靶向EMT调控分子的新型阻滞肽及HDAC抑制剂对晶体后囊膜混浊抑制效果的研究

项目名称： 靶向EMT调控分子的新型阻滞肽及HDAC抑制剂对晶体后囊膜混浊抑制效果的研究

项目编号： No.81470614

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： 裴澄

作者单位： 西安交通大学

项目金额： 67万元

中文摘要： 晶状体后囊膜混浊（PCO）是导致白内障病人手术后视力再次下降的主要原因。转化生长因子β2（TGF-β2）诱导的晶体上皮细胞上皮间质转化（EMT）对PCO的发生起关键作用。预实验发现结缔组织生长因子（CTGF）和Snail是TGF-β2信号下游的两个效应分子。CTGF通过与TGF-β2的相互作用促进细胞EMT转化，而Snail通过抑制E-Cadherin的表达来促进EMT发生。本课题拟以这两个分子为靶标尝试开发新的PCO防治手段。首先寻找介导TGF-β2和CTGF相互作用的多肽区段，并依此设计筛选阻遏该相互作用的多肽分子，然后检验其对晶体上皮细胞EMT和大鼠PCO发生的影响。其次阐明Snail对E-Cadherin的表达调控机理，用免疫共沉淀等技术研究Snail对组蛋白去乙酰化酶（HDAC）的招募结合情况，检验HDAC抑制剂对EMT及PCO发生的影响。从不同靶点角度探索抑制PCO发生的方法。

中文关键词： 后囊膜混浊；转化生长因子β2；结缔组织生长因子；上皮间质转化；组蛋白去乙酰化酶

英文摘要： Posterior Capsule Opacification（PCO）is the major cause of vision deterioration after cataract surgery. Previous studies have found that TGF-β2 and two of its downstream effectors (CTGF and Snail) participate in the regulation of EMT of lens epithilial cells and contribute to the onset of PCO. CTGF promotes EMT by enhancing TGF-β signaling via direct interaction with TGF-β,while Snail facilitates EMT process by transcriptional inhibition of E-Cadherin. This proposal aims to develop strategies that target CTGF or Snail for the prevention of PCO. We will initially study the mechanism of protein-protein interaction bewteen TGF-β2 and CTGF. Small peptide molecules that can potentially block this interaction will be designed，synthesized and screened for the highest blocking efficiency. Candidate peptide molecules will be tested in cell line and mouse PCO models for the ability to prevent EMT and the onset of PCO. In addition, we will investigate the mechanisms of E-Cadherin regulation by Snail. The interaction between Snail and HDACs will be examined using coimmunoprecipitation. Lastly, the effect of HDAC inhibitors on EMT and PCO will be inspected in cell line and mouse models. These stuides will provide guidance for the development of therapeutic strategies for PCO.

英文关键词： Posterior Capsule Opacification;TGF-β2;CTGF;EMT;HDAC