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

Gsk-3beta

• 批准号: 7116985
• 负责人: MARTINA H WIEDAU-PAZOS
• 金额: $ 17.74万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-07-01 至 2009-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7116985
• 关键词: Parkinson' s disease; apoptosis; cadherins; congenital nervous system disorder; dementia; electron microscopy; enzyme activity; genetically modified animals; immunocytochemistry; immunoprecipitation; laboratory mouse; microtubule associated protein; neural degeneration; phosphorylation; protein structure function; serine threonine protein kinase; tau proteins; western blottings

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.

描述（由申请人提供）：该提案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，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广度，并提高当前的研究技能，2) 填补对 17 号染色体帕金森病相关额颞叶痴呆 (FTDP-17) 细胞通路理解的知识空白，以及 3) 发表论文和学术领导力发展。该研究将在加州大学洛杉矶分校神经病学系进行，并拥有良好的机构支持和合作机会。突变 tau 蛋白导致 FTDP-17（一组与微管相关蛋白 tau 突变相关的遗传性痴呆）中神经退行性变的机制尚不清楚，因此在理解退行性痴呆细胞死亡途径方面存在重大知识空白。该项目的目标是通过关注一种候选机制来填补这一知识空白，tau 蛋白错误表达可能会导致神经退行性变。我们在之前对人类 tau 表达的果蝇模型的研究中发现了这种机制。该目标的重点是验证和扩展初步发现的研究，这些初步发现表明 GSK-3-β 和 β-catenin（Wnt 信号通路的两个组成部分）会加剧与 FTDP-17 相关的突变 tau 诱导的神经变性。初步结果表明，β-连环蛋白在易受神经变性影响的中枢神经系统区域积聚，并且 GSK-3-β 可能被突变型 tau 蛋白隔离。申请人将研究总体假设，即最常见的 tau 突变 P301L 会干扰 GSK-3-β 磷酸化 β-catenin 的能力，并且由此产生的 β-catenin 稳定会引发神经元死亡。具体来说，将解决β-连环蛋白积累和细胞死亡的开始之间的相关性。将探讨 GSK-3-beta 活性以及与可能导致 β-catenin 积累和神经变性的突变 tau 的关联。拟议的生化和细胞生物学研究将首先利用表达突变型 P301L tau 的转基因小鼠，该小鼠在临床和病理学方面模拟 FTDP-17 的各个方面。一旦相关研究提供了有关突变体 tau、GSK-3-β 和 β-catenin 潜在相互作用的信息，就计划对这些相互作用进行功能研究。