多基因突变小鼠模型与动脉粥样硬化研究

目前己知人类有近 2 0 0 0 0种疾病 ,其发生与发展都与基因受损有着直接或间接的关系 ,其中相当一部分疾病的发病涉及到两个以上的基因功能异常。动脉粥样硬化 (AS)、肥胖、糖尿病、高血压等多基因疑难疾病是目前严重影响人类健康的重大疾病。在AS的发病过程中 ,血脂代谢异常是其重要原因之一。在载脂蛋白E(apoE)通过与低密度脂蛋白受体 (LDLR)和乳糜微粒受体的特异性结合 ,介导血浆脂蛋白的转运与清除 ,在脂质的代谢中起着非常重要的作用。瘦素受体 (OB R)在体内介导瘦素的信号传导 ,调节能量代谢与平衡与肥胖以及血脂代谢有关。通过…

Establishment of Multi-Gene Mutation Mouse Model and Study on Mechanisms of Atheroslerosis

Many diseases such as cardiovascular disease, obesity, and diabetes are related with multi gene mutation. Multi gene interaction also plays a key role in the development of hyperlipidemia and atherosclerosis. Apolipoprotein E (apoE), a high affinity ligand of low density lipoprotein receptor (LDLR), mediates the clearance of the lipoprotein in vivo. OB R is the receptor of leptin, which can regulate the expenditure of energy and food intake. It has five spliced isoforms, the common two of which is the long form, OB Rb and the short form, OB Ra, the long receptor OB Rb has the capacity of signal transduction. The focus of the present study is to construct a multi gene mutation mouse model to characterize the mechanism of hyperlipidemia and atherosclerosis development based on the above three single gene mutation models (apoE -/- ,LDLR -/- ,and db/db mice). The results show that when with normal diet single mutation and multi gene mutation mice have a greatly elevated cholesterol and triglyceride level with progress of time, Plasma glucose level is significantly increased in the multi gene mutation mice and OB Rdb mice, While others have no distinct increase compared with wild type mice, and when with high fat diet, all the three plasma levels in the mutation mouse models especially in the multi gene mutation mice are improved remarkably in time of only two weeks, thereafter the intima of the aorta appears with typical pathological plaques. Take together, our data suggested such multi gene mutation were highly correlated with hyperlipidemia and even the process of atherosclerosis. The multi gene mutation mouse model also provides a more resemble human disease studying model, which can be very helpful to further study of pharmaceutical and gene mediated therapy.