蛋白质积聚体毒性作用在原发性开角型青光眼发病中的分子机制研究

项目名称： 蛋白质积聚体毒性作用在原发性开角型青光眼发病中的分子机制研究

项目编号： No.30872832

项目类型： 面上项目

立项/批准年度： 2009

项目学科： 金属学与金属工艺

项目作者： 卓业鸿

作者单位： 中山大学

项目金额： 30万元

中文摘要： 为阐明在原发性开角型青光眼发病过程中，突变型MYOC蛋白异常交联和堆积是否为最根本的分子、蛋白水平的病理变化，本课题组对另一家族性开角型青光眼家系- - 普宁1号家系(PN.1)进行研究，经全基因组扫描、单倍体型分析等发现其致病基因位于1号染色体的TIGR/MYOC基因，且存在Pro370Leu突变型,初步揭示了该家系独特表型背后的遗传本质以及疾病发生发展过程和TIGR/MYOC基因突变的可能相关机制。 对正常人及青光眼患者小梁细胞进行内质网应激、压力损伤、氧化损伤等，探索其在蛋白及分子水平的不同反应，证实青光眼患者小梁细胞的高敏性及易损伤性。研究发现以上损伤所致的细胞凋亡可能是POAG患者眼小梁细胞数目减少的原因之一。 为寻找有效的干预手段与药物靶点,进一步对细胞及动物体内的损伤进行保护研究，发现小分子肽类药物对小梁细胞及视神经具有靶向性保护作用，因其具有分子量小、制造工艺简单等优势，受体选择性小分子肽很有可能成为新型的视神经保护药物,本课题组系列研究内容为今后在分子水平及蛋白水平有效防治原发性开角青光眼提供新的理论依据。

中文关键词： 基因突变；蛋白质积聚体；毒性作用；原发性开角青光眼

英文摘要： To illustrate the fundamental molecular and pathological effect of mutation of MYOC protein crosslinking and debris in the pathogenesis of POAG.Our research group studied another family of OAG pedigree –PN.1.After full gene group scan, haploid type analysis and gene sequence measuring,we found its is located in the 1st chromosome of TIGR/MYOC gene and existed Pro370Leu mutation.The result revealed the potential role and related mechanism of TIGR/MYOC gene mutation with the genetic nature of clinical features of OAG pedigree. The effect of endoplasmic reticulum stress,high pressure and oxidative damage on normal and glaucoma patients trabecular meshwork cells were studied, and we found that different reactions exist in protein and molecular level and confirmed the trabecular meshwork cells in patients with glaucoma were more sensitivity and vulnerable. Studies found endoplasmic reticulum stress, high pressure damage, mitochondrial dysfunction and oxidative stress induced apoptosis may be one of the reasons for the reduction of the number of trabecular meshwork cells in patients with POAG. In order to looking for effective intervention means and drug target points , our research group further explored the protection effect of small molecular peptide in damaged cells and animals, due to its advantages of small molecular volume, long half-life and simple manufacturing technology, receptor selective small molecular peptide may became new optic nerve protection drug,the series results of our research group provides new theoretical basis for effective control of POAG in molecular and the protein level in the future.

英文关键词： genetic mutation；aggresome； toxic effect；primary open angle glaucoma