Cadherin基因与急性一氧化碳中毒后迟发性脑病的相关性研究

Delayed encephalopathy after acute carbon monoxide poisoning (DEACMP) has not been recognized by the medical research community. There are 480 million rural population is still using charcoal for heating in our country,Acute carbon monoxide(C0) poisoning has become the main disease in winter hospital emergency,including a third of DEACMP. In this study group, we found that the Cadherin gene may be a susceptibility gene of DEACMP, which is a susceptibility gene.Nerve injury is one of the main pathological features of the disease,The study suggests that the signal pathway of Cadherin is related to the repair of nerve injury.In this study, the positive association of DEACMP was tested by independent samples,and then establish the DEACMP rat model,evaluated the model by means of neural pathology, cognitive behavior and EEG,then, analyze the calcium mucin signal pathway by biochemical test, RNA interference and gene over expression, drug control and so on,To investigate whether the signaling pathway can rescue the pathological changes of the model and the mechanisms involved in the repair of DEACMP nerve injury.The project is expected to further clarify the susceptible genes of DEACMP and preliminary explanation the relationship between cadherin signaling pathway and nerve injury, and to provide experimental evidence for the pathogenesis of DEACMP.

急性一氧化碳中毒后迟发性脑病(DEACMP)一直未得到医学研究界的重视。我国有4.8亿农村人口仍采用炭火取暖，急性一氧化碳(CO)中毒成为冬季医院急诊的主要病种，其中DEACMP者占1/3。本课题组在急性CO中毒群体中发现，钙黏蛋白基因可能是DEACMP的易感基因，该病具有遗传易感性。神经损伤是该病主要病理表现之一，研究提示钙黏蛋白信号通路与脱髓鞘等神经损伤的修复有关。本研究首先通过独立样本再次验证DEACMP阳性关联基因，然后建立DEACMP大鼠模型，通过神经病理、认知行为和脑电生理对模型进行评价；通过生化检测、RNA干扰和基因过表达、工具药调控等对钙黏蛋白信号通路进行分析，探讨该信号通路能否挽救模型病理改变以及参与DEACMP神经损伤后修复的作用机理。本项目预期将进一步明确DEACMP的易感基因，并初步解释钙黏蛋白信号通路异常与神经损伤的关系，为明确DEACMP发病机理提供实验证据。

急性一氧化碳中毒的发病机理是急性缺氧，所以人只要吸入过量的一氧化碳气体均会发病，而DEACMP并不是全部急性一氧化碳中毒患者的最终结局，国内外研究显示：在急性一氧化碳中毒程度、昏迷时间、年龄、性别、全身状况基本相同的患者中，只有少部分在清醒后，经历一定的“假愈期”会发生DEACMP，但大部分清醒后恢复正常，不会发生DEACMP，对DEACMP的发病机制的研究尚无法解释这一现象，有学者推测该现象可能与患者个体差异有关，现已有研究表明DEACMP具有遗传易感性，或许与DEACMP的发病有关。本课题组在对DEACMP患者的全基因组测序中发现Cadherin、NRXN3、MBP等基因与各种神经损伤之间存在着不容忽视的联系。据此，本项目提出如下假说：“DEACMP个体具有易感素质，Cadherin可能是DEACMP的易感基因， 急性一氧化碳中毒可能影响Cadherin分子信号通路的正常功能，从而造成神经脱髓鞘等损伤修复过程受阻，继而导致DEACMP的发生”。本研究在进一步验证Cadherin等DEACMP易感基因的基础上，已基本建立较为符合临床特点的DEACMP 大鼠模型，通过神经病理、认知行为和脑电生理对模型进行评价；然后通过生化检测、工具药调控等对Cadherin-ROCK分子信号通路进行分析，已基本验证该信号通路参与挽救大鼠模型神经损伤表型以及参与神经损伤后修复的作用机理。本项目进一步明确了DEACMP的易感基因如NSE、MBP、LRCH1与该疾病的相关性，并初步解释钙粘蛋白信号通路异常与神经损伤的关系以及ROCK抑制剂抑制该信号通路相关内因子从而改善DEACMP大鼠模型的认知及运动能力，同时为明确DEACMP发病机理提供实验证据。