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，PAX7+卫星细胞（SC）是静止的肌肉干细胞种群 在受伤时被激活，并引起迁移，分裂和融合的祖细胞产生新的 肌肉。我们对肌肉再生过程中这些过程的理解是不完整的。中央 该提案的假设是SCS利用整合素信号传导用于专业功能。 SC位于 肌肉纤维表面和细胞外基质（ECM）周围。主要的ECM结合 细胞表面的受体是整联蛋白异二聚体，由一种A-整合素和一个β-整合蛋白组成。 整合素将细胞锚定在ECM上，并系在肌动蛋白细胞骨架上。与ECM结合后，整联蛋白 细胞内信号，经常与生长因子受体协同。 SC表达了许多整合素，他们 需要系统地研究以了解SC生物学。该提议是长期的开始 计划探索整合素如何整合到SC功能的特定方面： AIM 1：在SC函数中取消β1-整合蛋白调节的信号传导：我们将确定β1-整合素如何 下游效应通过与FGF2的合作增强了SC的增殖和自我更新，并有可能 与Wnt7a。 目标2：确定β3-紧密素在SC功能中的作用：β3-和β1-整合蛋白都可以形成受体的受体 ECM成分纤连蛋白，在肌肉再生中起作用。我们将确定β3-紧密蛋白 SC中的功能。 AIM3：确定ILK在体内SC功能中的作用：ILK（整合素链接激酶）存在于基本 SC的膜为β1-整合蛋白。我们将破译ILK在SC中的作用。我们还将确定是否 以及ILK如何在SC中的整合素-FGF2协同作用中发挥作用。 。