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. .

项目概要 在骨骼肌内，Pax7+ 卫星细胞 (SC) 是一种静止的肌肉干细胞群， 受伤后被激活，并产生迁移、分裂和融合以产生新的祖细胞 肌肉。我们对肌肉再生过程中的这些过程的理解并不完整。中央 该提议的假设是 SC 利用整合素信号传导来实现特殊功能。 SC 位于 肌纤维表面并被细胞外基质 (ECM) 包围。主要 ECM 结合 细胞表面的受体是整合素异二聚体，由一个α-整合素和一个β-整合素组成。 整合素将细胞锚定至 ECM 并束缚至肌动蛋白细胞骨架。整合素与 ECM 结合后 细胞内信号，通常与生长因子受体协同作用。 SC 表达许多整合素，并且它们 需要系统地研究以了解 SC 生物学。该提案是一项长期计划的开始 计划探索整合素如何将自身整合到 SC 功能的特定方面： 目标 1：梳理 SC 功能中 β1-整合素调节的信号传导：我们将确定 β1-整合素如何调节 下游效应器通过与 FGF2 合作增强 SC 增殖和自我更新，并有可能 与 Wnt7a。 目标 2：确定 β3-整合素在 SC 功能中的作用：β3-和 β1-整合素均可形成以下受体： ECM 成分纤连蛋白，在肌肉再生中发挥作用。我们将确定 β3-整合素 SC 中的功能。 目的3：确定ILK在体内SC功能中的作用：ILK（整合素连接激酶）存在于基底细胞中 SC 膜为 β1-整合素。我们将破译ILK在SC中的角色。我们还将确定是否 以及 ILK 如何在 SC 中整合素-FGF2 协同作用中发挥作用。 。