MOLECULAR MECHANISMS OF AXONAL TRANSPORT

描述：轴突运输过程是 神经元功能与神经元的生长、维持和发育 再生。理解轴突运输是理解 神经系统的动力学。 功能多样，如传导动作电位，释放 神经递质，突触前终末的产生和维持， 神经元的发育和再生以及神经元的维持 建筑在很大程度上依赖于膜的快速轴突运输 沿微管排列的成束细胞器。同样，范围广泛的 神经病理情况，包括糖尿病和中毒性神经病变， 运动神经元病和神经系统退行性疾病 具有快速轴突中断所预期的特征 运输。基于对孤束核快速轴突运输的研究 机械化学新家族--鱿鱼巨型轴突的轴浆 ATPase，运动蛋白，已经被定义。动蛋白是一种用于 膜结合细胞器沿前行方向的运动 快速轴突运输。申请人之前的工作回答了一个问题 关于生物化学、分子生物学、细胞 动蛋白的生物学和神经生物学。申请人建议： 神经元中不同的动蛋白转录本和亚单位反映了 不同的生理角色。拟议的实验构成了一个 多学科的努力，将使用来自细胞和 确定神经元功能结构的分子生物学 激动素。这些实验将为运动蛋白提供分子基础 关于其生理作用的异构体和测试假说。动蛋白 在神经元中受到翻译后修饰的影响 建议进行实验，以确定其功能意义 重链和轻链中的运动蛋白的翻译后修饰。 申请人提出，它们可能会影响Kinesin与 膜结合细胞器的特定类别，对于 肌动蛋白功能的调节。要素和功能域 形成激动素与定义的相互作用的分子基础 神经元细胞器将在体外和体内被定义。申请人 提出了针对特定类别的膜的动蛋白 细胞器被独特的生化模体所束缚。建议进行的实验 在本申请书中是申请人当前学习的延伸 关于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.