ZN2+ AND CALCIUM PERMEABLE AMPA/KAINATE CHANNELS

描述：(改编自应用程序)从加州大学欧文分校开始 1991年底，申请者建立了一个研究细胞的实验室。 与脑老化相关的选择性神经退行性变的机制。 他获得了独立资金(R01和私人赠款)，并实现了 1996年8月晋升为副教授，终身教职。 为了解决他打算解决的复杂的机械问题，他将 构成了他的研究的核心，将有必要补充 毒性和组织学范式与荧光成像和组织学技术 膜片钳电生理学，两种研究心肌细胞行为的有力工具 他目前对活着的神经元的经验有限。 不幸的是，虽然校园专家可以提供技术援助，但他的 目前繁重的教学、临床和行政职务休假 没有足够的时间来掌握这些技巧。工资支持 由ISA提供的，通过保证80%的受保护的研究时间，将 对应聘者S事业发展的帮助是不可估量的。 高选择性神经退行性变的生理学基础 在许多老化的大脑疾病中所见的情况在很大程度上是未知的。最新研究 揭示了一条潜在的重要线索：虽然大多数AMPA/Kainate 受体门控通道是不透钙的，某些人群 神经元，包括阿尔茨海默氏症中优先退化的许多类型 疾病或缺血，高表达AMPA/海人藻酸受体门控通道 直接的钙离子渗透性。本提案是根据我们的初步建议提出的 研究表明，内源性突触释放的阳离子锌离子 似乎以特别快的速度渗透到钙离子渗透的AMPA通道 选择性地损伤表达这些通道的神经元。 因此，最初的实验将寻求检查细胞和亚细胞 锌、钙离子通透性AMPA/海人藻酸通道在海马区的分布 神经元。组织学方法和荧光成像将被用于 将这些通道本地化，将使用全细胞膜片钳技术 测定其对锌离子和钙离子的通透性。随后的实验 将研究锌离子通过这些通道渗透的后果。两者都有 神经毒性和生理效应将通过组织学、 荧光成像和电生理技术。人们希望， 这些实验将提供初步的线索，以了解 锌离子可能在AS疾病的选择性神经变性中起重要作用 以及正常的神经元功能。

DESCRIPTION: (Adapted from the application) Since starting at U.C. Irvine in late 1991, the applicant has established a laboratory studying cellular mechanisms of selective neurodegeneration of relevance to the aging brain. He has obtained independent funding (R01 and private grants), and achieved promotion to the rank of Associate professor, with tenure, in August, 1996. To address the sophisticated mechanistic questions which he intends will constitute the core of his research, it will be necessary to supplement toxicity and histology paradigms with techniques of fluorescent imaging and patch clamp electrophysiology, both powerful tools for studying behaviors of living neurons with which he presently has limited experience. Unfortunately, while experts on campus can provide technical assistance, his present heavy teaching, clinical and administrative duties leave insufficient time for mastery of these techniques. The salary support provided by an ISA, by assuring 80% protected time for research, would immeasurably aid the applicant s career development. The physiologic basis for the highly selective pattern of neurodegeneration seen in many diseases of the aging brain is largely unknown. Recent studies have revealed a potentially important clue: While most AMPA/kainate receptor-gated channels are Ca2+ impermeable, certain populations of neurons, including many types that preferentially degenerate in Alzheimer's disease or ischemia, express AMPA/kainate receptor gating channels with high direct Ca2+ permeability. The present proposal follows from our preliminary studies indicating that the endogenous synaptically released cation, Zn2+ appears to permeate Ca2+-permeable AMPA channels with particular rapidity selectively damaging neurons expressing these channels. Initial experiments will thus seek to examine the cellular and subcellular distribution of Zn2+ and Ca2+ permeable AMPA/kainate channel on hippocampal neurons. Histologic approaches and fluorescent imaging will be employed to localize these channels, and whole-cell patch-clamp techniques will be used to examine their permeabilities to Zn2+ and Ca2+. Subsequent experiments will examine consequences of Zn2+ permeation through these channels. Both neurotoxic and physiologic effects will be assessed, using histological, fluorescence imaging and electrophysiological techniques. It is hoped that these experiments will provide initial clues to physiological effects of Zn2+ that may be of importance to selective neurodegeneration in disease as well as to normal neuronal functioning.