COBRE: UNR: ROLE OF INTEGRINS IN CHLORIDE CHANNEL REGULATION

这个子项目是利用由NIH/NCRR资助的中心拨款提供的资源的许多研究子项目之一。子项目和调查员(PI)可能从另一个NIH来源获得了主要资金，因此可能会出现在其他CRISE条目中。列出的机构是针对中心的，而不一定是针对调查员的机构。细胞肿胀与容量敏感的外向整流性氯通道(VSOAC)激活有关的机制尚不清楚，尽管已涉及许多细胞内信号通路。这些通道的激活被认为参与了细胞体积的动态平衡，因为它们可能有助于调节体积减少(RVD)以响应细胞肿胀。有人推测，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，但缺乏直接证据支持VSOAC可能代表一类新的机械敏感阴离子通道的假说。最近，两项新的研究重新提出了机械敏感性假说，提供了令人信服的证据，表明VSOAC激活可能与位于心肌细胞膜上的整合素受体的机械拉伸有关(Browe&Baumgarten，J Gen Physiol 122：689-702,2003；&J Gen Physiol124：273-287,2004)。利用最先进的分子和功能方法，以及在体外和体内模型的验证，这一新的Cobre项目将专门研究整合素在心肌细胞VSOACs调节中的作用。将寻求三个具体目标：1)鉴定整合素？这些研究包括：2)确定电压门控氯通道ClC-3作为候选蛋白参与整合素受体激活的天然VSOAC的作用；3)建立体外和体内模型，以剖析整合素介导的VSOAC激活的分子通路。预计该项目将揭示与VSOAC通过整合素介导的膜拉伸激活有关的关键信号事件的新发现，这可能在与肥厚和心力衰竭相关的心脏功能改变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.