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）：该提案将使申请人能够成为遗传神经退行性疾病领域的独立研究人员。它基于候选人在衰老研究中的背景，并实施了一项全面的职业发展计划，旨在扩大细胞生物学和遗传学领域的研究技能的广度并增强当前的研究技能，2）填补了与parkinsonismiss的细胞途径有关的细胞途径的知识差距，与parkinsonismiss的领导力与parksonismiss的领导力相关联（FTDP-17（FTDP-17）和3），以及3），以及3），以及3），以及3），以及3），以及3）。该研究将在UCLA神经病学系进行，并提供出色的机构支持和合作的机会。人们对FTDP -17中引起神经退行性的机制 - 与微管相关蛋白tau的突变相关的一组遗传性痴呆症，从而鲜为人知，从而代表了对退化性痴呆症细胞死亡途径的理解的主要知识差距。该项目的目的是通过关注一种候选机制来填补这一知识差距，tau misexpression可能导致神经退行性。我们在先前对人tau表达的果蝇模型的研究中确定了这种机制。该目的集中在验证和扩展初步发现的研究上，表明GSK-3-beta和β-catenin是Wnt信号通路的两个组成部分，加剧了与FTDP-17相关的tau诱导的神经变性。初步结果表明，β-catenin在容易受到神经变性的中枢神经系统区域积聚，并且GSK-3-β可以被突变体Tau隔离。申请人将调查总体假设，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β-catenin触发的稳定性增强了神经元死亡。具体而言，将解决β-catenin积累和细胞死亡的发作的相关性。 GSK-3-β活性以及可能导致β-catenin积累和神经变性的突变体TAU的关联。拟议的生化和细胞生物学研究最初将利用表达突变体P301L TAU的转基因小鼠，该小鼠在临床和病理上对FTDP-17的方面进行了建模。一旦相关研究提供了有关突变tau，GSK-3-β和β-catenin的潜在相互作用的信息，则计划对这些相互作用进行功能研究。