Targeting PI3K/Akt/mTOR for the management of psoriasis

靶向 PI3K/Akt/mTOR 治疗银屑病

• 批准号: 9144314
• 负责人: Hasan Mukhtar
• 金额: $ 33.66万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-01 至 2020-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9144314
• 关键词: 70-kDa Ribosomal Protein S6 Kinases; Affect; Anthocyanidin; Anti-Inflammatory Agents; Anti-inflammatory; Apoptosis; Autoimmune Diseases; Binding; Biological Assay; Biology; Cells; Chronic; Clinical; Clonal Expansion; Competitive Binding; Computer Simulation; Computer software; Cyclin D1; Data; Development; Diet; Disease; Docking; Drug Targeting; Etiology; Extravasation; FRAP1 gene; Growth; Health; Human; Hyperplasia; Image Analysis; Imiquimod; Immune; Immune System Diseases; In Vitro; Inflammation; Inflammatory; Inhibition of Apoptosis; Insulin-Like Growth Factor I; Interleukin-1 alpha; Interleukin-17; Interleukin-6; Knock-out; Lesion; Life; MAPK3 gene; Modeling; Molecular; Monitor; Mus; Normal tissue morphology; PI3K/AKT; Pathogenesis; Pathology; Pathway interactions; Patients; Pattern; Pattern Recognition; Phosphotransferases; Physiological Processes; Play; Process; Property; Proto-Oncogene Proteins c-akt; Psoriasiform Dermatitis; Psoriasis; Psoriatic Arthritis; Raptors; Regulation; Role; STAT1 gene; Severities; Signal Transduction; Skin; Skin Tissue; System; T-Lymphocyte; TNF gene; Technology; Thick; Tissues; Transcription Factor AP-1; Transgenic Organisms; Vascular Endothelial Growth Factors; Vascularization; Water; angiogenesis; antimicrobial peptide; base; burden of illness; cardiovascular disorder risk; cell growth; chronic inflammatory skin; clinically relevant; cytokine; delphinidin; design; in vivo; inhibitor/antagonist; innovation; interleukin-22; keratinization; keratinocyte; novel; pre-clinical; psychosocial; reconstitution; skin disorder; skin lesion; stable cell line

 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.

 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。