表观遗传调控在急性肾损伤向慢性化转归中的作用和机制

项目名称： 表观遗传调控在急性肾损伤向慢性化转归中的作用和机制

项目编号： No.81470920

项目类型： 面上项目

立项/批准年度： 2015

项目学科： 医药、卫生

项目作者： 庄守纲

作者单位： 同济大学

项目金额： 73万元

中文摘要： 长期随访研究显示，约有1/4的急性肾损伤患者演变为慢性肾脏病，但分子调控机制不明。前期研究结果表明: 小鼠急性严重肾缺血损伤后，肾脏表皮生长因子受体持续上调，成纤维细胞活化，细胞外基质沉积， 阻断表皮生长因子受体明显减轻这些反应。在小鼠输尿管结扎致肾纤维化模型，阻断表观遗传调控分子之一的I类组蛋白去乙酰化酶（HDAC），也使肾脏纤维化减轻，表皮生长因子受体和TGF-β/Smad信号通路抑制。推测Ｉ类HDAC介导的纤维化通路活化与急性肾损伤后向慢性化转归密切相关。本项目拟利用小鼠急性肾缺血和中毒模型，I类HDAC抑制剂和多项分子生物学技术验证此假说。首先评估I类HDAC在急性肾损伤向慢性化转归中的作用；然后检查其在急性肾损伤后致纤维化因子产生和肾成纤维细胞活化中的作用；最后探讨其在多个纤维化相关受体表达和激活中的作用和机制。为阐明急性肾损伤向慢性化转归的调控机制，制定防治策略提供理论依据。

中文关键词： 急性肾损伤；慢性肾脏病；表观遗传调节；组蛋白去乙酰化酶；表皮生长因子受体

英文摘要： The long-term follow-up survey has demonstrated that approximately 1/4 patients with acute kidney injury (AKI) progress to chronic kidney disease, however, the regulatory mechanism in this process is not clear yet. Our previous studies have shown that following acute severe ischemic AKI in mice, renal EGFR expression is persistently upregulated, which is accompanied by activation of myofibroblasts and deposition of extracellular metrix. Inhibiting EGFR remarkably reduces these responses. In a mouse model of unilateral ureteral obstruction, blockage of class I histone deacetylases (HDACs) also attenuates renal fibrosis, and suppresses activation of epidermal growth factor receptor (EGFR) and transforming growth factor receptor-beta/Smad-3 signaling pathways. On this basis, we speculate that class I HDACs-mediated activation of fibrogenetic signaling pathways would be associated with the progression of AKI to chronic kidney disease (CKD). In this grant proposal, we will utilize the mouse models of acute ischemic and nephrotoxic AKI, class I HDAC inhibitors and multiple molecular techniques to (1) assess the role of class I HDACs in the progression of AKI to CKD, (2)examine the roles of class I HDACs in regulating production of profibrotic growth factors and activation of renal interstitial fibroblasts, and (3) explore the expression and activation of multiple growth factor receptors associated with renal fibrogensis. This study would provide the molecular basis for AKI progression to CKD and development of novel approaches for prevention and alleviation of this process.

英文关键词： Acute kidney injury;Chronic kidney disease;Epigenetic regulation;Histone acetylation;Epidermal growth factor receptor