PHYSIOLOGY OF ZINC PERMEABLE AMPA/KAINATE RECEPTORS

描述：(改编自申请表)申请者性格强健 致力于神经学的学术生涯，并最终希望 他在临床实践和基础科学研究之间对机制的研究 在老化的大脑疾病中的神经退化。他的职业计划是 用多学科方法研究选择性精神分裂症的细胞机制 神经退行性变。为了实现这些目标，他将从 KO1奖励提供的保护期，在此期间他可以学习某些 新技术和相关课程作业，同时完全沉浸在 研究。他选择了约翰·韦斯博士作为导师，因为他与 研究兴趣、专业知识和在选拔领域的领导地位 神经退行性变。他相信，密集的研究相结合 在他的指导下进行的培训，以及UCI卓越的研究环境 (在任何问题上有专家提供技术帮助)将充分 为他开始独立的研究生涯做好准备。 与老年性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 神经元丢失。一种可能导致选择性神经变性的因素 这些疾病是AMPA/海藻酸型谷氨酸受体门控表达 对钙离子具有通透性的通道。越来越多的证据表明 另一个可能的因素是内源锌离子。囊泡状锌离子可被释放 来自突触前谷氨酸能终末，并可移位到 可能引发变性的突触后神经元的细胞质。之前 实验室研究表明，锌离子可以渗透到钙离子渗透性AMPA/海人藻酸盐中 特别快的频道。这一建议是根据假设提出的 锌离子通过这些通道的渗透与衰老有关 神经退行性变。最初的实验将使用组织学、荧光学 成像和全细胞记录技术研究细胞和 这些通道的亚细胞表达部位以及它们的特征 对锌离子的渗透性。随后的实验将检验某些 这种锌离子渗透的后果与神经退化有关。 具体地说，锌离子进入对细胞内钙的处理或内流的影响 氧化代谢与线粒体功能及其相互作用 锌离子介导的损伤和B-淀粉样蛋白介导的损伤将被评估。希望是这样的 这些研究将增加对细胞损伤机制的理解 衰老的疾病，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.