Functions of BPAG1n

描述(由申请人提供)：广泛的长期目标是澄清 神经细胞功能障碍和丢失的分子机制 退行性神经疾病。BPAG1基因缺失小鼠轴突变性 感觉神经元的损伤会导致运动神经的剧烈和进行性退化 功能。这个零鼠标为我们研究细胞提供了一个强有力的工具 神经退行性变的分子机制。定义生物学的 BPAG1的功能将极大地促进我们对 发病机制。在以前的研究中，我们记录了BPAG1n1和BPAG1n3，它们 起到细胞骨架组织蛋白的作用，连接所有三个网络。 最近，我们发现了BPAG1的另一个亚型，BPAG1n4，其 我们的初步研究表明了功能的重要性。我们 假设BPAG1n4在大鼠脑皮质轴突运输中起重要作用 水泡。BPAG1神经元亚型的消融导致脑组织的解体 轴突细胞骨架网络、囊泡轴突运输中断和 靶向神经营养支持失败。这一缺陷最终在 受影响的神经元死亡。第一个目标将进一步审查和确认 BPAG1n4在超微结构水平的亚细胞定位。第二 目的是研究BPAG1n4的所有潜在功能。功能界别 BPAG1n4和细胞骨架蛋白之间的相互作用将在 体外和体内。第三个目标是确定与BPAG1n4结合的蛋白质 利用酵母双杂交系统与之相互作用。拟议的研究将加强 我们对细胞骨架组织生物学功能的认识 轴突中的蛋白质及其在维持神经元存活中的作用(S)。我们预计 以获得关于死亡的分子发病机制的重要见解 被剥夺了靶神经支配的神经元。我们的发现将 导致对神经退行性变的更好的理解和可能的治疗 精神错乱。我相信，我的研究重点将提供一个完美的融合 我对了解神经系统的发育和功能的兴趣和 我渴望帮助人们，并探索疾病的机制。该部门 斯坦福大学神经病学教授为 把我的学术生涯发展成神经生物学领域的一流研究人员 疾病的威胁。

DESCRIPTION (provided by applicant): The broad long-term goal is to elucidate the molecular mechanisms responsible for the dysfunction and loss of neurons in degenerative neurological disorders. In BPAG1 null mouse, axonal degeneration of sensory neurons leads to dramatic and progressive deterioration in motor functions. This null mouse provides us a powerful tool for studying cellular and molecular mechanisms of neurodegeneration. Defining the biological functions of BPAG1 would significantly advance our understanding of pathogenesis. In previous studies, we documented BPAG1n1 and BPAG1n3, which function as cytoskeleton organizing proteins interconnecting all 3 networks. Most recently, we identified an additional isoform of BPAG1, BPAG1n4, whose functional importance has been suggested by our preliminary studies. We hypothesize that BPAG1n4 plays an important role in axonal transport of vesicles. Ablation of BPAG1 neuronal isoforms leads to disorganization of axonal cytoskeletal networks, disruption of axonal transport of vesicles and failure of target-derived neurotrophic support. This defect culminates in the death of affected neurons. The first Aim will further examine and confirm the sub-cellular localization of BPAG1n4 at the ultrastructural level. The second Aim is to characterize all potential functions of BPAG1n4. The functional interactions between BPAG1n4 and cytoskeletal proteins will be explored both in vitro and in vivo. The third Aim is to identify the proteins with which BPAG1n4 interact with by using yeast two-hybrid system. The proposed study will enhance our understanding of the biological functions of cytoskeletal organizing proteins in axons and their role(s) in sustaining neuronal survival. We expect to obtain important insights regarding the molecular pathogenesis of the death of neurons that have been deprived of target innervations. Our findings will lead to a better understanding and possible treatment for neurodegenerative disorders. I believe that my research focus will provide a wonderful fusion of my interest in understanding the development and function of nervous system and my desire to help people and to explore the disease mechanisms. The Department of Neurology at Stanford University provides an ideal environment for developing my academic career into a leading investigator in the neurobiology of disease.