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：
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
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/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

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

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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（由适用提供）：该提案的持续目的是确定PI3K/AKT/MTOR在牛皮癣发病机理中的关键作用，并开发用于管理牛皮癣的Delphinidin，这是一种常见的慢性炎性皮肤病，这是一种影响全球1.25亿人的慢性炎症性皮肤病。尽管牛皮癣没有威胁生命，但它表现出使身体和社会心理不适的残疾以及与银屑病关节炎和心血管疾病风险相关的全球疾病伯宁。作为多因素，击中单个目标不太可能会显着使患者受益，因此需要开发有效机制和基于目标的药物来治疗牛皮癣。在牛皮癣疾病中实施的许多信号网络中，PI3K/AKT/MTOR途径已成为临床相关的靶标，因为它可能会协同促进牛皮癣。与匹配的对照相比，使用回顾性人牛皮癣和咪喹莫德（IMQ）诱导的鼠牛皮癣样皮肤病变组织，我们观察到Akt/mTOR信号的激活。这些观察结果构成了我们提出的基础，即对PI3K/AKT/MTOR的简单靶向可能是治疗牛皮癣的有效方法。根据这一假设以及我们对皮肤中促分化和抗炎特性的无毒天然药物的追求，我们最近对Delphinidin进行了一些新颖而令人兴奋的观察结果。 delphinidin治疗的人角质形成细胞预先刺激/不使用IL-22的人类抑制PI3K，AKT和MTOR激活。进一步的竞争结合和在硅对接分析中表明，Delphinidin与PI3K，MTOR和P70S6K激酶的物理相互作用，其结合能为-7至-8.9kcal/Mol范围，在此应用中，我们建议利用Delphinidin和PIDOR的多种功能，并涉及：1）牛皮癣发病机理中的次要信号传导； 2）使用（i）使用（i）In-Vitro 2D培养物，i）3D重建的牛皮癣的人体皮肤模型以及III）Vivo IMQ诱导的BALBC和TPA诱导的K14/VEGF Transgenic Murine psoriassorial模型，研究了Delphinidin的效率。该提案的成功完成可能会导致我们通过解剖PI3K/AKT/MTOR的相互作用以及Delphindin作为一种新型药物的发展，从而导致我们对牛皮癣发病机理的理解。