Modulating the PI3K Pathway During the Managing of Wound Contracture and Accelerated Healing

皮肤是人体最大的器官，具有显著的生理和社会功能。表皮 皮肤的一部分负责防水并起到机械屏障的作用；因此，它是 与重要功能相关的。一旦受伤，表皮及其干细胞的即时反应旨在 局部动态平衡的重建；然而，烧伤患者常可观察到的大面积损伤可能 压倒治愈的能力。如果表皮驱动的动态平衡没有恢复，生物体就会经历 脱水，增加感染和死亡的机会。旨在加速的新治疗策略 上皮干细胞的迁移和积聚是改善烧伤健康的迫切需要 患者和取得更好的临床结果。我们的研究连接了茎领域的新发现 磷脂酰肌醇3-激酶(PI3K)分子作用的细胞生物学研究进展 上皮性损伤的反应机制。PTEN最初被认为是PI3K的负性调节因子 信号，细胞生长、新陈代谢和生存的主要调节因子。通过靶向干扰PTEN基因 从含有干细胞的皮肤上皮层，我们观察到细胞增殖的活跃。 与更多的移民相关。此外，我们还发现，表皮中PTEN的破坏也 结果在上皮干细胞的积累表明PI3K信号通路在 维持上皮细胞动态平衡和对外部损伤的反应。在这里，我们提出了一种新的治疗方法 隔离前通过增加供体部位皮肤干细胞数量来治疗伤口的策略 并在受伤的受者部位进行移植。此外，我们还将确定其治疗效果。 PI3K信号在烧伤后再上皮化和瘢痕形成中的药理作用。人类- 相关的临床前动物模型将被用来检验我们关于PI3K在 烧伤的治疗。这一应用具有重要意义；一旦实现，将探索能够 加速上皮迁移和伤口闭合，诱导表皮干细胞积聚，减少 创面疤痕的发展。

The skin is the largest organ in the body with remarkable physiological and social functions. The epidermal portion of the skin is responsible for waterproofing the body and acting as a mechanical barrier; thus, it is associated with vital functions. Upon injury, the immediate response of the epidermis and its stem cells aims at the reestablishment of local homeostasis; however extensive injuries, often observed in burn patients, may overwhelm the capacity to heal. If the epidermis-driven homeostasis is not restored, the organism undergoes dehydration and increased chances for infection and death. New therapeutic strategies aiming at accelerated epithelial migration and accumulation of epithelial stem cells are in great need to improve the health of burn patients and the achievement of better clinical outcomes. Our research bridges new findings in the field of stem cell biology with recent understanding of the role of the phosphatidylinositide 3-kinases (PI3K) molecular mechanisms in response to epithelial injury. PTEN was initially identified as a negative regulator of the PI3K signaling, the main regulator of cell growth, metabolism, and survival. By targeted disrupting the PTEN gene from the epithelial layer of the skin containing stem cells, we observed a brisk activation of cellular proliferation associated with increased migration. Moreover, we found that disruption of PTEN from the epidermis also results in the accumulation of epithelial stem cells indicating a critical role of the PI3K signaling pathway in the maintenance of epithelial homeostasis and response to external injuries. Here, we propose a novel therapeutic strategy to treat wounds by increasing the population of skin stem cells at the donor site before the isolation and graft in the injured recipient site. Furthermore, we will determine the therapeutic effectiveness of pharmacological action on the PI3K signaling during the re-epithelization and scarring after burn. Human- relevant preclinical animal models will be used to test our hypothesis on the efficacy of the PI3K in the treatment of burn. This application is significant; once that will explore novel druggable pathways capable of accelerating epithelial migration and wound closure, induce accumulation of epidermal stem cells, and reduce the development of wound scar.