Enhancement of Myoblast Chemotactic Migration

成肌细胞趋化迁移的增强

• 批准号: 6666947
• 负责人: Janice A Dominov
• 金额: $ 10.51万
• 依托单位: BOSTON BIOMEDICAL RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-09-26 至 2005-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6666947
• 关键词: cell adhesion; cell adhesion molecules; cell migration; chemokine; chemotaxis; cytokine; laboratory mouse; muscular dystrophy; myoblasts; stem cell transplantation; tissue /cell culture; vascular endothelium

DESCRIPTION (provided by applicant): Genetic defects underlying several degenerative muscle diseases such as Duchenne muscular dystrophy (DMD) are known, yet effective therapies for these disorders have not been found. One approach has been cell-based therapy in which normal myoblasts or genetically modified patient myoblasts are injected into diseased muscle with the intent that engraftment would be sufficient to compensate for protein deficiencies. Little success has been achieved with this approach however due to problems such as poor graft survival and impractical requirements for numerous muscle injections. Recently, systemic delivery of muscle precursor cells via tail vein or arterial injection in mice has been demonstrated resulting in low-level donor cell engraftment of regenerating muscle tissue. Vascular migration and extravasation of precursor cells thus occurs and could provide a useful route for improved cell-based therapy for these devastating diseases. The specific aims of the proposed work are to 1) Identify molecules expressed in myoblasts that are involved in the attachment to activated endothelial cells and promote trans-endothelial cell migration, 2) Improve the efficiency of myoblast trans-endothelial migration, if possible, by cytokine-induced expression of molecules known to regulate attachment and extravasation of immune system cells. Methods: Murine skeletal muscle myoblasts will be studied to determine expression levels of proteins known to function in leukocyte extravasation. Inflammatory cytokines will be used to induce myoblast expression of proteins relevant to chemotactic movement. In vitro trans-endothelial cell migration assays will be used to assess the role of specific chemokines, receptors and cell adhesion molecules in this process and the influence of inflammatory cytokine stimulation on myoblast migration. Normal myoblasts and those induced by cytokines will be injected into tail veins of mdx mice (model for DMD) undergoing muscle regeneration and extravasation into tissues assessed. Results will further our understanding of the mechanisms that promote systemic engraftment of donor myoblasts into diseased muscle could significantly advance the therapeutic use of myogenic precursor cells for the treatment of muscular dystrophy.

描述（由申请人提供）： 已知几种退化性肌肉疾病（例如Duchenne肌肉营养不良（DMD））的遗传缺陷是已知的，但尚未发现这些疾病的有效疗法。一种方法是基于细胞的治疗，其中正常的成肌细胞或转基因的患者肌细胞被注入患病的肌肉，目的是植入足以补偿蛋白质缺陷。 然而，由于诸如移植物生存不良以及对大量肌肉注射的不切实际要求等问题，这种方法几乎没有成功。最近，已经证明，通过尾静脉或小鼠动脉注射的肌肉前体细胞的全身递送已被证明导致低水平的供体细胞植入再生肌肉组织。因此发生了前体细胞的血管迁移和渗出，可以为改善这些毁灭性疾病的基于细胞的治疗提供有用的途径。提出的工作的具体目的是1）确定在肌细胞中表达的分子，这些分子与活化的内皮细胞相连，并促进经内层细胞迁移，2）提高肌细胞经内内皮细胞迁移的效率，如果可能通过细胞因子诱导的分子固定和跨性别的分子互动。方法：将研究鼠骨骼肌成肌细胞，以确定已知在白细胞渗出中起作用的蛋白质的表达水平。炎性细胞因子将用于诱导与趋化运动相关的蛋白质的成肌细胞表达。体外跨内皮细胞迁移分析将用于评估特定趋化因子，受体和细胞粘附分子在此过程中的作用，以及炎性细胞因子刺激对肌细胞迁移的影响。正常的成肌细胞和细胞因子诱导的肌细胞将被注射到经受肌肉再生和渗出的MDX小鼠（DMD模型）中的尾静脉中。结果将进一步了解我们对促进供体成肌细胞全身植入肌肉的机制，可以显着提高肌原前体细胞治疗肌肉营养不良的治疗用途。