Gsk-3beta & beta-Catenin in pathophysiology of FTDP-17

描述(申请人提供)：这项建议将使申请人成为遗传性神经退行性疾病领域的独立研究人员。它以候选人在衰老研究方面的背景为基础，并实施全面的职业发展计划，旨在1)扩大细胞生物学和遗传学领域的研究技能的广度，并提高当前的研究技能，2)填补在理解与17号染色体相关的帕金森症(FTDP-17)的额颞痴呆(FTDP-17)细胞通路方面的知识空白，以及3)导致出版和学术领导力的发展。这项研究将在加州大学洛杉矶分校神经病学系进行，有很好的机构支持和合作机会。突变tau导致FTDP-17-一组与微管相关蛋白tau突变相关的遗传性痴呆-神经变性的机制尚不清楚，因此在了解退行性痴呆的细胞死亡途径方面存在着重大的知识缺口。该项目的目标是通过专注于一种候选机制来填补这一知识空白，通过这种机制，tau的错误表达可能导致神经退化。我们在之前对人类tau表达的果蝇模型的研究中发现了这一机制。这些目的集中在验证和扩展初步发现的研究上，这些研究表明，Wnt信号通路的两个组成部分GSK-3-β和β-catenin可以加剧突变tau诱导的与FTDP-17相关的神经变性。初步结果表明，β-连环蛋白积聚在易发生神经变性的中枢神经系统区域，GSK-3-β可能被突变体tau隔离。申请者将调查总体假设，即最常见的tau突变P301L干扰GSK-3-β磷酸化β-连环素的能力，并由此导致β-连环素的稳定触发增强的神经元死亡。具体地说，将讨论β-连环蛋白积累开始和细胞死亡之间的相关性。GSK-3-β的活性和与突变tau的关联可能导致β-连环蛋白积累和神经退化，将被探索。拟议的生化和细胞生物学研究将首先利用表达突变P301L tau的转基因小鼠，这是FTDP-17临床和病理方面的模型。一旦相关研究提供了关于突变tau、GSK-3-β和β-catenin潜在相互作用的信息，这些相互作用的功能研究就会计划进行。

DESCRIPTION (provided by applicant): This proposal will enable the applicant to become an independent researcher in the field of inherited neurodegenerative disorders. It builds upon the candidate's background in aging research and implements a comprehensive career development plan that aims to 1) expand the breadth of research skills in the area of cell biology and genetics and enhance current research skills, 2) fill knowledge gaps in the understanding of cellular pathways in frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17), and 3) result in publications and academic leadership development. The research will be conducted at the UCLA Department of Neurology with excellent institutional support and opportunities to collaborate. The mechanisms by which mutant tau causes neurodegeneration in FTDP-17 - a group of inherited dementias linked to mutations of the microtubule-associated protein tau - are poorly understood, thereby representing a major knowledge gap in the understanding of cell death pathways in degenerative dementias. The goal of the project is to fill this knowledge gap by focusing on one candidate mechanism, by which tau misexpression may lead to neurodegeneration. We identified this mechanism in previous studies of a Drosophila model of human tau expression. The Aims focus on studies that verify and extend preliminary findings suggesting that GSK-3-beta and beta-catenin, both components of the Wnt signaling pathway, exacerbate mutant tau-induced neurodegeneration related to FTDP-17. Preliminary results suggest that beta-catenin accumulates in CNS regions vulnerable to neurodegeneration and that GSK-3-beta may be sequestered by mutant tau. The applicant will investigate the overall hypothesis that the most common tau mutation, P301L, interferes with the ability of GSK-3-beta to phosphorylate beta-catenin and that the resulting stabilization of beta-catenin triggers enhanced neuronal death. Specifically, correlations of the onset of beta-catenin accumulation and cell death will be addressed. GSK-3-beta activity and association with mutant tau that may lead to beta-catenin accumulation and neurodegeneration will be explored. The proposed biochemical and cell biological studies will initially utilize transgenic mice expressing mutant P301L tau, which model aspects of FTDP-17 clinically and pathologically. Once correlative studies have provided information regarding potential interactions of mutant tau, GSK-3-beta and beta-catenin, functional studies of these interactions are planned.