基于APOE ε4分型的阿尔茨海默病组学数据挖掘及药靶发现

发布时间：2018-11-02 11:26

【摘要】：阿尔茨海默病(Alzheimer's Disease, AD)是65岁及65岁以上人群中最常见的一种痴呆症,以伴随有明显病理改变(例如淀粉样蛋白斑(Abeta)及神经纤维缠结(Tau))的认知功能障碍为特征,并且具有一定的遗传易感性。最常见的非家族性AD——迟发型AD病因极为复杂,但APOE ε4是公认的AD易感因子。AD APOE ε4携带者与非携带者在的病理和临床表现不同,对药物治疗反应性也不同,表明两者的发病机制与药靶不同,亟需整合研究和分层治疗。单基因水平的研究对复杂性疾病而言已不能满足现代精确医学的要求,AD组学数据库为在系统水平上研究AD提供契机,利用现有的大数据分析手段,从中挖掘出前所未知的疾病生物学信息和新的药靶。本课题以AD APOE ε4携带者与非携带者之间的差异性作为基础,利用公共及申请数据库,采用GWAS、遗传学、系统药理学、统计学以及图论等方法以及分子生物学实验技术,构建差异共表达网络与蛋白-蛋白互作网络,对ADAPOE ε4携带者与非携带者之间的遗传和基因表达差异进行探索和新药靶的发现。研究结果表明：① AD APOE 4携带者与非携带者之间存在着明显的遗传异质性,AD APOE ε4非携带者特异性易感位点rs6816078与单倍型块rs28604990-rs7955747与脑脊液生物标记物(Abeta 和 Tau)相关。②AD APOEε4携带者与非携带者存在特异性共表达模块(携带者中有violet和darkmagenta模块,非携带者中有lightcyan模块),AD APOE ε4携带者的模块具有显著的遗传基础。AD APOE ε4携带者与非携带者的特异性共表达模块中的ACLY, GAD2, DDIT3等基因是潜在AD药物的靶标。①AD APOE ε4携带者与非携带者之间存在很多不同的易感基因,实验验证进一步表明AD APOE ε4携带者的关键基因FYN和CAMK2A/2B的蛋白表达水平受到APOE ε4的调控,并且发现FYNsiRNA可显著逆转APOE ε4对神经轴突的毒性作用。本研究首次在系统层面上阐明了AD APOE ε4携带者与非携带者在遗传水平和基因表达水平上的差异并发现了潜在药靶一一逆转APOE ε4经毒性作用的新型siRNA,为进一步开展AD的精细化分型和系统药理学研究提供了实验依据和理论基础。
[Abstract]:Alzheimer's disease (Alzheimer's Disease, AD) is the most common form of dementia in people 65 and older. It is characterized by cognitive impairment associated with obvious pathological changes, such as amyloid spot (Abeta) and neurofibrillary tangles (Tau), and has a certain genetic susceptibility. The most common etiology of non-familial AD-- delayed type AD is very complicated, but APOE 蔚 4 is a recognized AD susceptibility factor. AD APOE 蔚 4 carriers and non-carriers in the pathological and clinical manifestations are different, and the response to drug treatment is also different. These results suggest that the pathogenesis of both is different from that of drug target, so it is necessary to integrate research and stratification therapy. The study of single gene level can no longer meet the requirements of modern accurate medicine for complex diseases. The AD database provides an opportunity for the study of AD at the system level and makes use of existing big data analysis methods. Discover previously unknown biological information and new drug targets. Based on the differences between carriers and non-carriers of AD APOE 蔚 4, using common and application databases, GWAS, genetics, systematic pharmacology, statistics and graph theory, and molecular biological experimental techniques, the study was carried out. The differential coexpression network and protein-protein interaction network were constructed to explore the genetic and gene expression differences between carriers and non-carriers of ADAPOE 蔚 4 and to find new drug targets. The results showed that: 1 there was significant genetic heterogeneity between AD APOE 4 carriers and non carriers. The specific susceptibility site (rs6816078) of AD APOE 蔚 4 was associated with haplotype rs28604990-rs7955747 and cerebrospinal fluid biomarkers (Abeta and Tau). 2AD APOE 蔚 4 carriers and non-carriers had specific coexpression modules (violet and darkmagenta modules in carriers). There is a significant genetic basis for), AD APOE 蔚 4 carriers in non-carriers, and ACLY, GAD2, in specific coexpression modules of. AD APOE 蔚 4 carriers and non-carriers. DDIT3 and other genes are targets of potential AD drugs. There are many different susceptibility genes between 1AD APOE 蔚 4 carriers and non-carriers. The results showed that the expression of FYN and CAMK2A/2B in AD APOE 蔚 4 carriers was regulated by APOE 蔚 4, and FYNsiRNA could reverse the toxicity of APOE 蔚 4 to axons. This study was the first time to elucidate the genetic and gene expression levels of AD APOE 蔚 4 carriers and non carriers at the systemic level, and found a novel siRNA, with potential drug targets to reverse the toxic effects of APOE 蔚 4. It provides the experimental and theoretical basis for the further development of the fine classification of AD and systematic pharmacology research.
【学位授予单位】：上海交通大学
【学位级别】：博士
【学位授予年份】：2015
【分类号】：R749.16

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