Targeting inflammasome mediated disorders with green tea

用绿茶治疗炎症小体介导的疾病

• 批准号: 8084189
• 负责人: HAROLD M HOFFMAN
• 金额: $ 19.12万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-06-15 至 2012-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8084189
• 关键词: Adverse effects; Anti-Inflammatory Agents; Anti-inflammatory; Antioxidants; Cell Death; Cells; Clinical; Clinical Trials Design; Complex; Development; Disease; Disease model; Epigallocatechin Gallate; Genes; Gout; Green tea; Heart; Human; In Vitro; Inflammation; Inflammatory; Inherited; Interleukin-1; Malignant Neoplasms; Mediating; Modeling; Mus; Mutant Strains Mice; Mutation; Oncogenic; Pathogenesis; Pathway interactions; Patients; Process; Property; Research Personnel; Role; Syndrome; Testing; Therapeutic; Urate; anti-cancer therapeutic; arthropathies; clinical efficacy; control trial; cytokine; design; effective therapy; in vivo Model; meetings; novel; protein complex; public health relevance; success

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.

描述（由申请人提供）：几个世纪以来，绿茶一直被用来治疗许多不同的疾病，从癌症到炎症性疾病。在过去的几年里，研究人员已经开始阐明EGCG的主要活性成分的几种作用机制，并且已经启动了用于治疗各种癌症的对照试验，以及针对炎症性疾病的其他研究。然而，一种治疗性化合物最终在临床取得成功的最重要因素之一是选择正确的目标疾病。许多常见病的发病途径复杂，发病机制多因素，临床疗效难以得到充分证明。因此，我们选择研究一种罕见的遗传性疾病，称为crypyrin相关周期综合征（CAPS），通过识别致病基因和揭示与该疾病相关的炎症途径，从而产生新颖有效的靶向治疗。进一步的研究表明，相关炎症性疾病痛风的发病机制与痛风相似，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茶研究的目的1中采用相同的发展方法，通过使用人类CAPS患者和敲入突变小鼠的细胞来研究EGCG在CAPS介导的炎症和细胞死亡中的作用，这些小鼠被设计成具有在人类患者中观察到的相同突变。我们假设绿茶会有多种作用机制，因此我们建议比较EGCG和其他已知机制的化合物在cap炎症途径的不同点上的作用。在目标2中，我们将研究EGCG对尿酸钠（MSU）介导的体外和体内炎症模型的影响，尿酸钠是常见疾病痛风的原因。虽然现在有治疗CAPS和痛风的方法，但治疗要么非常昂贵（CAPS中IL-1靶向治疗），要么由于副作用（痛风），许多患者的耐受性很差。因此，开发EGCG作为一种具有多作用机制、副作用小的潜在优势的新疗法，将满足尚未满足的临床需求。