Nucleoskeleton-Cytoskeleton Connections and Cell Polarity in Aging

衰老过程中的核骨架-细胞骨架连接和细胞极性

基本信息

批准号：
10289402
负责人：
Gregg G Gundersen
金额：
$ 40.5万
依托单位：
COLUMBIA UNIVERSITY HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-08-01 至 2024-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10289402
关键词：
Actins Adhesions Affect Aging Alzheimer&apos s Disease Alzheimer&apos s disease related dementia American Amyloid beta-Protein Award Biological Models Cell Nucleus Cell Polarity Cells Cellular Morphology Cerebellar Ataxia Characteristics Child Complex Cytoskeletal Proteins Cytoskeleton Defect Dementia Development Disease Fibroblasts Filament Foundations Functional disorder Funding Generations Grant Hippocampus (Brain)Individual Lead MAPT gene Mediating Microfilaments Microtubules Movement Nervous System Physiology Neuraxis Neurodegenerative Disorders Neurons Nuclear Nuclear Inner Membrane Nuclear Lamina Nuclear Outer Membrane Parents Pathogenesis Pathologic Physiological Play Progeria Proteins Rattus Research Role Structure Syndrome System Testing abeta oligomer aged cell age design druggable target experimental study extracellular hyperphosphorylated tau migration neurodegenerative dementia neuron development neuron loss novel overexpression parent grant parent project tau Proteins tau aggregation tau phosphorylation therapeutic development

项目摘要

SUMMARY The cytoskeleton and its connections to the nucleus play fundamental critical roles in establishing cellular morphology, polarity, migration and substrate adhesion. We have discovered a fundamental cell polarity defect that occurs in physiological aging and in children with the accelerated aging disorder Hutchinson-Gilford progeria syndrome. This defect results from imbalanced connections between the nuclear lamina on the inner aspect of the inner nuclear membrane and two major cytoskeletal protein systems: actin/microfilaments and microtubules. These connections are mediated by the Linker of Nucleoskeleton and Cytoskeleton (LINC) complex composed of inner nuclear membrane SUN and outer nuclear membrane KASH proteins. In aging, there is a preferential interaction of increased SUN1 with microtubules versus SUN2 with actin/microfilaments. The parent funded grant (R01 AG064944) for this supplemental application is designed to test the hypothesis that altered nucleocytoskeletal connections mediated by the LINC complex cause an intrinsic cell polarity defect in aging. In this supplement, we will expand the parent project to examine nucleocytoskeletal connections in Alzheimer disease (AD) and related neurodegenerative dementias. The neuronal microtubule-associated protein tau accumulates in a hyperphosphorylated form in neurons in these disorders and amyloid-beta (Aβ) oligomers accumulate extracellularly and induce hyperphosphorylation of tau. We will therefore test the hypothesis that tau and oligomeric Aβ alter microtubule association with LINC complexes and interfere with the generation of cell polarity in a fibroblast model system and in primary neurons. In Aim 1, we will determine if tau and Aβ influence the interactions of microtubules with LINC complexes and alter the generation of cell polarity. To do so, we will use a robust fibroblast model system as proposed in the funded parent award. In Aim 2, we will determine if tau hyperphosphorylation induced by oligomeric Aβ oligomers increases microtubule interactions with the nucleus and perform experiments to establish if these altered interactions underlie concurrent pathological changes in primary neurons. Finally, we will also assess the effects of SUN1 overexpression, which occurs with aging, on primary neurons. This research will implicate tau/Aβ-induced dysfunction of the LINC complex in the pathogenesis of AD and related dementia, and potentially identify targets for the development of therapeutic treatments.

概括细胞骨架及其与核的连接在建立细胞中起着基本关键作用形态，极性，迁移和底物粘附。我们发现了一个基本的细胞极性缺陷这发生在身体衰老和患有加速衰老疾病的儿童Hutchinson-Gilford启动中综合征。这种缺陷是由于核椎板之间的连接不平衡，在内部核膜和两个主要的细胞骨架蛋白系统：肌动蛋白/微丝和微管。这些连接是由核骨骼和细胞骨架（LINC）复合物的接头介导的内部核膜太阳和外核膜kash蛋白。在衰老中，有一个优先 Sun1与微管与SUN2与肌动蛋白/微丝相互作用的相互作用。父母资助的赠款（R01 AG064944）对于此补充应用，旨在测试改变的假设 linc络合物介导的核细胞骨架连接会导致衰老中固有的细胞极性缺陷。在这种补充，我们将扩大父母项目，以检查阿尔茨海默氏症中的核眼骨骨骼连接疾病（AD）和相关的神经退行性痴呆。神经元微管相关蛋白TAU 在这些疾病和淀粉样蛋白β（Aβ）低聚物的神经元中以热磷酸化形式积聚细胞外积聚并诱导tau的高磷酸化。因此，我们将检验tau的假设寡聚Aβ改变微管与林复合物的关联并干扰细胞的产生成纤维细胞模型系统和原发性神经元中的极性。在AIM 1中，我们将确定Tau和Aβ是否影响微管与肿瘤复合物的相互作用并改变了细胞极性的产生。为此，我们会使用资助的父母奖中提出的强大成纤维细胞模型系统。在AIM 2中，我们将确定是否tau 寡聚Aβ低聚物诱导的高磷酸化增加了微管与细胞核的相互作用并执行实验以确定这些改变的相互作用是否是同时发生的病理变化的基础原发性神经元。最后，我们还将评估随着衰老而发生的Sun1过表达的影响原发性神经元。这项研究将暗示tau/aβ诱导的LINC复合物的功能障碍 AD和相关痴呆的发病机理，并可能识别出治疗性发展的靶标治疗。