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细胞核的连接在建立细胞我们发现了基本的细胞极性缺陷。发生在生理衰老和患有加速衰老疾病哈钦森-吉尔福德早衰症的儿童中这种缺陷是由于核层内部的连接不平衡造成的。内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。这些连接由核骨架和细胞骨架连接器 (LINC) 复合物介导内核膜SUN和外核膜KASH蛋白在衰老过程中具有优先性。增加的 SUN1 与微管的相互作用与 SUN2 与肌动蛋白/微丝的相互作用父母资助的赠款。（R01 AG064944）此补充申请旨在测试改变的假设由 LINC 复合物介导的核细胞骨架连接导致衰老过程中内在的细胞极性缺陷。在这个补充中，我们将扩展父项目来检查阿尔茨海默病的核细胞骨架连接疾病（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) 寡聚体中，神经元中以过度磷酸化的形式积累因此，我们将检验 tau 蛋白在细胞外积累并诱导 tau 蛋白过度磷酸化的假设。和寡聚 Aβ 改变微管与 LINC 复合物的关联并干扰细胞的生成在目标 1 中，我们将确定 tau 和 Aβ 是否影响成纤维细胞模型系统和初级神经元中的极性。为此，我们将研究微管与 LINC 复合物的相互作用并改变细胞极性的产生。使用资助家长奖中提出的强大的成纤维细胞模型系统在目标 2 中，我们将确定 tau 是否存在。寡聚 Aβ 寡聚物诱导的过度磷酸化增加微管与细胞核的相互作用并进行实验以确定这些相互作用是否是同时发生的病理变化的基础最后，我们还将评估随衰老而发生的 SUN1 过度表达对初级神经元的影响。这项研究将暗示 tau/Aβ 诱导的 LINC 复合物功能障碍。 AD 和相关痴呆症的发病机制，并可能确定开发治疗药物的目标治疗。