MOLECULAR MECHANISMS OF AXONAL TRANSPORT

描述：轴突运输的过程是必不可少的， 神经元功能和神经元生长、维持和 再生理解轴突运输是理解 神经系统的动力学 其功能多种多样，如动作电位的传导， 神经递质，突触前末梢的产生和维持， 神经元的发育和再生，以及神经元的维持 结构关键取决于膜的快速轴突运输 沿沿着微管有界的细胞器。同样， 神经病理状况，包括糖尿病和中毒性神经病， 运动神经元疾病和神经系统变性疾病 具有预期的快速轴突中断的特征， 运输基于对离体海马神经元快速轴突运输的研究， 鱿鱼巨轴突的轴质，一个新的机械化学家族 ATP酶，即驱动蛋白，已被定义。驱动蛋白是 膜结合的细胞器在顺行方向的运动， 快速轴突运输申请人以前的工作已经回答了 一些关于生物化学、分子生物学、细胞 以及驱动蛋白的神经生物学。申请人提议， 神经元中不同的驱动蛋白转录本和亚基反映了 不同的生理作用。拟议的实验构成了一个 多学科的努力，将使用从细胞和 分子生物学来定义神经元的功能结构 驱动蛋白这些实验将为驱动蛋白的研究提供分子基础 同种型和测试关于其生理作用的假设。驱动蛋白 在神经元中受到翻译后修饰， 实验提出，将确定的功能意义 驱动蛋白重链和轻链的翻译后修饰。 申请人提出，它们可能影响驱动蛋白与 特定类别的膜束缚细胞器，并对 驱动蛋白功能的调节。因子和功能域， 形成了驱动蛋白与定义的 将在体外和体内定义神经元细胞器。申请人 提出驱动蛋白是针对特定类别的膜 由独特的生化基序约束的细胞器。拟议的实验 本申请是申请人当前研究的扩展 快速轴突运输的分子机制。

DESCRIPTION: The processes of axonal transport are essential for neuronal function and underlie neuronal growth, maintenance and regeneration. Understanding axonal transport is a key to understanding the dynamics of the nervous system. Functions as diverse as conduction of the action potential, release of neurotransmitter, generation and maintenance of the presynaptic terminal, neuronal development and regeneration, and maintenance of neuronal architecture depend critically on fast axonal transport of membrane bounded organelles along microtubules. Similarly, a wide range of neuropathological conditions, including diabetic and toxic neuropathies, motor neuron diseases and degenerative diseases of the nervous system have characteristics expected from a disruption of fast axonal transport. Based on studies of fast axonal transport in isolated axoplasm from the squid giant axon, a new family of mechanochemical ATPases, the kinesins, has been defined. Kinesins are motors for the movement of membrane bounded organelles in the anterograde direction of fast axonal transport. Previous work by the applicant has answered a number of questions about the biochemistry, molecular biology, cell biology, and neurobiology of kinesin. The applicant proposes that different kinesin transcripts and subunits in the neuron reflect distinct physiological roles. The proposed experiments constitute a multidisciplinary effort that will use methods from both cellular and molecular biology to define the functional architecture of neuronal kinesins. These experiments will provide a molecular basis for kinesin isoforms and test hypotheses about their physiological roles. Kinesin is subject to posttranslational modifications in the neuron and experiments are proposed that will determine the functional significance of posttranslational modifications to kinesin heavy and light chains. The applicant proposes that they may affect kinesin interactions with specific classes of membrane bounded organelles and be important for regulation of kinesin function. Factors and functional domains which form the molecular basis for interactions of kinesin with defined neuronal organelles will be defined in vitro and in vivo. The applicant proposes that kinesins are targeted to specific classes of membrane bounded organelles by unique biochemical motifs. Experiments proposed in this application are an extension of current studies by the applicant on the molecular mechanisms of fast axonal transport.