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 在负载轴承处加强骨骼。 再生潜力，通常是通过其扩散和区分能力来衡量的。 健康会导致骨质疏松症并延迟愈合，最终导致生活和生命的减少 增加医疗费用。 相关的再生医学是躁动和床架如何阻碍MSC健康。 核是所有细胞活性的中心，都依赖于机械输入和分子 传感器调节最终确定细胞功能和的核内染色质组织 命运。 过程。 减少的是组织的能力和外部刺激的措施。 细胞骨架和细胞核之间的机械连接促进了核骨骼的接头和 核骨骼（LINC）复合物，通过深情的βCatenin和Taz损害机制 信号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 破坏核机械转移。 通过此修订，对蜂窝结构中的[PA16-442]变更的响应提交了 在衰老期间（R01），我们将通过两个特定目的来解决主假设，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Agling相关损失如何 LINC复合物限制已知机械转换器βCatenin和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 lins lins lin lin的机械理解 驱动器在衰老中降低机械感应性。 具有（1）基于（1）基于（1）改善linc介导的再生方式的社区 机械信号和（2）健康和老化的茎中的基础结构 - 函数数据 细胞。