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: 10548349
• 负责人: Gunes Uzer
• 金额: $ 7.27万
• 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/10548349
• 关键词: Actins; Address; 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; Differentiation and Growth; 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; Lead; Measures; Mechanics; Mediating; Medical Care Costs; Mesenchymal Differentiation; Mesenchymal Stem Cells; Modality; Molecular; Mus; Musculoskeletal; Musculoskeletal System; Natural regeneration; Nuclear; Nuclear Envelope; Nuclear Translocation; Obesity; Osteogenesis; Osteoporosis; Perception; Phenotype; Physical activity; Prevalence; Prevention; Process; 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; base; bone; bone quality; design; effective therapy; improved; in vivo; interest; mechanical signal; mechanotransduction; novel; osteogenic; preservation; prevent; regeneration potential; regenerative; response; skeletal; stem cell aging; stem cell function; stem cell growth; stem cell proliferation; stem cells; 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）为骨骼，更换和 在负载轴承部位加强骨骼。当我们年龄或长时间的床架上，MSC失去了他们的 再生潜力，通常通过其增殖和分化能力来衡量。 MSC的损失 健康会导致骨质疏松症和延迟愈合，最终导致生活质量下降和 增加医疗费用。一个基本知识差距，以防止在衰老和MSC中有效疗法 相关的再生医学是衰老和床架如何阻碍MSC健康。 核是所有细胞活性的中心，都依赖于机械输入及其分子 传感器调节最终确定细胞功能和的核内染色质组织 命运。那就是，未能将此信息传输到细胞核将导致这些信息的崩溃 过程。在这里，我们询问衰老是否是限制信息流入核的过程，最终 降低其组织能力和对外部刺激的反应。正如我们将显示的那样，禁用 细胞骨架和细胞核之间由核骨架和核制备的核之间的机械连接 核骨骼（LINC）复合物，通过影响βCatenin和Yap/taz来损害机理的敏感性 信号。这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-Connctectitive的丧失显着促进了MSC的老化 破坏核机械转导。 通过对[PA16-442]的响应提交的此修订 - 细胞体系结构的变化 在衰老期间（R01），我们将通过两个特定目标解决我们的主要假设，每种目标都使用 独特的假设，以检查如何抑制LINC复合功能以及与衰老相关的损失如何 LINC复合物限制已知机械转换器βCatenin和YAP/TAZ的MSC机械信号。 我们将进一步确定持续体育锻炼如何保护LINC的力引起的机制 复杂表达在衰老的背景下增强MSC和骨骼机械信号。 如果成功的话，我们将首次建立对Linc Complex损失的机械理解 驱动力降低了衰老的机理感知能力。这些目标的完成将提供研究 具有（1）基于（1）基于LIV的再生方式效率的社区，以改善LINC介导 机械信号和（2）健康和老化的茎中的基础结构功能关系数据 细胞。