TBX6基因突变导致先天性肾脏和尿路发育异常的分子机制研究

Congenital anomalies of kidney and urinary tract are common birth defects and major causes of chronic kidney disease in infants and young children. Embryonic kidney abnormalities, especially metanephros dysplasia induce CAKUT occurrence, genetic factor plays a vital role during the metanephros development. Our preliminary study detected TBX6 mutation can cause CAKUT in pediatric patients, meanwhile, we constructed TBX6 mutation mouse model by CRISR Case9 technology and observed CAKUT phenotype in mouse model. However, the detail pathogenesis is still unknown. In this study, we will use Hoxb7/mVnus mice to construct fluorescence marked TBX6 mutation mice, and dynamically observe the impact on the process of ureteric bud eruption and branching, through systematically research on the key regulatory molecules to explore the mechanism of ureteric bud eruption in TBX6 mutation mice, and provide a new understanding of developmental biology and disease.

先天性肾脏及尿路畸形（CAKUT）占新生儿出生缺陷的20-30%，是儿童慢性肾脏病（CKD）及终末期肾病（ESRD）的主要病因。后肾发育异常是CAKUT的发生基础，研究证实遗传因素是导致CAKUT的重要因素。本课题组前期研究发现TBX6基因突变可导致儿童CAKUT的发生，并且构建TBX6基因突变小鼠存在CAKUT表型，但是TBX6基因突变导致CAKUT发生的具体机制目前尚未明确。本课题通过已经构建的TBX6基因突变小鼠模型和已构建的新型动态研究后肾的Hoxb7/mVnus小鼠模型，进一步构建后肾带有荧光标记的TBX6基因突变小鼠，动态观察TBX6基因突变对输尿管芽的萌出、生长及分支的影响；通过体内及体外实验阐明TBX6基因调控后肾发育的具体分子机制及信号通路。为CAKUT的致病机制提供新的认识及为CAKUT的早期分子诊断提供依据。

先天性肾脏及尿路畸形（CAKUT）占新生儿出生缺陷的20-30%，是儿童慢性肾脏病（CKD）及终末期肾病（ESRD）的主要病因。后肾发育异常是CAKUT的发生基础，研究证实遗传因素是导致CAKUT的重要因素。本课题组前期研究发现TBX6基因突变可导致儿童CAKUT的发生，并且构建TBX6基因突变小鼠存在CAKUT表型，但是TBX6基因突变导致CAKUT发生的具体机制目前尚未明确。本课题通过已经构建的TBX6基因突变小鼠模型和已构建的新型动态研究后肾的Hoxb7/mVnus小鼠模型，进一步构建后肾带有荧光标记的TBX6基因突变小鼠，动态观察证实TBX6基因突减少输尿管牙的萌出；通过体内及体外实验阐明TBX6基因主要通过ROBO2-slit2调控后肾发育的具体分子机制及信号通路。为CAKUT的致病机制提供新的认识及为CAKUT的早期分子诊断提供依据