Targeting PI3K/Akt/mTOR for the management of psoriasis

 描述(申请人提供)：这项提案的持续目标是确定PI3K/Akt/mTOR在牛皮癣发病机制中的关键作用，并开发用于治疗牛皮癣的Delphinidin。牛皮癣是一种常见的慢性炎症性皮肤病，影响着全球1.25亿人。尽管牛皮癣不会危及生命，但它会导致身体和心理上的不适，以及与牛皮癣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，打击单一靶点不太可能使患者显著受益，因此需要开发有效的机制 以及治疗牛皮癣的靶向药物。在与银屑病相关的许多信号网络中，PI3K/AKT/mTOR通路可能协同促进银屑病，因此已成为临床上相关的靶点。使用回顾性的人银屑病和咪喹莫特(ImQ)诱导的小鼠银屑病样皮肤皮损组织，我们观察到与匹配对照组相比AKT/mTOR信号的激活。这些观察结果构成了我们的建议的基础，即同时靶向PI3K/Akt/mTOR可能是治疗银屑病的有效方法。根据这一假设，在我们寻求无毒的天然制剂的过程中，赋予皮肤促分化和抗炎特性，我们最近对Delphinidin进行了一些新颖和令人兴奋的观察。Delphinidin处理IL-22预刺激的人角质形成细胞可抑制PI3K、Akt和mTOR的激活。进一步的竞争结合和电子对接分析表明，Delphindin与PI3K，mTOR和p70S6K激酶物理上相互作用，结合能在-7到-8.9Kcal/mol范围内，在这个应用中，我们建议利用Delphindin的多管齐下的能力，并设计用于：1)研究PI3K/Akt/mTOR和二次信号转导在银屑病发病机制中的作用；2)利用(I)体外二维培养，i)三维重建的银屑病皮肤模型，以及iii)体内ImQ诱导的Balbc和TPA诱导的K14/VEGF转基因银屑病小鼠模型。这项研究的成功完成可能有助于我们通过解剖PI3K/AKT/mTOR的相互作用，以及将Delphindin作为一种治疗包括银屑病在内的增殖性角化性疾病的新药物的开发，来理解银屑病的发病机制。

 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.