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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：
10153650
负责人：
Gregg G Gundersen
金额：
$ 41.65万
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/10153650
关键词：
Actins Actomyosin Address Adhesions Age Aging Cell Aging Cell Nucleus Cell Polarity Cell physiology Cells Cellular Morphology Centrosome Child Complex Cytoplasm Cytoskeletal Proteins Cytoskeleton Data Defect Dermis Disease Dynein ATPase Fibroblasts Filament Functional disorder Genes Human Impaired wound healing Individual Lead Mass Spectrum Analysis Mediating Mendelian disorder Methods Microfilaments Microtubules Molecular Movement Mus Nuclear Nuclear Envelope Nuclear Inner Membrane Nuclear Lamina Nuclear Outer Membrane Physiological Play Process Progeria Protein Isoforms Proteins RNA Splicing Role Skin Skin wound healing Splice-Site Mutation Structure Syndrome System Testing Transgenic Mice Variant age related aged autocrine cell age healing human subject in vivo insight lamin C migration normal aging novel overexpression paracrine prelamin A protein purification reconstitution release factor skin wound tissue culture wound wound healing

项目摘要

Project Summary The cytoskeleton and its connections to the nucleus play fundamental roles in establishing cellular morphology, polarity, migration and adhesion. Because of their essential roles in these cellular functions, it is critically important to understand the changes that take place in cytoskeletal systems and their nuclear connections during the normal process of cellular aging. Despite this importance, remarkably little is known about the role of the cytoskeleton in physiologically aging. Our preliminary studies have led to the discovery of a fundamental cell polarity defect that occurs in fibroblasts from children with the accelerated aging disorder Hutchinson- Gilford progeria syndrome and also in fibroblasts from physiologically-aged individuals. This defect results from unbalanced 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/nesprin proteins. In aging, there is a preferential increased interaction of nesprin-2G with microtubules (supported by SUN1) versus actin microfilaments (supported by SUN2). This has led to our overall hypothesis that altered nucleocytoskeletal connections mediated by the LINC complex causes an intrinsic cell polarity defect in physiological aging as well as an accelerated aging disorder. We further hypothesize that this defect is at least in part mediated by a protein factor secreted by cells from aged individuals. We propose to test these hypotheses in three specific aims. In Aim 1, we will decipher the mechanism underlying the cell polarity defect in physiological aging. We will determine how increased SUN1 levels are established in the nuclear envelope during aging, explore how SUN1 interaction with nesprin-2G biases its interaction toward microtubules and examine how cytoplasmic microtubules are impacted by their excessive interaction with the nuclear envelope. In Aim 2, we will examine the role of the age-dependent cell polarity defect in would healing in vivo. We will examine cutaneous wounds from young and old mice to determine if the same mechanisms that generate polarity defects in tissue culture are operative in vivo as well as examine wound healing and fibroblast polarity in transgenic mice overexpressing SUN1 in fibroblasts. In Aim 3, we will purify and characterize a soluble factor secreted from aged cells that leads to defective cell polarity. We will use complementary methods of mass spectrometry and protein purification to identify this factor we call FRAC, for Factor Released from Aged Cells. Completion of these aims will lead to novel insights into how alterations in nucleocytoskeltal connections at the LINC complex lead to a fundamental cell polarity defect in aging.

项目总结