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

Gsk-3beta

• 批准号: 6864862
• 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/6864862
• 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。它建立在候选人在老龄化研究的背景，并实施了一个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，并提高目前的研究技能，2）填补知识空白，了解与17号染色体相关的帕金森氏症（FTDP-17）的额颞叶痴呆症的细胞通路，（3）导致出版物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，并有良好的机构支持和合作机会。突变tau蛋白导致FTDP-17神经变性的机制-一组遗传性痴呆与微管相关蛋白tau的突变有关-知之甚少，因此代表了对退行性痴呆细胞死亡途径理解的主要知识空白。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蛋白的错误表达可能导致神经退行性变。我们在以前的研究中确定了这种机制的果蝇模型的人tau蛋白表达。这些目标侧重于验证和扩展初步研究结果的研究，这些研究结果表明GSK-3-β和β-连环蛋白（Wnt信号通路的两种组分）加剧了与FTDP-17相关的突变tau诱导的神经变性。初步结果表明，β-连环蛋白积聚在中枢神经系统的区域，易受神经变性和GSK-3-β可能被隔离的突变tau。申请方将研究最常见的tau突变P301 L干扰GSK-3-β磷酸化β-连环蛋白的能力以及由此产生的β-连环蛋白稳定性触发增强的神经元死亡的总体假设。具体而言，β-连环蛋白积累和细胞死亡的发病相关性将得到解决。将探索GSK-3-β活性以及与可能导致β-连环蛋白蓄积和神经退行性变的突变tau蛋白的相关性。拟议的生物化学和细胞生物学研究最初将利用表达突变型P301 L tau的转基因小鼠，其在临床和病理学上模拟FTDP-17的各个方面。一旦相关研究提供了关于突变tau、GSK-3-β和β-连环蛋白的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。