PATCH CLAMP STUDY OF HEPATOCYTE K CHANNEL REGULATION

1.候选人：科恩博士将从事学术医学 基础研究与临床教学相结合。 在博士后期间， 他在耶鲁大学格哈德·吉比施博士的指导下获得了生理学奖学金， 获得了上皮运输生理学的广泛背景， 丰富的经验，电气技术有用的研究这些 包括膜片钳方法的运输过程， 记录单个离子通道。 科恩博士致力于开发一种 用于将该技术应用于肾上皮的合适制剂（参见 附录）和微电极研究的基底外侧K+通道在一个 两栖动物近端小管 这里提出的研究是一个逻辑 继续这项工作。 2.研究：肝细胞含有钾传导， α和β肾上腺素能药物以及各种激素。 它 也对细胞内Ca++和环AMP有反应，这两个 物质似乎介导激素的作用， 神经传递素 这种电导被认为在 将激素信号转化为代谢活动。 电导 也已知其直接随Na+ K+ ATP酶的转运速率而变化。 这似乎是许多上皮细胞K+电导的一个特性。 使用膜片钳技术的初步工作已经证明， 肝细胞中存在K+通道。 在拟议的研究中， 将探索通道的钙敏感性， 钙离子与cAMP之间的相互作用。 耦合机制 将研究泵和活动之间的关系，特别是假设 将测试钙敏感性的改变是这种偶联的基础。 进一步的研究将探索新陈代谢和 通道，再次强调钙敏感性的调节。 这些 后一项研究涉及的问题是， K+渗透性在细胞损伤的病理生理学中起作用， 缺氧 3.环境：马萨诸塞州总医院肾脏科成员 医院积极参与与此相关的几个研究领域 应用包括环磷酸腺苷作用的生物化学。 赞助商， 博士亚历山大叶，一直是上皮运输的领导者之一， 多年来，近年来，他一直致力于 缺氧的后果。

1. The candidate: Dr. Cohen will be pursuing a career in academic medicine combining basic research with clinical teaching. During a postdoctoral fellowship in physiology at Yale University under Dr. Gerhard Giebisch he obtained a broad background in the physiology of epithelial transport and extensive experience in electrical techniques useful in studying these transport processes including the patch-clamp method which allows direct recording of single ionic channels. Dr. Cohen worked on developing a suitable preparation for applying this technique to renal epithelia (see appendix) and on microelectrode studies of the basolateral K+ channel in an amphibian proximal tubule. The studies proposed here are a logical continuation of that work. 2. The research: Hepatocytes contain a potassium conductance that responds to Alpha and Beta adrenergic agents as well as a variety of hormones. It is also responsive to intracellular Ca++ and cyclic AMP and these two substances appear to mediate the action of the hormones and neurotransmitters. This conductance is thought to play a role in the translation of the hormonal signals into metabolic events. The conductance is also known to vary directly with transport rate of the Na+ K+ ATPase. This seems to be a property of many epithelial K+ conductances. Preliminary work using the patch-clamp technique has demonstrated the presence of a K+ channel in hepatocytes. In the proposed studies, the calcium sensitivity of the channel will be explored as will the nature of the interaction between calcium and cyclic AMP. The mechanism of coupling between pump and activity will be studied and in particular the hypothesis that altered calcium sensitivity underlies this coupling will be tested. Further studies will explore the interaction between metabolism and the channel, again, with emphasis on modulation of calcium sensitivity. These latter studies are relevant to the question of whether changes in membrane K+ permeability play a role in the pathophysiology of cell damage during anoxia. 3. The environment: Members of the Renal Unit at the Massachusetts General Hospital are actively engaged in several areas of research relevant to this application including the biochemistry of cyclic AMP action. The sponsor, Dr. Alexander Leaf, has been one of the leaders in epithelial transport for many years and in recent years has been focusing his efforts on the consequences of anoxia.