伴随肥胖和2型糖尿病的增加，NAFLD的发病率达到20%-30%之间。NAFLD可能发展成为肝硬化，肝功能衰竭，肝癌。目前临床上无有效逆转或阻止NAFLD的药物。最新的研究表明T3能够逆转或阻止NAFLD，但会引起心动过速，肌肉萎缩，骨质疏松等严重副作用。这是由于活性T3全身分布并作用于组织广泛表达的甲状腺激素受体引起的。本项目的目标就是靶向甲状腺激素进入肝脏中，实现逆转或阻止NAFLD的作用，同时不影响非肝脏组织的功能。体内存在大量活性被天然TBG沉默的甲状腺激素。利用重组蛋白技术，滴定技术等我们将能够理解TBG识别结合甲状腺激素的机制；以上述机制为基础，结合糖基化技术我们将能获取高结合力并靶向肝脏的重组TBG；研究重组TBG竞争捕获体内甲状腺激素并靶向肝脏后对NAFLD的治疗效果。这项研究不仅将为NAFLD的治疗提供一种创新方法，还可能为其它疾病的治疗提供通用的小分子药物靶向传输系统。

With increases of obesity and type 2 diabetes, the prevalence of NAFLD(Non-alcoholic Fatty Liver Disease) is estimated to be between 20% and 30%. NAFLD potentially progresses to cirrhosis, liver failure, and hepatocellular cancer. Now, there is no effective clinical drug to reverse or prevent NAFLD. New studies show that T3 can effectively reverse or prevent NAFLD, but would lead to serious side effects such as tachycardia, muscle wasting, osteoporosis, etc. The reason is that acitve T3 circulates throughout the body and interacts with thyroid hormone receptor expressed widely in most tissuses. The objectives of the proposal are to target thyroid hormones into liver and achieve the reversal or prevention of NAFLD, and at the same time, not influence other tissues except for liver. In vivo, there is much inactive thyroid hormone silenced by native TBG(Thyroxine-binding Globulin). By using recombinant protein technology, titration technique, etc, We will be able to undersand the mechanism responsible for the recognition and binding of thyroid hormones by TBG. Based on the above mechanism and combined with glycosylation technology, we will be able to gain recombinant TBG with higher affinity to T3/T4 and targeting to liver. We will study the therapeutic effect on NAFLD by recombinant TBG, which competes to capture in vivo thyroid hormones and then targets them into liver. This research will provide not only an innovative therapeutic approach for the treatment of NAFLD, but also a general targeting delivery system which can target small-molecule drugs for the treatment of other diseases.