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(申请人提供)：几个世纪以来，绿茶一直被用作治疗从癌症到炎症性疾病的许多不同疾病。在过去的几年里，研究人员开始阐明主要活性成分EGCG的几种作用机制，并启动了用于治疗各种癌症的对照试验，还提出了其他针对炎症性疾病的研究。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作为靶点。许多常见病的发病机制复杂，致病因素多，临床疗效不佳。因此，我们选择通过确定致病基因和揭示与这种疾病有关的炎症途径来研究一种罕见的遗传性疾病，即低温比林相关周期综合征(CAPS)，这导致了新颖而有效的靶向治疗。进一步的研究表明，在相关的炎症性疾病痛风中也有类似的发病机制，这已被用于CAPS的相同靶向治疗的有效治疗所证实。我们建议在绿茶研究的目标1中采取相同的开发方法，使用来自人类CAPS患者和敲门基因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，这些细胞被设计为具有与人类患者相同的突变。我们假设绿茶将有多种作用机制，因此建议将EGCG的作用与其他已知机制的化合物在CAPS炎症途径的不同点进行比较。在目标2中，我们将研究EGCG对由尿酸单钠(MSU)介导的炎症模型的影响，MSU是常见疾病痛风的原因。虽然现在有治疗CAPS和痛风的方法，但由于副作用(痛风)，治疗要么极其昂贵(CAPS中的IL-1靶向治疗)，要么对许多患者耐受性差。因此，开发EGCG作为一种新的治疗方法，具有多种作用机制和副作用少的潜在优势，将满足尚未满足的临床需求。 与公共健康相关：绿茶以其潜在的抗炎和抗癌治疗作用而闻名；然而，这些作用的机制还不清楚。这项建议将侧重于绿茶对两种炎症性疾病模型的影响，包括罕见的低温比林相关周期性综合征和常见病痛风。这项研究的结果将被用于设计绿茶对这些疾病患者的临床试验。