Functional role of the renal risk gene WDR37 in renal disease

慢性肾脏疾病是全球第十大致死原因。10%-15%的人口受到慢性肾脏疾病的影响。慢性肾脏疾病会导致部分患者出现肾功能衰竭，需要进行肾移植或透析。慢性肾脏疾病的常见原因是糖尿病、自身免疫性疾病、高血压或遗传综合征，但在30%-40%的人中，原因尚不清楚。为了更好地了解肾脏疾病的发病机制，在大型遗传学研究中已经确定了肾功能降低的风险基因。在我们课题组的无关调查中，发现其中一个危险基因是LKB1的交互作用基因。我们之前已经将LKB1描述为调节肾脏炎症和纤维化(疤痕形成)的关键分子。由于肾功能的丧失总是与纤维化有关，我们推测上述风险基因编码的蛋白在功能上与LKB1周围的调节模块相互作用，在肾脏损伤和纤维化的发展中发挥作用。我们的目标是检测候选蛋白在不同肾脏疾病的活检组织中的表达。我们将删除小鼠肾脏中的候选基因，以研究其在正常肾脏以及损伤后的功能。我们将测试候选蛋白是否在成人缓慢进行性多囊肾病(ADPKD)中发挥作用，在ADPKD中，LKB1具有既定的作用。我们将使用细胞系统来确定候选蛋白质的分子机制。这项拟议的研究将有助于阐明慢性肾脏疾病发病机制的新方面，并澄清候选蛋白是否为潜在的治疗靶点。

Chronic kidney disease is the tenth leading cause of death worldwide. 10-15 % of the population are affected by chronic kidney disease. Chronic kidney disease causes renal failure in a subset of patients, necessitating kidney transplantation or dialysis. Common causes of chronic kidney disease are diabetes, auto-immune disease, hypertension or inherited syndromes, yet in 30-40 % the cause is unclear. To improve the understanding of the mechanisms underlying kidney diseases, risk genes for decreased renal funcion have been identified in large genetic studies (GWAS). In unrelated investigations of our research group, one of the risk genes was found as an interactor of LKB1. We have previously characterized LKB1 as a key molecule that regulates inflammation and fibrosis (scarring) in the kidney. Since the loss of renal function is invariably associated with fibrosis, we postulate that the protein encoded by the risk gene mentioned above funtionally interacts with the regulatory module surrounding LKB1 to play a role in renal injury and the development of fibrosis. We aim to examine expression of the candidate protein in biopsies of different renal diseases. We will delete the candidate gene in the mouse kidney to study its function in normal kidneys, as well as after injury. We will test if the candidate protein plays a role in adult slowly progressive polycystic kidney disease (ADPKD), where LKB1 has an established role. We will employ cellular systems to define molecular mechanisms of the candidate protein. The proposed investigation will help to elucidate new aspects of the pathogenesis of chronic kidney disease and clarify if the candidate protein is a potential therapeutic target.