Myoregenerative Potential of ABCB5+ Progenitors

干细胞移植作为人类遗传性疾病的治疗策略具有很大的前景，包括 肌肉萎缩症该提案旨在理解和解决基于细胞的免疫的三个主要障碍。 杜氏肌营养不良症的治疗方法：干细胞分离、增殖和移植。 该建议是基于新的ATP结合盒转运蛋白ABCB 5的最新表征 申请人的P-糖蛋白，其标记肌肉中表达干细胞表型的细胞亚群， 皮肤，并作为膜电位祖细胞融合的决定因素进行调节， 分化初步研究表明ABCB 5祖细胞在体外具有成肌潜能。具体 本研究的目的是1.为了确定ABCBS阳性祖细胞的成肌潜能， 肌肉或皮肤相对维斯ABCB阴性细胞群的作用，并剖析ABCB 5在调节 使用ABCB 5特异性细胞分化和融合将肌祖细胞融合成多核肌管 体外测定。2.确定与ABCBS阳性相关的分子调控网络， 祖细胞表型，并确定这种网络是否可以特异性地调节，以诱导在 离体肌祖细胞增殖3.研究异种或同种异体移植ABCBS阳性细胞的能力， 从人或鼠的肌肉或皮肤分离的肌祖细胞，以恢复肌营养不良蛋白在肌肉中的表达。 在DMD的免疫缺陷小鼠模型（NOD/Rag 1 nullDMDmdx 5cv）中，并确定ABCB 5在DMD中的作用。 供体细胞融合到受体肌纤维中，并因此在供体细胞移植和干细胞治疗中 功效因此，该建议与开发新的治疗方法的努力高度相关 杜氏肌营养不良症和其他遗传性肌病。

Stem cell transplantation holds great promise as a therapeutic strategy in human genetic disorders, including muscular dystrophies. This proposal aims at understanding and addressing three major hurdles of cell-based therapeutic approaches to Duchenne muscular dystrophy: stem cell isolation, propagation and engraftment. The proposal is based on the recent characterization of the novel ATP-binding cassette transporter ABCB5 P-glycoprotein by the applicant, which marks stem cell phenotype-expressing cell subsets in muscle and skin, and regulates as a determinant of membrane potential progenitor cell fusion and resultant differentiation. Preliminary studies indicate a myogenic potential of ABCB5 progenitors in vitro. The specific aims of this study are 1. To define the myogenic potential of ABCBS-positiveprogenitors derived from muscle or skin vis-a-vis ABCBS-negative cell populations, and to dissect the role of ABCB5 in regulating myoprogenitor fusion into multinucleated myotubes using ABCB5-specific cell differentiation and fusion assays in vitro. 2. To identify the molecular regulatory networks associated with the ABCBS-positive progenitor phenotype and to determine whether such networks can be specifically modulated to induce in vitro myoprogenitor propagation. 3. To investigate the capacity of xeno- or allografted ABCBS-positive myoprogenitors isolated from human or murine muscle or skin to restore dystrophin expression in an immunodeficient mouse model of DMD (NOD/Rag1nullDMDmdx5cv) in vivo, and define the role of ABCB5 in donor cell fusion into recipient myofibers, and hence in donor cell engraftment and stem cell therapeutic efficacy. Thus, the proposal is highly relevant to efforts directed at developing novel therapeutic approaches to Duchenne muscular dystrophy and other inherited myopathies.