CAM Center for Epigenetic Regulation of Inflammation

描述(申请人提供)：这是一个续签申请，旨在调查表观遗传途径，通过这些途径，植物类药物通常被用作CAM，抑制炎症。在之前的资金周期中，我们在确定新的细胞和分子途径方面取得了显著进展，植物药物通过这些途径调节其抗炎特性。炎症可引发多种疾病，包括自身免疫疾病、心血管疾病、神经退行性疾病、肥胖和某些类型的癌症。因此，不仅要发现迄今未知的免疫机制和炎症介质，而且要找到新的治疗方式。因为目前还没有药物可以有效地治疗慢性炎症和相关的疼痛而没有显著的副作用，我们建议的研究具有非常重要的意义。传统上，印度的阿育吠陀和中国使用草药来治疗炎症性疾病。此外，超过25%的药物来自植物，这表明植物药物提供了抗炎的新方法。染色质和DNA的表观遗传修饰最近被证明在包括炎症在内的人类病理过程中发挥着关键的调节作用。因此，植物类药物作为CAM可能通过表观遗传调节来调节其作用的概念是高度创新的。该中心的主要目标是检验目前植物类药物被用作CAM的主要假说，通过与免疫细胞上的特定受体相互作用来调节表观遗传信号通路，从而调节基因表达，从而缓解炎症。这将通过四个研究项目进行测试：1)确定白藜芦醇(RES)触发髓系抑制细胞(MDSCs)调节神经炎症的表观遗传途径。2)西洋参(AG)抑制结肠癌炎症反应中Nrf2信号通路的表观遗传调控。3)阐明饮食吲哚介导的改善结肠炎症的表观遗传学机制，特别是吲哚如何激活AhR促进Tregs和抑制Th17细胞。4)确定玄参甲素B作为TLR2和TLR4拮抗剂的作用，从而通过表观遗传调控抑制肝脏炎症。这些项目是高度整合和协同的，所有这些项目都涉及表观遗传途径，以便一个项目产生的数据将惠及其他项目。这些项目将使用一个行政核心，它将协调中心的所有活动，并确保科学和方案方面的进展。所有项目还将使用分析核心，该核心将执行全基因组DNA甲基化、组蛋白甲基化/乙酰化、微RNA阵列、免疫监测、生物信息学和天然产品完整性测试。我们的CAM中心将共同确定表观遗传生物标志物和植物药物抑制炎症的途径，从而为更好地治疗炎症性疾病铺平道路。

DESCRIPTION (provided by applicant): This is a renewal application aimed at investigating the epigenetic pathways through which botanicals used commonly as CAM, suppress inflammation. During the previous funding cycle, we have made outstanding progress identifying novel cellular and molecular pathways through which botanicals mediate their anti- inflammatory properties. Inflammation can trigger a wide range of diseases including autoimmune, cardiovascular, neurodegenerative, obesity, and certain types of cancer. For this reason, it is not only critical to uncover as-yet-unknown immune mechanisms and mediators of inflammation but also find novel treatment modalities. Because currently there are no medications that can effectively treat chronic inflammation and associated pain without significant side effects, our proposed studies are highly significant. Traditionally, the medicine practiced in India (Ayurveda) and China have used herbal products to treat inflammatory disorders. Also, more than 25% of the pharmaceuticals are derived from plants, which suggests that botanicals offer novel modalities against inflammation. Epigenetic modifications of chromatin and DNA have been shown recently to play a critical role in the regulation in human pathologies, including inflammation. Thus, the concept that botanicals used as CAM may mediate their effects through epigenetic regulation is highly innovative. The primary objective of the Center is to test the overarching hypothesis that botanicals currently used as CAM, regulate the epigenetic signaling pathways through interactions with specific receptors on immune cells to modulate gene expression leading to amelioration of inflammation. This will be tested using four research projects, 1) Identifying epigenetic pathways through which resveratrol (RES) triggers myeloid- derived suppressor cells (MDSCs) in the regulation of neuroinflammation. 2) Epigenetic regulation of Nrf2 signaling pathway in American ginseng (AG)-mediated suppression of inflammation in the colon and colon cancer. 3) Elucidation of the epigenetic mechanisms underlying dietary indole-mediated amelioration of inflammation in the colon specifically addressing how indoles activate AhR to promote Tregs and suppress Th17 cells. 4) Identifying the role of Sparstolonin B (a compound isolated from Sparganium stoloniferum tubers), as a TLR2 and TLR4 antagonist, thereby suppressing inflammation in the liver through epigenetic regulation. The projects are highly integrated and synergistic, all addressing epigenetic pathways so that the data generated from one project will benefit other projects. The projects will use an Administrative Core which will coordinate all activities of the Center and ensure scientific and programmatic progress. All projects will also use an Analytical Core which will perform genome-wide DNA methylation, histone methylation/acetylation, microRNA arrays, immune monitoring, bioinformatics and natural product integrity testing. Together, our CAM Center will identify epigenetic biomarkers and pathways through which botanicals suppress inflammation thereby paving the way for better treatment modality against inflammatory diseases.