STAT3在髓系抑制细胞遗传和表观遗传因素相互调控网络中的作用

项目名称： STAT3在髓系抑制细胞遗传和表观遗传因素相互调控网络中的作用

项目编号： No.31470876

项目类型： 面上项目

立项/批准年度： 2015

项目学科： 生物科学

项目作者： 杨荣存

作者单位： 南开大学

项目金额： 80万元

中文摘要： 肿瘤和慢性炎症相关疾病通常伴有髓系抑制细胞的极化和扩增，它们控制着疾病的发生与发展。前期研究发现髓系抑制细胞的极化和扩增伴有明显的组蛋白甲基化修饰改变。鉴于STAT3在髓系抑制细胞极化和扩增过程的关键作用, 因此假设STAT3和表观遗传修饰之间可能存在着相互调控。该项目通过分析STAT3在遗传和表观遗传因素相互调控网络中的作用，寻找在髓系抑制细胞极化过程中起关键作用的表观遗传调控因素，解析髓系抑制细胞在病理环境中的调控机理。强调以下目的：1）确定STAT3在髓系抑制细胞极化和扩增过程中的作用；2）确定STAT3对组蛋白甲基化修饰的影响；3）鉴定STAT3相关组蛋白甲基化调控因素；4）分析STAT3组蛋白调控因素对相关基因的调控；5）决定STAT3信号对组蛋白甲基化调控因素的调控机理；6）评价组蛋白甲基化修饰因素对髓系抑制细胞极化及疾病发生发展的影响。研究结果为发展新的免疫治疗策略奠定基础。

中文关键词： STAT3；髓系抑制细胞；表观遗传调控；组蛋白修饰；信号传导

英文摘要： Myeloid derived suppressor cells (MDSCs) are often polarized and expanded with the development of chronic inflammation associated diseases and tumors. These MDSCs can cause serious immune suppression to promote the development of diseases. Studies have shown that STAT3 is critical for MDSC polarization and expansion under tumor and chronic inflammatory environments. Our recent results also point at the possible involvement of unique epigenetic changes at the histone modification and involvement of LNCRNAs （long no-coding RNA）via chromatin remodeling in response to different environments. All of these led us to hypothesize that a complex milieu of epigenetic changes could sense the chronic inflammatory and tumor environments to regulate MDSC polarization that lead to immunopolarization associated with complications and disease progression. Therefore, our general objective is to explore the mechanisms underlying the linkage between epigenetic modification and MDSC polarization by analyzing the regulation of STAT3 on the integrated network of genetic and epigenetic factors, which could lead us to the development of epigenetic intervention modalities to increase immune potency and disease regression. More specifically we aim to: 1) Characterize polarized MDSC under chronic inflammatory and tumor conditions and define the impacts of STAT3; 2) Characterize STAT3 associated epigenetic marks of histone methylation modifications and associated genes critical in MDSC polarization and suppressive function; 3) Identify the STAT3 associated methyltransferase (s) and/or demethylase (s) that play a critical role in the polarizing MDSCs; 4) Determine the effect of STAT3-associated methyltransferase (s) and/or demethylase (s) on MDSC associated genes; 5) Determine the mechanisms of STAT3 signal-mediated expression and activity of the methyltransferase(s) and/or demethylase (s) involved in MDSC polarization, and 6) Assess the effect of epigenetic treatments on MDSC polarization and disease stages. Our results are expected to highlight the epigenetic modifications playing a role in MDSC polarization and immunosuppressive features and enable defining the critical roles of STAT3 in these processes, which is expected to form a solid ground for the development of new potential strategies towards recuperation of the host's suppressed immune system and disease regression.

英文关键词： STAT3;myeloid derived suppressor cell;epigenetics;histone modification;signal transduction