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

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（由申请人提出）：确定PI3K/mTOR在牛皮癣ESI中的关键作用的持续目标，并为牛皮癣的管理开发Delphinidin，这是一种常见的慢性炎性皮肤病，这是一种影响全球范围内1.25亿人它不会威胁生命，它可以预防物理和心理社会不适，全球疾病负担与银屑病关节炎和心血管疾病风险相关。基于牛皮癣的基于临床的牛皮癣，因为它可能会诱发牛皮癣的牛皮癣。 PI3K/AKT/MTOR可能是治疗牛皮癣的有效方法。对接分析表明，在此应用中，Delphindin与He PI3K，MTOR和P70S6K激酶有物理相互作用，在此应用中，我们建议利用Delphinidin的多功能能力，并设计为：1）。检查PI3K/AKT/MTOR和次级信号在PSO RIASIS发病机理中的参与； IMQ诱导的BALBC和TPA诱导的K14/VEGF转基因鼠模型S概括了人牛皮癣的许多特征。