PHYSIOLOGY OF ZINC PERMEABLE AMPA/KAINATE RECEPTORS

说明：（改编自申请）申请人强烈 致力于神经病学的学术生涯，并最终希望分裂 他在临床实践和基础科学研究之间的时间， 衰老大脑疾病中的神经退化。 他的职业规划是 使用多学科的方法来研究选择性的细胞机制， 神经变性为了实现这些目标，他将大大受益于 KO 1奖励提供的保护期，在此期间，他可以学习某些 新技术，并采取相关的课程工作，同时完全沉浸在 research. 他选择了约翰韦斯博士作为导师，因为他的重叠 研究兴趣和专业知识和领导力在该领域的选择 神经变性 他相信，结合密集的研究， 在他的指导下进行培训，以及UCI出色的研究环境 (with专家提供技术援助的任何问题）将充分 为他开始独立的研究生涯做好准备。 与衰老疾病相关的神经元损伤的一个重要特征 大脑（包括阿尔茨海默病; AD）是一种高度选择性的模式， 神经元缺失 一个可能导致选择性神经变性的因素， 这些疾病是AMPA/红藻氨酸型谷氨酸受体门控的表达 通道是可渗透的Ca 2+。 越来越多的证据表明 另一个可能的因素是内源性Zn ~（2+）。 可以释放囊泡状的Zn 2 + 从突触前神经元能末梢，并可以转移到 突触后神经元的细胞质，在那里它可能引发变性。 之前 实验室研究表明，Zn 2+渗透Ca 2+渗透AMPA/红藻氨酸盐 渠道特别快。 这一建议是根据以下假设提出的： 通过这些通道的Zn 2+渗透有助于与衰老相关的 神经变性 最初的实验将采用组织学，荧光 成像和全细胞记录技术来研究细胞和 这些通道的亚细胞表达位点，并表征其 对Zn 2+的渗透性。 接下来的实验将检验某些 这种Zn 2+渗透的后果与神经变性有关。 具体而言，Zn 2+进入对细胞内Ca 2+处理或内流的影响 对氧化代谢和线粒体功能的影响，以及 将评估Zn 2+介导的和B-淀粉样蛋白介导的损伤。 希望 这些研究将增加对细胞损伤机制的理解， 并提出新的治疗方法。

DESCRIPTION: (Adapted from the application) The applicant is strongly committed to an academic career in neurology and ultimately hopes to divide his time between clinical practice and basic science research into mechanisms of neurodegeneration in diseases of the aging brain. His career plan is to use a multi-disciplinary approach to study cellular mechanisms of selective neurodegeneration. To achieve these goals, he will greatly benefit from the protected period provided by a KO1 award, during which he can learn certain new techniques and take relevant course work, while being fully immersed in research. He has chosen Dr. John Weiss as mentor because of his overlapping research interest and expertise and leadership in the field of selective neurodegeneration. He is confident that the combination of intensive research training under his guidance, and the outstanding research environment at UCI (with experts available for technical assistance on any problem) will fully prepare him for launching an independent research career. A critical feature of neuronal damage associated with diseases of the aging brain (including Alzheimer's disease; AD) is a highly selective pattern of neuronal loss. A factor that may contribute to selective neurodegeneration in these diseases is expression of AMPA/kainate type glutamate receptors gating channels that are permeable to Ca2+. A growing body of evidence suggests another possible factor: endogenous Zn2+. Vesicular Zn2+ can be released from pre-synaptic glutamatergic terminals and can translocate into the cytoplasm of postsynaptic neurons where it may trigger degeneration. Prior studies from the lab indicate that Zn2+ permeates Ca2+ permeable AMPA/kainate channels with particular rapidity. This proposal follows from the hypothesis that Zn2+ permeation through these channels contributes to aging related neurodegeneration. Initial experiments will employ histologic, fluorescent imaging and whole cell recording techniques to investigate cellular and subcellular sites of expression of these channels and to characterize their permeability to Zn2+. Subsequent experiments will examine certain consequences of such Zn2+ permeation of relevance to neurodegeneration. Specifically, effects of Zn2+ entry on intracellular Ca2+ handling or influx on oxididative metabolism and mitochondrial function, and interactions between Zn2+ mediated and B-amyloid mediated injury will be assessed. It is hoped that these studies will increase understanding of cell injury mechanisms in diseases of aging and suggest new therapies.