Cellular and molecular regulation of muscle stem cells

描述(申请人提供)：肌肉前体细胞(MFC)是组织特异性干细胞，对肌肉生长和再生至关重要。MPC通常是静止的，但在生长刺激下被激活增殖并经历分化/融合。MPC的一部分必须保持无差别，以便恢复MPC池并使其可用于满足未来的增长需求。对MPC自我更新与分化的调控机制研究较少。干细胞抗原-1(SCA-1，Ly-6A/E)是在免疫细胞中被广泛研究的Ly-6蛋白家族的成员。SCA-1的功能在很大程度上尚不清楚，但已提出在免疫细胞中发挥多种功能，如细胞信号、细胞黏附和调节干细胞自我更新。根据我们的初步数据，我们假设SCA-1在生长期对MPC池起到调节作用。我们表明，SCA-LPOS细胞代表了复制较慢且不分化的MPC池。我们假设，SCA-1的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池。从体外(Aim 1)和体内(Aim 2)分析SCA-1的功能，细胞因子和NFAT依赖的信号转导对其表达的调控(Aim 3)以及其配体的克隆(Aim 4)。将使用细胞和分子方法的组合。我们提出的研究将在肌肉中定义一条调控组织特异性干细胞的新途径。对SCA-1的研究可能导致在疾病、修复和衰老中操纵肌源性干细胞的新策略，并确定促进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.