CAM Center for Epigenetic Regulation of Inflammation

描述（由申请人提供）：这是一项更新申请，旨在研究通常用作CAM的植物药抑制炎症的表观遗传途径。在上一个资助周期中，我们在确定植物药介导抗炎特性的新型细胞和分子途径方面取得了突出进展。炎症可引发多种疾病，包括自身免疫性疾病、心血管疾病、神经退行性疾病、肥胖症和某些类型的癌症。因此，不仅要揭示未知的免疫机制和炎症介质，还要找到新的治疗方法。因为目前还没有药物可以有效治疗慢性炎症和相关疼痛而没有明显的副作用，我们提出的研究是非常重要的。传统上，印度（阿育吠陀）和中国的医学使用草药产品来治疗炎症性疾病。此外，超过25%的药物来自植物，这表明植物药提供了对抗炎症的新模式。染色质和DNA的表观遗传修饰最近已被证明在人类病理学（包括炎症）的调节中起关键作用。因此，作为CAM的植物药可能通过表观遗传调节介导其作用的概念是高度创新的。该中心的主要目标是测试总体假设，即目前用作CAM的植物药通过与免疫细胞上的特定受体相互作用调节表观遗传信号通路，以调节基因表达，从而改善炎症。这将使用四个研究项目进行测试，1）鉴定表观遗传途径，通过该途径白藜芦醇（RES）在神经炎症的调节中触发髓源性抑制细胞（MDSC）。2)Nrf 2信号通路在西洋参（AG）介导的结肠炎症和结肠癌抑制中的表观遗传调节。3)阐明饮食吲哚介导的结肠炎症改善的表观遗传机制，特别是吲哚如何激活AhR以促进Tcl 3和抑制Th 17细胞。4)鉴定Sparstolonin B（一种从三棱块茎中分离的化合物）作为TLR 2和TLR 4拮抗剂的作用，从而通过表观遗传调节抑制肝脏中的炎症。这些项目是高度整合和协同的，都涉及表观遗传途径，以便从一个项目产生的数据将有利于其他项目。这些项目将使用一个行政核心，该核心将协调中心的所有活动，并确保科学和方案的进展。所有项目还将使用一个分析核心，该核心将进行全基因组DNA甲基化、组蛋白甲基化/乙酰化、microRNA阵列、免疫监测、生物信息学和天然产物完整性测试。我们的CAM中心将共同确定植物药抑制炎症的表观遗传生物标志物和途径，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.