Cellular and molecular regulation of muscle stem cells

描述（由申请人提供）：肌肉前体细胞（MFC）是对肌肉生长和再生至关重要的组织特异性干细胞。MPC通常是静止的，但响应于生长刺激被激活以增殖并经历分化/融合。MPC的一部分必须保持未区分，使得MPC池被恢复并且可用于满足未来的增长要求。调节MPC自我更新与分化的机制研究很少。干细胞抗原-1（Sca-1，Ly-6A/E）是免疫细胞中广泛研究的Ly-6蛋白家族的成员。Sca-1的功能在很大程度上是未知的，但在免疫细胞中已经提出了细胞信号传导、细胞粘附和干细胞自我更新调节等多种功能。基于我们的初步数据，我们假设Sca-1在生长期间调节MPC池中起作用。我们发现Sca-lpos细胞代表了MPC的一个池，其复制较慢并且不分化。我们假设Sca-1表达作为一种保护机制，在MPC激活后维持肌肉组织中足够的MPC库。提出了一组4个目的，以分析Sca-1在体外（Aim 1）和体内（Aim 2）的功能，通过细胞因子和NFAT依赖性信号传导调节其表达（Aim 3）以及克隆其配体（Aim 4）。将利用细胞和分子方法的组合。我们提出的研究将确定一个新的途径，在肌肉调节组织特异性干细胞。对Sca-1的研究可能会导致在疾病、修复和衰老中操纵肌源性干细胞的新策略，并确定增强肌肉生长的新治疗靶点。

DESCRIPTION (provided by applicant): Muscle precursor cells (MFC) are tissue specific stem cells critical for muscle growth and regeneration. MPC are normally quiescent but in response to a growth stimulus are activated to proliferate and undergo differentiation/fusion. A portion of MPC must remain undifferentiated such that the MPC pool is restored and available to meet future growth requirements. The mechanisms that regulate MPC self-renewal vs. differentiation have been little studied. Stem cell antigen-1 (Sca-1, Ly-6A/E) is a member of the Ly-6 family of proteins that have been extensively studied in immune cells. The function of Sca-1 is largely unknown, but functions as diverse as cell signaling, cell adhesion and regulation of stem cell self-renewal have been proposed in immune cells. Based on our preliminary data, we postulate that Sca-1 plays a role in regulating the MPC pool during periods of growth. We show that Sca-lpos cells represent a pool of MPC that replicate slower and do not differentiate. We hypothesize that Sca-1 expression serves as a protective mechanism to maintain an adequate pool of MPC in muscle tissue after MPC activation. A set of 4 aims are proposed to analyze Sca-1 function in vitro (Aim 1) and in vivo (Aim 2) , regulation of its expression by cytokines and NFAT dependent signaling (Aim 3) and cloning of its ligand (Aim 4). A combination of cellular and molecular approaches will be utilized. Our proposed studies will define a novel pathway in muscle for regulating tissue specific stem cells. Studies of Sca-1 may lead to new strategies for manipulating myogenic stem cells in disease, repair and aging and define novel therapeutic targets for enhancing muscle growth.