Targeting inflammasome mediated disorders with green tea

描述（由申请人提供）：几个世纪以来，绿色茶一直被用作从癌症到炎症性疾病的许多不同疾病的治疗方法。在过去的几年里，研究人员已经开始阐明被称为EGCG的主要活性成分的几种作用机制，并且已经开始了用于治疗各种癌症的对照试验，并且已经提出了用于炎性疾病的其他研究。然而，治疗化合物最终临床成功的最重要因素之一是选择正确的疾病靶向。许多常见疾病具有复杂的途径，具有多因素发病机制，因此难以证明足够的临床疗效。因此，我们选择研究一种罕见的遗传性疾病，称为cryopyrin相关周期性综合征（CAPS），通过鉴定致病基因并揭示参与这种疾病的炎症通路，从而产生了新的有效的靶向治疗方法。进一步的研究表明，相关炎症性疾病痛风的发病机制相似，这已被CAPS中使用的相同靶向治疗的有效治疗所证实。我们建议在我们的绿色茶研究的目标1中采取相同的开发方法，通过使用来自人类CAPS患者的细胞和设计为具有在人类患者中观察到的相同突变的敲入突变小鼠来研究EGCG在CAPS介导的炎症和细胞死亡中的作用。我们假设绿色茶将具有多种作用机制，因此建议将EGCG的作用与其他化合物在CAPS炎症途径的不同点上的已知机制进行比较。目的2：研究表没食子儿茶素没食子酸酯（MSU）介导的炎症模型的离体和体内效应，MSU是常见的痛风病的病因。虽然现在有CAPS和痛风的治疗方法，但治疗要么非常昂贵（CAPS中的IL-1靶向治疗），要么由于副作用（痛风）而被许多患者耐受性差。因此，开发EGCG作为一种具有多种作用机制和副作用少的潜在优势的新型疗法将满足未满足的临床需求。 公共卫生相关性：绿色茶以其潜在的抗炎和抗癌治疗特性而闻名;然而，负责这些作用的机制尚不清楚。该提案将集中于绿色茶对两种炎性疾病模型的影响，包括罕见的冷比林相关的周期性综合征和常见疾病痛风。这项研究的结果将用于设计绿色茶在这些疾病患者中的临床试验。

DESCRIPTION (provided by applicant): For centuries, green tea has been used as a therapy for many different diseases ranging from cancer to inflammatory disorders. Over the last few years, investigators have begun to elucidate several mechanisms of action of the primary active ingredient known as EGCG, and controlled trials have been initiated for the treatment of various cancers and other studies have been proposed for inflammatory diseases. However, one of the most important factors in the ultimate clinical success of a therapeutic compound is choosing the right disease to target. Many common diseases have complex pathways with multifactorial pathogenesis making it difficult to demonstrate adequate clinical efficacy. Therefore, we have chosen to study a rare inherited disease known as cryopyrin associated periodic syndrome (CAPS) by identifying the causative gene and uncovering the inflammatory pathways involved in this disease, which has resulted in novel and effective targeted therapies. Further studies have shown similar pathogenesis in the related inflammatory disease gout and this has been confirmed by effective treatment with the same targeted therapies used in CAPS. We propose to take the same developmental approach in aim 1 of our study of green tea by investigating the role of EGCG in CAPS mediated inflammation and cell death using cells from human CAPS patients and knockin mutant mice designed to have the same mutations observed in human patients. We hypothesize that green tea will have multiple mechanisms of action and therefore propose to compare the effects of EGCG to other compounds with known mechanisms at various points in the inflammatory pathways of CAPS. In aim 2, we will study the effects of EGCG on ex vivo and in vivo models of inflammation mediated by monosodium urate (MSU), the cause of the common disease gout. Although therapies are now available for CAPS and gout, treatments are either extremely expensive (IL-1 targeted therapy in CAPS) or poorly tolerated by many patients due to side effects (gout). Therefore, development of EGCG as a novel therapy with the potential advantage of multiple mechanisms of action and few side effects would meet an unmet clinical need. PUBLIC HEALTH RELEVANCE: Green tea is known for its potential anti-inflammatory and anti cancer therapeutic properties; however, the mechanisms responsible for these actions are not well understood. This proposal will focus on the effects of green tea on two inflammatory disease models including the rare cryopyrin associated periodic syndrome and the common disease gout. Results of this study will be used to design clinical trials of green tea in patients with these diseases.