COBRE: UNR: ROLE OF INTEGRINS IN CHLORIDE CHANNEL REGULATION

这个子项目是许多利用 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 细胞肿胀激活体积敏感性外向整流氯离子通道（VSOAC）的机制仍然未知，即使一些细胞内信号通路已牵连。这些通道的激活被认为涉及细胞体积稳态，因为它们可能有助于响应于细胞肿胀的调节性体积减小（RVD）。据推测，通道激活的实际刺激可能涉及膜的机械拉伸，而不是细胞体积本身的变化，因此这些通道可能是机械敏感的。然而，尽管进行了许多尝试，但仍然缺乏支持VSOAC可能代表一类新的机械敏感性阴离子通道的假设的直接证据。最近，两项新的研究通过提供VSOAC活化可能与位于肌细胞膜上的整联蛋白受体的机械拉伸有关的令人信服的证据而恢复了机械敏感性假说（Browe和Baumgarten，J Gen Physiol 122：689-702，2003; & J Gen Physiol 124：273-287，2004）。使用最先进的分子和功能方法，以及经验证的体外和体内模型，这个新的COBRE项目将专门研究整合素在心肌细胞VSOAC调节中的作用。三个具体目标将寻求：1）确定整合素？本发明的目的在于：（1）确定参与心脏中VSOAC调节的亚基和细胞外基质蛋白;（2）确定电压门控氯离子通道ClC-3作为负责通过整联蛋白受体刺激激活的天然VSOAC的候选蛋白的作用;和（3）开发体外和体内模型以剖析参与整联蛋白介导的VSOAC激活的分子途径。 预计该项目将揭示与整合素介导的膜拉伸激活VSOAC相关的关键信号事件相关的新发现，这些事件可能在与肥大和心力衰竭相关的心脏功能变化和重塑中发挥重要作用。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The mechanisms that link cell swelling to activation of volume-sensitive outwardly rectifying chloride channels (VSOACs) remain unknown even though a number of intracellular signaling pathways have been implicated. The activation of these channels is believed to be involved in cell volume homeostasis since they may contribute to regulatory volume decreases (RVD) in response to cell swelling. It has been speculated that the actual stimulus for channel activation may involve mechanical stretch of the membrane, rather than cell volume changes per se, and thus these channels might be mechanosensitive. However, despite numerous attempts, direct evidence supporting the hypothesis that VSOACs may represent a new class of mechanosensitive anion channels has been lacking. Recently, two new studies have resurrected the mechanosensitive hypothesis by providing convincing evidence that VSOAC activation may be linked to mechanical stretch of integrin receptors located on the myocyte membrane (Browe & Baumgarten, J Gen Physiol 122: 689-702, 2003; & J Gen Physiol 124: 273-287, 2004). Using state of the art molecular and functional methods, as well as validated in vitro and in vivo models, this new COBRE project will specifically examine the role of integrins in the regulation of VSOACs in cardiac myocytes. Three specific aims will be sought: 1) Identify the integrin ? subunit(s) and exctracellular matrix proteins involved in the regulation of VSOACs in the heart; 2) Determine the role of the voltage-gated chloride channel ClC-3 as a candidate protein responsible for the native VSOAC activated by integrin receptor stimulation; and 3) Develop in vitro and in vivo models to dissect the molecular pathways involved in integrin-mediated VSOAC activation. It is anticipated that this project will unravel novel findings with respect to key signaling events involved in the activation of VSOACs by integrin-mediated stretch of the membrane which could play an important role in the functional changes and remodeling of the heart associated with hypertrophy and heart failure.