miR-200c在微囊藻毒素-LR损伤胰岛β细胞功能中的机制研究

Microcystins (MCs) are a class of the most important environmental pollutants released by several genera of freshwater cyanobacteria. Ambient levels of MCs at Lake Taihu can increase blood glucose, decrease insulin level and injure pancreatic β cell function in mice. In our previous study, we found that MCs had β cell toxicity. They could induce β cell apoptosis and cause the expression of apoptosis-related miR-200c up-regulated. Although miR-200c was closely related to GLP-1R pathway which could inhibit apoptosis in β cell, the underlying mechanism between them is unclear. Therefore, this project plans to focus on miR-200c and around GLP-1R pathway. First, applied the WHO recommended safe consumption level for MCs as the basic treatment dose, observe the toxic effect of low-dose and chronic exposure to MCs on β cell function. Then, study the underlying mechanism of MCs induced Min6 cell function injury after low dose MCs exposure in vitro.The project is useful to find out the molecular target and biomarker after MCs treatment, helps us to understand the potential risk of MCs on diabetes, and has great significance in protecting people’s health.

微囊藻毒素（MCs）是由蓝藻释放的重要环境污染物，富含MCs的太湖水能显著升高小鼠血糖、降低其胰岛素水平，损伤胰岛β细胞功能。申请人前期发现MCs具有胰岛β细胞毒性作用，能诱导其凋亡，且显著上调凋亡相关的miR-200c表达。miR-200c与抑制β细胞凋亡的GLP-1受体通路密切相关，但二者的作用关系并未明确。因此，本项目拟以miR-200c为研究焦点，围绕GLP-1受体通路，首先参照WHO饮水MCs规定值，长时间染毒小鼠，确认低浓度MCs长时间暴露对小鼠胰岛β细胞功能的危害，然后通过体外实验探明低浓度MCs暴露诱导小鼠胰岛Min6细胞凋亡进而损伤其功能的分子机制，从而发现MCs毒性作用的分子靶点及可利用的、敏感的生物标志物。该研究对于提高人们对MCs增加糖尿病风险的认识，保障人群健康具有重要意义。

微囊藻毒素（MCs）是由蓝藻释放的重要环境污染物，富含MCs的太湖水能显著升高小鼠血糖、降低其胰岛素水平，损伤胰岛β细胞功能。申请人前期发现MCs具有胰岛β细胞毒性作用 ，能诱导其凋亡，且显著上调凋亡相关的miR-200c表达，但miRNA在MCs导致的胰岛β细胞毒性中的作用机制并未明确。. 本项目以miRNA为研究焦点，参照WHO饮水MCs规定值，长时间染毒小鼠，确认低浓度MCs长时间暴露对小鼠胰岛β细胞功能的危害；然后通过体外实验，在确认MCs对胰岛β细胞直接毒性的基础上，采用miRNA和mRNA芯片技术筛选及分析，寻找在MCs胰岛β细胞毒性中起关键作用的靶基因。结果发现，miR-3473及其靶基因Kcnj11具有重要的调控作用，进而围绕miR-3473/Kcnj11，探明低浓度MCs暴露诱导小鼠胰岛Min6细胞功能损伤的分子机制，从而发现MCs毒性作用的分子靶点及可利用的、敏感的生物标志物。该研究对于提高人们对MCs增加糖尿病风险的认识，保障人群健康具有重要意义。