Targeting PI3K/Akt/mTOR for the management of psoriasis

 描述（由申请人提供）：本提案的持续目标是确定PI 3 K/Akt/mTOR在银屑病发病机制中的关键作用，并开发用于治疗银屑病的飞燕草素，银屑病是一种常见的慢性炎症性皮肤病，影响全球1.25亿人。尽管银屑病不会危及生命，但它会带来致残的身体和心理社会不适以及与银屑病关节炎和心血管疾病风险相关的全球疾病负担。由于是多因素的，因此不太可能击中单一目标将使患者显著受益，因此需要开发有效的机制 以及治疗银屑病的靶向药物。在参与银屑病疾病的许多信号传导网络中，PI 3 K/AKT/mTOR通路已成为临床相关靶点，因为它可能协同促进银屑病。使用回顾性人类银屑病和咪喹莫特（IMQ）诱导的鼠银屑病样皮肤病变组织，我们观察到与匹配对照相比AKT/mTOR信号转导的激活。这些观察结果构成了我们提出的同时靶向PI 3 K/Akt/mTOR可能是治疗银屑病的有效方法的基础。根据这一假设，并且在我们对在皮肤中赋予促分化和抗炎性质的无毒天然试剂的追求中，我们最近对飞燕草素进行了一些新颖且令人兴奋的观察。用/不用IL-22预刺激的人角质形成细胞的飞燕草苷处理抑制PI 3 K、Akt和mTOR活化。进一步的竞争结合和计算机对接分析显示，飞燕草素与PI 3 K、mTOR和p70 S6 K激酶以-7至-8.9Kcal/mol范围的结合能物理地相互作用。在本申请中，我们提出利用飞燕草素的多管齐下的能力，并且设计用于：1）检查PI 3 K/Akt/mTOR和次级信号在银屑病发病机制中的参与; 2）使用（i）体外2D培养物，i）银屑病的3D重建人皮肤模型，和iii）体内MQ诱导的Balbc和TPA诱导的K14/VEGF转基因鼠银屑病样模型研究飞燕草素的功效，所述模型概括了人银屑病的许多特征。该提案的成功完成可能会导致我们通过剖析PI 3 K/AKT/mTOR的相互作用来理解银屑病发病机制，并开发Delphindin作为对抗增殖性角化疾病（包括银屑病）的新型药物。

 DESCRIPTION (provided by applicant): The continued objective of this proposal is to determine the critical role of PI3K/Akt/mTOR in psoriasis pathogenesis and to develop delphinidin for the management of psoriasis, a common chronic inflammatory skin disorder that affects 125 million people worldwide. Although psoriasis is not life- threatening, it presents disabling physical and psychosocial discomfort and global disease burden associated with psoriatic arthritis and cardiovascular disease risks. Being multifactorial, it is unlikely that hiting a single target will significantly benefit patients, thus the need for developing effective mechanism and target-based agents to treat psoriasis. Among the many signaling networks implicated in psoriasis disease, the PI3K/AKT/mTOR pathway has emerged as clinically relevant target, as it may cooperatively promote psoriasis. Using retrospective human psoriatic and imiquimod (IMQ)-induced murine psoriasis-like skin lesional tissues we observed activation of AKT/mTOR signaling compared to matched controls. These observations form the basis of our proposal that simultaneous targeting of PI3K/Akt/mTOR may be an effective approach for treating psoriasis. In line with this hypothesis and in our pursuit for non-toxic natural agents endowed with pro- differentiation and anti-inflammatory properties in skin, we recently made some novel and exciting observations with delphinidin. Delphinidin treatment of human keratinocytes pre-stimulated with/without IL-22 inhibited PI3K, Akt and mTOR activation. Further competitive binding and in silico docking analyses revealed that delphindin physically interacts with the PI3K, mTOR and p70S6K kinases with binding energy of -7 to -8.9Kcal/mol range, In this application, we propose to take advantage of the multi-pronged ability of delphinidin and is designed to: 1) Examine the involvement of PI3K/Akt/mTOR and secondary signaling in psoriasis pathogenesis; 2) Investigate the efficacy of delphinidin using (i) in-vitro 2D cultures, i) 3D reconstituted human skin models of psoriasis, and iii) in-vivo IMQ-induced Balbc and TPA-induced K14/VEGF transgenic murine psoriasiform models that recapitulates many features of human psoriasis. A successful completion of this proposal may result in our understanding of mechanism of psoriasis pathogenesis via dissecting interaction of PI3K/AKT/mTOR and the development of delphindin as a novel agent against proliferative keratinizing disorders, including psoriasis.