Epithelial Angiogenic Signaling in Polycystic Diseases of the Liver

描述（由申请人提供）：我们研究的更广泛目标是了解上皮细胞对损伤的反应，特别是胆上皮在肝脏修复和再生中的作用。肝内胆道树疾病（“胆管病”）是严重的慢性衰弱性肝脏疾病，影响儿童和年轻人。多囊性肝病是一组遗传性胆管疾病，其特征是胆道上皮进行性囊性扩张，可能导致需要肝移植的并发症。这些疾病具有特别的科学意义，因为它们与初级纤毛上的蛋白质功能改变有关。成人显性多囊肾病（ADPKD）是由多囊蛋白1或-2的遗传缺陷引起的。这些蛋白作为机械感受器，参与调节细胞分化和上皮形态发生的信号通路。上皮血管生成信号，特别是VEGF和血管生成素-1，在ADPKD的胆道上皮细胞（胆管细胞）中被显示上调，并可能在肝脏疾病的发病机制中发挥作用。本研究提出的假设是，源自胆道上皮的自分泌和旁分泌血管生成信号是ADPKD中肝囊肿生长和疾病进展的机制之一。这一假设将通过三个具体目标进行验证：1)研究遗传缺陷与ADPKD患者胆道上皮血管生成信号上调之间的关系；2)研究自分泌VEGF-和血管生成素-1介导的刺激胆管细胞生长和存活的细胞内通路；3)在ADPKD小鼠模型中研究阻断血管生成信号是否能抑制肝囊肿的生长。这些问题将在体外和体内用多囊蛋白1或多囊蛋白2条件失活的小鼠来解决。这些研究将a)增加我们对VEGF在分泌上皮中的调控和信号传导的认识，b)更好地阐明VEGF/血管生成素信号传导在肝脏疾病中的作用，c)为ADPKD中囊肿进行性生长的机制提供重要信息，d)为抗血管生成治疗控制ADPKD中肝脏和肾脏囊肿的生长提供重要的概念证明。

DESCRIPTION (provided by applicant): The broader goal of our studies is to understand how epithelia react to damage and in particular the role of the biliary epithelium in the repair and regeneration of the liver. Diseases of the intrahepatic biliary tree ("cholangiopathies") are severe chronic debilitating liver diseases affecting the pediatric and young adult population. Polycystic liver diseases, a group of genetic cholangiopathies, are characterized by progressive cystic dilations of the biliary epithelium that may cause complications requiring liver transplantation. These diseases are of particular scientific interest because of their association with an altered function of proteins localized on the primary cilia. Adult Dominant Polycystic Kidney Disease (ADPKD) is caused by genetically transmitted defect in polycystin-1 or -2. These proteins function as mechanoceptors, and are involved in signaling pathways that regulate also cell differentiation and epithelial morphogenesis. Epithelial angiogenic signaling, particularly VEGF and Angiopoietin-1, were shown to be upregulated in biliary epithelial cells (cholangiocytes) from ADPKD and may play a role in the pathogenesis of liver disease. The hypothesis addressed in this proposal is that autocrine and paracrine angiogenic signals originating from the biliary epithelium are one of the mechanisms responsible for liver cysts growth and disease progression in ADPKD. This hypothesis will be tested trough three specific aims: 1) to examine the relationships between genetic defects and up-regulation of angiogenic signaling in the biliary epithelium of ADPKD patients; 2) to study the intracellular pathways involved in autocrine VEGF- and angiopoieting-1 mediated stimulation of cholangiocyte growth and survival; 3) To study if blockade of angiogenic signaling reduces liver cysts growth in vivo in ADPKD mouse models. These questions will be addressed in vitro and in vivo using mice with conditional inactivation of polycystin-1 or polycystin 2. These studies will a) increase our understanding of VEGF regulation and signaling in secretory epithelia, b) better clarify the role of VEGF/angiopoietin signaling in liver diseases c) provide important information on mechanisms leading to the progressive growth of cysts in ADPKD d) provide an important proof of concept for the role anti-angiogenic therapy to control the growth of liver and kidney cysts in ADPKD. Public Health Relevance: Polycystic liver diseases are a group of inherited conditions characterized by an abnormal development of the cells that line the bile ducts. This leads to the formation of multiple biliary microhamartomas that progressively dilate to macroscopic cysts, scattered throughout the liver. Although liver function is usually preserved in these disorders, severe cyst complications (mass effect, hemorrhage, infection or rupture) may develop and require urgent liver transplantation, since no forms of medical treatment are currently available to prevent biliary cyst enlargement. Stimulation of the growth of bile duct cells by angiogenic growth factors aberrantly overexpressed in these disorders may be responsible for the cyst enlargement that leads to the severe complications of the liver disease. In this application we aim to use animals with genetic defects that reproduce this disease in order to understand its cause and to develop new ways to treat its complications. Specifically, we will test antiangiogenic strategies. It is expected that therapeutic strategies devised for the liver may also be effective in the kidney, functional impairment of which contributes to morbidity in these patients. Moreover, the ability to block progression of the disease would not only benefit these patients but could spare organs for transplantation of others.