A model of TRPV4 channelopathy

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轴突变性，导致肌无力和感觉丧失。由于对潜在的分子和细胞触发因素的不完全理解以及缺乏可药物化的治疗靶点，有效疗法的开发受到阻碍。瞬时受体电位香草酸4（TRPV 4）突变导致Charcot-Marie-Tooth病2C型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。TRPV 4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TRPV 4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，该模型在内源性小鼠TrpV 4基因中含有R269 C突变。我们对年轻的基因敲入小鼠的初步研究表明它们的外周神经生理异常。使用该模型，我们提出1）表征TRPV 4 R269 C敲入小鼠中神经元功能障碍和变性的空间和时间演变，以及2）测试我们的假设，即R269 C突变导致神经元中TRPV 4通道活性的获得，其可以被TRPV 4拮抗剂抑制。这些研究将共同确定神经病相关的TRPV 4突变如何改变TRPV 4在外周神经元中的功能，评估TRPV 4拮抗剂可能代表患者潜在治疗策略的程度，并确定TRPV 4诱导的小鼠神经变性的结果指标，这些指标可用于未来的机制和治疗研究。

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.