IMPROVING MUSCLE HEALING THROUGH PREVENTION OF FIBROSIS

通过预防纤维化改善肌肉愈合

• 批准号: 6368885
• 负责人: JOHNNY HUARD
• 金额: $ 27.39万
• 依托单位: CHILDREN'S HOSP PITTSBURGH/UPMC HLTH SYS
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-08-10 至 2005-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6368885
• 关键词: decorin; disease /disorder proneness /risk; extracellular matrix; fibrosis; gene therapy; immunocytochemistry; intramuscular injections; laboratory mouse; musculoskeletal regeneration; polymerase chain reaction; recombinant proteins; scars; statistics /biometry; striated muscles; transfection /expression vector; transforming growth factors; trauma; western blottings; wound healing

Muscle injuries, especially pulls and strains, present a challenging problem in traumatology and are among the most common and most often disabling injuries in athletes. The injured muscles are capable of healing, although very slowly and often with incomplete functional recovery. The injured muscle can promptly initiate regeneration for the healing process, but that process in inefficient and is hindered by fibrosis ie, scar tissue formation. More importantly, the scar tissue that replaces the damaged myofibers is a potential contributing factor in the tendency of strains to recur. We have identified various growth factors capable of enhancing myoblast proliferation and differentiation, and their delivery within injured muscle improves muscle regeneration, but the development of fibrosis still limits recovery. On the other hand, it has been reported that the over expression of transforming growth factor (TGF-) in various injured tissues is the major cause of fibrosis in animals and humans. Indeed, we have observed that TGF- plays a central role in skeletal muscle fibrosis and, more importantly, that the use of antifibrosis agents, such as decorin, that inactivate the effect of this molecule can reduce muscle fibrosis and consequently improve muscle healing to a near complete recovery after injuries. Our recent observation that decor in can also enhance muscle regeneration makes this molecule more than ideal to improve muscle healing after injury. We therefore propose to investigate the kinetics of TGF- expression, muscle regeneration, and fibrosis after strain and to delineate the mechanism by which this molecule initiates the fibrosis cascade in skeletal muscle. We will consequently develop biological approaches based on decor in to efficiently prevent the scarring process by blocking the action of TGF- and activate muscle regeneration at the adequate time period post-injury. We finally propose to characterize efficient way to deliver therapeutic and lasting levels of decor in into the injured muscle through the following strategies: (1) direct intramuscularly injection of the recombinant proteins and (2) in vivo gene delivery by gene vectors. These studies should further our understanding of the muscle healing process, expedite the methodology to promote efficient muscle healing, and contribute to the development of innovative therapies for other muscle diseases, such as dystrophies.

肌肉损伤，尤其是拉力和菌株，在创伤学上带来了一个具有挑战性的问题，是运动员中最常见，最常见的伤害。 受伤的肌肉能够愈合，尽管非常缓慢，并且通常具有不完全的功能恢复。 受伤的肌肉可以迅速引发愈合过程的再生，但是该过程的效率低下，受到纤维化的阻碍，即疤痕组织形成。 更重要的是，取代受损肌纤维的疤痕组织是菌株趋势复发的潜在因素。 我们已经确定了能够增强肌细胞增殖和分化的各种生长因子，并且它们在受伤的肌肉中的递送改善了肌肉再生，但是纤维化的发展仍然限制了恢复。 另一方面，据报道，各种受伤组织中转化生长因子（TGF-）的过度表达是动物和人类纤维化的主要原因。的确，我们已经观察到TGF-在骨骼肌纤维化中起着核心作用，更重要的是，使用抗纤维化剂（例如DecorIn）（例如DecorIn），使该分子的效果失活可以减少肌肉纤维化的作用，从而减少肌肉纤维化，从而使肌肉恢复受伤后几乎完全康复。 我们最近的观察结果，即装饰也可以增强肌肉再生，使该分子远远超出了损伤后改善肌肉愈合的理想选择。 因此，我们建议研究菌株后TGF表达，肌肉再生和纤维化的动力学，并描述该分子启动骨骼肌中纤维化级联反应的机制。 因此，我们将基于装饰的装饰开发生物学方法，以通过阻止TGF-的作用并在受伤后足够的时间内激活肌肉再生，从而有效防止疤痕过程。 我们最终建议通过以下策略来表征有效的方法，以将治疗和持久的装饰水平输送到受伤的肌肉中：（1）直接在肌肉内注射重组蛋白，以及（2）通过基因载体输送体内基因。 这些研究应进一步了解我们对肌肉愈合过程的理解，加快促进有效肌肉愈合的方法，并为其他肌肉疾病（例如营养不良）的创新疗法发展做出贡献。