensory; Spinal Ganglia; System; Testing; Therapeutic; Tissues; Vanilloid; Work; afferent nerve; axonal degeneration; axonopathy; base; cohort; disability; disease-causing mutation; effective therapy; in vivo; insight; mouse model; mutant; novel; public health relevance; ratiometric; receptor; research study; response; small molecule; therapeutic target

DESCRIPTION (provided by applicant): Peripheral neuropathy results in axonal degeneration of motor and sensory nerve fibers causing muscle weakness and sensory loss. Development of effective therapies has been hampered by incomplete understanding of the underlying molecular and cellular triggers and a lack of druggable therapeutic targets. The discovery that mutations of transient receptor potential vanilloid 4 (TRPV4) cause Charcot- Marie-Tooth disease type 2C marks the first example of an ion channel causing inherited sensorimotor neuropathy. TRPV4 is expressed at the cell surface membrane and several small molecule antagonists have already been developed. In order to further investigate mechanisms of TRPV4-induced neuropathy, we recently developed a novel knock-in mouse model containing the R269C mutation in the endogenous mouse TrpV4 gene. Our preliminary studies of young knock-in mice indicate abnormalities of their peripheral nerve physiology. Using this model, we propose 1) to characterize the spatial and temporal evolution of neuronal dysfunction and degeneration in TRPV4R269C knock-in mice and 2) to test our hypothesis that the R269C mutation causes of gain-of-TRPV4 channel activity in neurons that can be suppressed by TRPV4 antagonists. Together these studies will determine how neuropathy-associated TRPV4 mutations alter TRPV4 function in peripheral neurons, assess the extent to which TRPV4 antagonists may represent a potential therapeutic strategy for patients, and define outcome measures of TRPV4-induced neurodegeneration in mice that can be utilized during future mechanistic and treatment studies.

描述（由申请人提供）：周围神经病变导致运动和感觉神经纤维的轴突变性，导致肌肉无力和感觉丧失。由于对潜在分子和细胞触发因素的不完全了解以及缺乏可药物治疗靶点，有效疗法的开发受到阻碍。瞬时受体电位香草酸 4 (TRPV4) 突变导致 2C 型腓骨肌萎缩症的发现标志着离子通道导致遗传性感觉运动神经病的第一个例子。 TRPV4 在细胞表面膜上表达，并且已经开发了几种小分子拮抗剂。为了进一步研究TRPV4诱导的神经病变的机制，我们最近开发了一种新的敲入小鼠模型，该模型含有内源性小鼠TrpV4基因中的R269C突变。我们对年轻敲入小鼠的初步研究表明，它们的周围神经生理学存在异常。使用该模型，我们建议1）表征TRPV4R269C敲入小鼠中神经元功能障碍和变性的空间和时间演变，2）测试我们的假设，即R269C突变导致神经元中TRPV4通道活性的增加，而这种活性可以被TRPV4拮抗剂抑制。这些研究将共同​​确定神经病相关的 TRPV4 突变如何改变周围神经元中的 TRPV4 功能，评估 TRPV4 拮抗剂在多大程度上可能代表患者的潜在治疗策略，并确定 TRPV4 诱导的小鼠神经变性的结果测量，可在未来的机制和治疗研究中使用。