Targeting PI3K/Akt/mTOR for the management of psoriasis

靶向 PI3K/Akt/mTOR 治疗银屑病

基本信息

批准号：
9030172
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
项目类别：
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/9030172
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 Growth Human Hyperplasia Image Analysis Imiquimod Immune Immune System Diseases In Vitro Inflammation Inflammatory Inhibition of Apoptosis Insulin-Like Growth Factor I 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 Technology Thick Tissues Transcription Factor AP-1 Transgenic Organisms Tumor Necrosis Factor-alpha Vascular Endothelial Growth Factors Vascularization Water angiogenesis antimicrobial peptide base burden of illness cardiovascular disorder risk cell growth clinically relevant cytokine delphinidin design human FRAP1 protein in vivo inhibitor/antagonist innovation interleukin-22 keratinization keratinocyte novel pre-clinical psychosocial public health relevance reconstitution skin disorder skin lesion stable cell line

项目摘要

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（由申请人提供）：该提案的持续目标是确定 PI3K/Akt/mTOR 在银屑病发病机制中的关键作用，并开发飞燕草素用于治疗银屑病，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。多因素影响，达到单一目标不太可能使患者显着受益，因此需要制定有效的机制在与银屑病疾病有关的许多信号网络中，PI3K/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的发生。在诱导的小鼠银屑病样皮肤病变组织中，我们观察到与匹配对照相比 AKT/mTOR 信号传导的激活，这些观察结果构成了我们建议的基础：同时靶向 PI3K/Akt/mTOR 可能是治疗牛皮癣的有效方法根据这一假设，并在我们追求具有皮肤促分化和抗炎特性的无毒天然药物的过程中，我们最近做了一些新的研究。进一步的竞争性结合和计算机对接分析显示，用花翠素处理预刺激的人角质形成细胞（使用/不使用 IL-22）可抑制 PI3K、Akt 和 mTOR 激活。揭示飞燕草素与 PI3K、mTOR 和 p70S6K 激酶发生物理相互作用，结合能为 -7 至 -8.9Kcal/mol 范围。在本应用中，我们建议利用飞燕草素的多管齐下的能力，并设计为：1 ) 检查 PI3K/Akt/mTOR 和次级信号传导在银屑病发病机制中的参与情况 2) 使用飞燕草素研究其功效； (i) 体外 2D 培养物，i) 3D 重建人类银屑病皮肤模型，以及 iii) 体内 IMQ 诱导的 Balbc 和 TPA 诱导的 K14/VEGF 转基因小鼠银屑病模型，该模型概括了人类银屑病的许多特征。该提案的完成可能会导致我们通过剖析银屑病发病机制的相互作用来了解银屑病的发病机制。 PI3K/AKT/mTOR 以及飞燕草素作为对抗增殖性角化性疾病（包括牛皮癣）的新型药物的开发。