Integrin signaling in skeletal muscle regeneration

骨骼肌再生中的整合​​素信号传导

• 批准号: 9905485
• 负责人: CHEN-MING FAN
• 金额: $ 35.54万
• 依托单位: CARNEGIE INSTITUTION OF WASHINGTON, D.C.
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-07-10 至 2022-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9905485
• 关键词: Actins; Adult; Affect; Binding; Blood coagulation; Cell Aging; Cell Death; Cell Proliferation; Cell Shape; Cell Surface Receptors; Cell fusion; Cell physiology; Cell surface; Cells; Cellular biology; Cues; Cytoplasmic Tail; Cytoskeleton; Data; Defect; Degenerative Disorder; ECM receptor; Environment; Event; Extracellular Matrix; FGF2 gene; Family; Fibronectins; Financial compensation; Focal Adhesion Kinase 1; Foundations; Genes; Germ Lines; Growth Factor Receptors; ITGB3 gene; Individual; Injury; Integrin alpha Chains; Integrin beta Chains; Integrins; Knockout Mice; Knowledge; Life; Ligands; Link; Mediating; Membrane; Mus; Muscle; Muscle Cells; Muscle Fibers; Muscle satellite cell; Myoblasts; Natural regeneration; PTK2 gene; Phenotype; Play; Process; Regenerative response; Regulation; Reporting; Research; Residual state; Role; Signal Transduction; Skeletal Muscle; Surface; Tissues; Visualization; Work; conditional knockout; design; in vivo; in vivo regeneration; injured; insight; integrin-linked kinase; interest; mechanical force; member; migration; muscle regeneration; mutant; prevent; progenitor; receptor binding; regenerative; response; satellite cell; self-renewal; stem; stem cell population; stem cells; synergism; therapeutic development; therapeutic target; tissue regeneration

PROJECT SUMMARY Within the skeletal muscle, Pax7+ satellite cells (SCs) are a quiescent muscle stem cell population that becomes activated upon injury and gives rise to progenitors that migrate, divide, and fuse to generate new muscles. Our understanding for these processes during muscle regeneration is incomplete. The central hypothesis of this proposal is that SCs utilize integrin signaling for specialized functions. SCs are located on the muscle fiber surface and surrounded by the extracellular matrix (ECM). The primary ECM binding receptors on the cell surface are the integrin heterodimers, composed of one a-integrin and one β-integrin. Integrins anchor cells to the ECM and tether to the actin cytoskeleton. Upon binding to the ECM, integrins signal intracellularly, frequently in concert with growth factor receptors. SCs express many integrins, and they need to be studied systematically to understand SC biology. This proposal is the beginning of a long-term plan to explore how integrins integrate themselves into specific aspects of SC function: Aim 1: To tease out β1-integrin-regulated signaling in SC function: We will determine how β1-integrin's downstream effectors enhance SC proliferation and self-renewal, via cooperation with FGF2, and potentially with Wnt7a. Aim 2: To determine the role of β3-integrin in SC function: Both β3- and β1-integrins can form receptors for the ECM component fibronectin, which has a role in muscle regeneration. We will determine β3-integrin's function in the SC. Aim3: To determine the role of ILK in SC function in vivo: ILK (integrin linked kinase) is present at the basal membrane of SCs as β1-integrin. We will decipher the role of ILK in the SC. We will also determine whether and how ILK plays a role in integrin-FGF2 synergy in SCs. .

项目摘要 在骨骼肌内，Pax 7+卫星细胞（SC）是静止的肌肉干细胞群， 在受伤时被激活，并产生祖细胞，这些祖细胞迁移、分裂和融合， 肌肉.我们对肌肉再生过程中的这些过程的理解是不完整的。中央 该提议的假设是SC利用整合素信号传导来实现专门功能。SC位于 肌纤维表面被细胞外基质（ECM）包围。主要ECM结合 细胞表面上的受体是由一个α-整联蛋白和一个β-整联蛋白组成的整联蛋白异二聚体。 整联蛋白将细胞锚在ECM上并与肌动蛋白细胞骨架相连。在与ECM结合后，整合素 细胞内信号，经常与生长因子受体协同作用。SC表达许多整合素，并且它们 需要系统地研究才能理解SC生物学。这项提议是一项长期的 计划探索整合素如何将自身整合到SC功能的特定方面： 目的1：梳理出β1-整合素调节的信号在SC功能：我们将确定β1-整合素是如何调节SC功能的。 下游效应子通过与FGF 2的合作增强SC增殖和自我更新， WNT7A。 目的2：确定β3-整合素在SC功能中的作用：β3-和β1-整合素都可以形成受体， ECM成分纤连蛋白，其在肌肉再生中具有作用。我们将检测β3整合素 在SC中发挥作用。 目的3：为了确定ILK在体内SC功能中的作用：ILK（整联蛋白连接激酶）存在于基底膜上。 β1-整合素。我们会研究ILK在SC中的角色，并决定是否 以及ILK如何在SC中的整合素-FGF 2协同作用中发挥作用。 .