TRPV4: Mechanosensitivity and Skeletal Dysplasia

与视觉、嗅觉和味觉不同，听觉、触觉和血液的分子机制- 压力或全身渗透压感知是未知的。离子通道是如何接受机械的 除细菌通道MSCL、MSCs外，作用力仍不清楚。我们正在使用RAT TRP 频道V4子类型，以帮助填补这一知识空白。我们现在已经直接播放了TRPV4的S 非洲爪哇卵母细胞膜片钳下对膜拉伸的反应。我们还开发了 酵母作为剖析TRPV4的新竞技场。我们的工作挑战了以前的TRPV4的S渗透门 模特。我们计划使用策略肽在TRPV4中定义力敏感域 插入和嵌合体。 2008-11年度发现TRPV4功能获得突变可导致两组人类疾病： 骨骼发育不良(SD)和成人周围神经病。我们检查了14个SD等位基因，发现 基础TRPV4活性升高的水平与SD疾病的严重程度平行。此外 为了了解野生型TRPV4通道的工作原理，我们现在计划研究17 Ankyrin-Repeat结构域(ARD)的突变，其晶体结构已知。这部作品 旨在了解ARD突变如何导致两种不同的疾病。在……里面 合作，我们还将使用TRPV4-/-基因敲除小鼠来测试TRPV4在骨折中的作用 治愈。

Unlike vision, smell, and tastes, the molecular mechanisms of hearing, touch, and blood- pressure or systemic-osmolarity sensing are unknown. How ion channels receive mechanical forces remain obscure, except for bacterial channels MscL, MscS. We are using the rat TRP channel V4 subtype, to help fill this knowledge gap. We have now shown TRPV4's direct response to membrane stretch under Xenopus oocyte patch clamp. We have also developed yeast as a new arena to dissect TRPV4. Our work challenges a previous TRPV4's osmotic-gating model. We plan to define the force-sensing domain within TRPV4, using strategic peptide insertions and chimeras. 2008-11 found TRPV4 gain-of-function mutations to cause two sets of human diseases: skeletal dysplasia (SD) and adult peripheral neuropathy. We examined 14 SD alleles and found the level of increased basal TRPV4 activity parallels the severity of the SD disease. Besides understanding the working of the wild-type TRPV4 channels, we now plan to examine 17 mutations in the ankyrin-repeat domain (ARD), of which crystal structure is known. This work aims towards understanding how ARD mutations can lead to two disparate diseases. In collaboration, we will also use trpV4-/- knock-out mice to test the role of TRPV4 in fracture healing.