Role of LINC-mediated Mechanosignaling in MSC Aging

LINC 介导的机械信号传导在 MSC 衰老中的作用

• 批准号: 10559581
• 负责人: Gunes Uzer
• 金额: $ 28.06万
• 依托单位: BOISE STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-03-01 至 2025-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10559581
• 关键词: Actins; Affect; Age; Aging; Architecture; Attenuated; Bed rest; Binding; Bone Marrow; Cell Aging; Cell Differentiation process; Cell Nucleus; Cell Proliferation; Cell physiology; Cells; Chemicals; Chromatin; Clinical; Communication; Communities; Complex; Cytoskeleton; Data; Disabled Persons; Disease; Effectiveness; Elements; Environment; Exercise; F-Actin; Failure; Foundations; Gene Targeting; Genes; Genetic Transcription; Health; Impaired healing; Impairment; In Vitro; Individual; Inferior; Knowledge; Measures; Mechanics; Mediating; Medical Care Costs; Mesenchymal Differentiation; Mesenchymal Stem Cells; Modality; Molecular; Mus; Musculoskeletal; Musculoskeletal System; Natural regeneration; Nuclear; Nuclear Envelope; Nuclear Structure; Nuclear Translocation; Obesity; Osteogenesis; Osteoporosis; Perception; Phenotype; Physical activity; Prevalence; Prevention; Process; Proliferating; Proteins; Quality of life; Recovery; Regenerative Medicine; Regenerative capacity; Reporting; Research; Role; Signal Transduction; Site; Skeleton; Source; Stimulus; Structure-Activity Relationship; Testing; Therapeutic Intervention; Time; Tissues; Transcriptional Regulation; Transducers; Weight-Bearing state; age related; aged; bone; bone quality; design; effective therapy; improved; in vivo; interest; mechanical signal; mechanotransduction; mimetics; novel; osteogenic; preservation; prevent; regeneration potential; regenerative; response; skeletal; stem cell aging; stem cell function; stem cell growth; stem cell proliferation; stem cells; transmission process; vibration

Project Summary Mesenchymal stem cells (MSC) in bone marrow provide regenerative capacity for bone, replacing and reinforcing the skeleton at load bearing sites. When we age or in prolonged bedrest, MSCs lose their regenerative potential, often measured by their proliferative and differentiation capacity. This loss of MSC health causes osteoporosis and delayed healing, ultimately resulting in decreased quality of life and increased medical costs. A fundamental knowledge gap preventing effective therapies in aging and MSC related regenerative medicine is how aging and bedrest impedes MSC health. The nucleus, central to all cellular activity, relies on both mechanical input as well as its molecular transducers to regulate intra-nuclear chromatin organization that ultimately determine cell function and fate. Thus, failure to transmit this information to the nucleus would lead to the breakdown of these processes. Here, we ask if aging is a process that limits information flow into the nucleus, ultimately diminishing its organizational capacity and responsiveness to outside stimuli. As we will show, disabling the mechanical connection between cytoskeleton and nucleus facilitated by Linker of Nucleoskeleton and Nucleoskeleton (LINC) complexes, impairs mechanosensitivity by affecting βcatenin and YAP/TAZ signaling. This leads to decreased proliferation and differentiation of mesenchymal stem cells. Our principal hypothesis is that loss of LINC-connectivity significantly contributes to MSC aging by disrupting nuclear mechanotransduction. Through this revision submitted in response to [PA16-442] - Changes in Cellular Architecture During Aging (R01), we will address our principal hypothesis through two specific aims, each using a distinct hypotheses to examine how inhibiting LINC complex function as well as how aging related loss of LINC complex limits MSC mechanosignaling of known mechanotransducers βcatenin and YAP/TAZ. We will further determine the force-induced mechanisms of how sustained physical activity protects LINC complex expression to augment MSC and bone mechanosignaling within the context of aging. If successful, we will establish, for the first time, a mechanistic understanding of how loss of LINC complex drives decreased mechanosensory capability in aging. Completion of these aims will provide research communities with (1) efficacy of LIV based regenerative modalities that improve LINC-mediated mechanosignaling and (2) foundational structure-function relationship data in healthy and aged stem cells.

项目摘要 骨髓中的间充质干细胞(MSC)提供骨的再生能力，取代和 在承重部位加固骨架。当我们变老或长时间卧床时，骨髓间充质干细胞会失去 再生能力，通常通过它们的增殖和分化能力来衡量。失去MSC 健康导致骨质疏松症和延迟愈合，最终导致生活质量下降和 增加了医疗费用。阻碍衰老和骨髓间充质干细胞有效治疗的基本知识差距 与再生医学相关的是衰老和卧床休息如何阻碍MSC的健康。 细胞核是所有细胞活动的中心，它既依赖于机械输入，也依赖于它的分子。 转导分子调节核内染色质组织，最终决定细胞功能和 命运。因此，如果不能将这一信息传递给原子核，将导致这些细胞的崩溃。 流程。在这里，我们问，衰老是否是一个最终限制信息流进入核心的过程 削弱其组织能力和对外界刺激的反应能力。正如我们将展示的，禁用 核骨架连接体促进细胞骨架与细胞核的机械连接 核骨架复合体，通过影响β连环蛋白和YAP/TAZ而损害机械敏感性 发信号。这会导致间充质干细胞的增殖和分化减少。 我们的主要假设是LINC连接性的丧失通过以下方式显著促进MSC老化 破坏了核的机械转导。 通过响应[PA16-442]提交的修订-蜂窝架构中的更改 在老龄化(R01)期间，我们将通过两个特定的目标来解决我们的主要假设，每个目标都使用 不同的假设来研究抑制LINC复合体如何发挥作用以及如何与衰老相关的损失 LINC复合体限制了已知的机械信号转导系统β、连环蛋白和YAP/TAZ的机械信号传导。 我们将进一步确定持续体力活动如何保护LINC的力诱导机制 在衰老的背景下，增加MSC和骨机械信号的复杂表达。 如果成功，我们将第一次建立对LINC复杂性损失的机械性理解 在老化过程中，驱动器降低了机械感觉能力。完成这些目标将提供研究 具有(1)改进LINC介导的基于LIV的再生方式的有效性的社区 健康和衰老茎的机械信号和(2)基本结构-功能关系数据 细胞。