Functions of BPAG1n

描述（由申请人提供）：广泛的长期目标是阐明 负责神经元功能障碍和损失的分子机制 退行性神经系统疾病在BPAG 1基因敲除小鼠中， 感觉神经元的损伤导致运动神经元的急剧和进行性退化， 功能协调发展的这种空小鼠为我们研究细胞生物学提供了一个有力的工具 和神经退化的分子机制。生物学定义 BPAG1的功能将大大促进我们对 发病机制在以前的研究中，我们记录了BPAG 1n1和BPAG 1n3， 作为细胞骨架组织蛋白，将所有3个网络连接起来。 最近，我们鉴定了BPAG1的另一种亚型BPAG1n4，其 我们的初步研究表明了功能的重要性。我们 假设BPAG 1n4在轴突运输中起重要作用， 囊泡BPAG1神经元亚型的消融导致神经元的结构紊乱。 轴突细胞骨架网络，破坏轴突运输囊泡， 靶向神经营养支持的失败。这一缺陷最终导致 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 目的是表征BPAG 1n4的所有潜在功能。功能 BPAG1n4和细胞骨架蛋白之间的相互作用将在以下两个方面进行探索： 体外和体内。第三个目的是鉴定BPAG 1n4与其结合的蛋白质。 利用酵母双杂交系统，拟议的研究将加强 我们对细胞骨架组织的生物学功能的理解 轴突中的蛋白质及其在维持神经元存活中的作用。我们预计 以获得关于死亡的分子发病机制的重要见解 失去了目标神经支配的神经元。我们的发现将 从而更好地理解和治疗神经退行性疾病 紊乱我相信，我的研究重点将提供一个美妙的融合， 我对了解神经系统的发育和功能的兴趣， 我想帮助人们并探索疾病机制的愿望。部 斯坦福大学的神经病学提供了一个理想的环境， 将我的学术生涯发展成为神经生物学领域的领先研究者 疾病。

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.