环境污染物协同易感基因增加自闭症风险的内在分子机制

项目名称： 环境污染物协同易感基因增加自闭症风险的内在分子机制

项目编号： No.21477089

项目类型： 面上项目

立项/批准年度： 2015

项目学科： 化学工业

项目作者： 黄长江

作者单位： 温州医科大学

项目金额： 85万元

中文摘要： 自闭症是一种神经发育紊乱疾病，尽管遗传因素被认为是其主因，但仅从基因变异很难解释该病近年来为何呈现出爆炸式的增长。一些最新研究表明环境污染可能是诱发自闭症的另一主因，但其是否与基因变异协同作用而增加自闭症的风险尚属未知。鉴于自闭症的敏感窗口正好是神经前体细胞的增殖期，而细胞周期异常又是神经系统疾病的发病机制之一，我们提出环境污染物可能协同易感基因变异导致神经前体细胞分裂周期异常而增加自闭症发病风险的假说。本项目将以斑马鱼胚胎为研究材料，通过显微注射、基因人为调控、污染物水体暴露、自闭症症状综合评价、深度测序及其分析等方法来：1）察看环境风险污染物和易感基因是否在引发自闭症上存在叠加效应；2）寻找环境污染物和易感基因导致自闭症的早期作用靶细胞；3）探索环境污染物和易感基因引发自闭症的相同的或不同的内在分子机制。研究结果可以用来诠释环境污染物是否会协同易感基因增加自闭症的发病风险及其内在机制。

中文关键词： 环境污染物；发育神经毒性；斑马鱼胚胎；分子机制；细胞分化

英文摘要： The prevelance of autism specturm disorders (ASD) has been reported to increase dramatically in the past several decades. Though genetic factors such as gene mutations and copy number variants have been considered as main underlying causes for ASD, these factors alone can only explain about 20% of syndromic and non-syndromic ASD. Recent research findings indicated that environmental factors (e.g., pollutants) might also play an important role in the etiology of ASD. Currently, it is unknown whether environmental and genetic factors will interact with each other and play a causative role in ASD outbreak. Given the fact that mid-pregnancy, corresponding to the neural progenitor proliferation phase of fetal brain, was one of the most sensitive stages for ASD induction in experimental models, yet aberrant cell cycle play a causative role in many neural disorder related diseases, we thus hypothesize that the increased ASD incidence could result from a combined risk of environmental pollutants and susceptible genes that was mediated through aberrant cell cycle of neural progenitor cells. To test our hypothesis, we propose to use the embryonic zebrafish model, which allows mimicking the fetal exposure scenario as in humans while simultaneously provides an easy platform for experimental manipulation and in vitro observation. We will also take the advantage of genetic manipulation tools such as microinjection of morpholino or mRNA into single cell stage zebrafish embryos to down or up regulate targeting susceptible genes. Effects of environmental pollutants on ASD development in zebrafish will be performed through waterborne exposure of environmental relevant doses at early developmental stages. The specific objectives of our proposal are to 1) observe whether environmental pollutants in coupled with susceptible genes will pay a synergic role in ASD induction; 2) identify early targets of environmental pollutants and/or susceptible genes induced ASD; and 3) explore the molecular mechanism for combined risk of ASD from environmental pollutants and susceptible genes. The findings of our research will not only reveal the underlying molecular mechanisms responsible for environmental pollutants and/or susceptible genes induced ASD, but also help unravel the underlying causes for increased prevalence, pathogenic complexity, and clinical heterogeneity associated with ASD.

英文关键词： environmental pollutants;developmental neurotoxicity;zebrafish embryo;molecular mechanism;cell differentiation