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

在处理伤口挛缩和加速愈合过程中调节 PI3K 通路

• 批准号: 10226838
• 负责人: Rogerio Moraes Castilho
• 金额: $ 35.1万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-06-19 至 2023-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10226838
• 关键词: Achievement; Affect; Animal Model; Burn injury; Cell Proliferation; Cessation of life; Cicatrix; Clinical; Contracture; Dehydration; Development; Down-Regulation; Epidermis; Epithelial; Extracellular Matrix; FDA approved; FRAP1 gene; Fibroblasts; Fire - disasters; Foundations; Gene Expression; Genes; Genetic; Goals; Grant; Health; Home; Homeostasis; Human; Individual; Infection; Inflammation; Inflammatory Infiltrate; Injury; Knowledge; Maintenance; Mechanics; Metabolism; Molecular; Myofibroblast; Operative Surgical Procedures; Organ; Organism; Outcome; PTEN gene; Pathway interactions; Patients; Pharmacologic Actions; Pharmacology; Phosphotransferases; Physiological; Play; Population; Process; Property; Quality of life; Research; Role; Signal Pathway; Signal Transduction; Sirolimus; Site; Skin; Skin graft; Small Interfering RNA; Social Functioning; Testing; Therapeutic Effect; Time; Translations; base; burn scars; burn therapy; burn wound; cell growth; circadian pacemaker; cytokine; design; epidermal stem cell; epithelial injury; epithelial stem cell; global health; healing; improved; in vivo; inhibitor/antagonist; injured; innovation; mTOR Inhibitor; mTOR Signaling Pathway; mTOR inhibition; migration; mouse model; novel; novel therapeutic intervention; novel therapeutics; porcine model; pre-clinical; prevent; psychologic; regenerative tissue; response; siRNA delivery; stem cell biology; stem cell function; stem cell population; stem cells; therapeutic effectiveness; tissue repair; wound; wound bed; wound closure; wound healing; wound treatment

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.

皮肤是人体最大的器官，具有显著的生理和社会功能。表皮 皮肤的一部分负责使身体防水并充当机械屏障;因此， 与重要功能有关。损伤后，表皮及其干细胞的立即反应旨在 局部内环境平衡的重建;然而，在烧伤患者中经常观察到的广泛损伤可能 无法治愈如果表皮驱动的稳态没有恢复，生物体就会经历 脱水和增加感染和死亡的机会。新的治疗策略旨在加速 上皮干细胞的迁移和聚集是改善烧伤健康的迫切需要 患者和实现更好的临床结果。我们的研究为干细胞领域的新发现搭建了桥梁 细胞生物学与磷脂酰肌醇3-激酶（PI 3 K）分子作用的最新认识 对上皮损伤的反应机制。PTEN最初被鉴定为PI 3 K的负调节因子， 信号传导，细胞生长、代谢和生存的主要调节因子。通过靶向破坏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激活 与移民增加有关。此外，我们发现表皮中的PTEN的破坏也 导致上皮干细胞的积累，表明PI 3 K信号通路在上皮干细胞增殖中的关键作用。 维持上皮内环境稳定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， 通过在分离前增加供体部位皮肤干细胞数量来治疗伤口的策略 移植到受伤的受体部位此外，我们还将确定 在烧伤后再上皮化和瘢痕形成过程中对PI 3 K信号传导的药理作用。人类- 相关的临床前动物模型将用于测试我们关于PI 3 K在以下方面的功效的假设： 烧伤的治疗这一应用意义重大;一旦它将探索新的药物途径， 加速上皮迁移和伤口闭合，诱导表皮干细胞的积累，并减少 伤口瘢痕的形成。

项目成果

Topical delivery of mTOR inhibitor halts scarring.

局部施用 mTOR 抑制剂可以阻止疤痕形成。

• DOI: 10.1016/j.jdermsci.2019.06.008
• 发表时间: 2019
• 期刊: Journal of dermatological science
• 影响因子: 4.6
• 作者: Webber,LianaP;Yip,Brian;NascimentoFilho,CarlosHVdo;Park,HaB;Castilho,RogerioM;Squarize,CristianeH
• 通讯作者: Squarize,CristianeH

Skin wound healing triggers epigenetic modifications of histone H4.

皮肤伤口愈合会触发组蛋白 H4 的表观遗传修饰。

• DOI: 10.1186/s12967-020-02303-1
• 发表时间: 2020
• 期刊: Journal of translational medicine
• 影响因子: 7.4
• 作者: Nascimento-Filho,CarlosHV;Silveira,ErickaJD;Goloni-Bertollo,EnyM;deSouza,LeliaBatista;Squarize,CristianeH;Castilho,RogerioM
• 通讯作者: Castilho,RogerioM