Epithelial Angiogenic Signaling in Polycystic Diseases of the Liver

肝脏多囊性疾病中的上皮血管生成信号

• 批准号: 8053839
• 负责人: Mario Strazzabosco
• 金额: $ 32.44万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-04-01 至 2013-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8053839
• 关键词: Accounting; Address; Adult; Affect; Angiogenesis Inhibitors; Angiopoietin-1; Angiopoietins; Animals; Autosomal Dominant Polycystic Kidney; Autosomal Recessive Polycystic Kidney; Biliary; Cell Differentiation process; Cell Line; Cells; Child; Childhood; Chronic; Cilia; Cyst; Cystic kidney; Defect; Development; Disease; Disease Progression; Disease model; Epithelial; Epithelial Cells; Epithelium; Etiology; Functional disorder; Genetic; Goals; Growth; Growth Factor; Hemorrhage; Hepatic Cyst; Hepatocyte; In Vitro; Infection; Inflammatory; Inherited; Kidney; Kidney Failure; Liver; Liver Fibrosis; Liver Regeneration; Liver diseases; Mediating; Medical; Mesenchymal; Morbidity - disease rate; Morphogenesis; Mus; Mutate; Mutation; Natural regeneration; Organ Transplantation; PKD2 protein; Pathogenesis; Pathway interactions; Patients; Physiological; Play; Population; Property; Proteins; Reaction; Regulation; Role; Role Concepts; Rupture; Signal Pathway; Signal Transduction; Syndrome; Testing; Therapeutic; Up-Regulation; Variant; Vascular Endothelial Growth Factor Receptor-2; Vascular Endothelial Growth Factors; autocrine; base; bile duct; biliary tract; cholangiocyte; cytokine; density; functional disability; improved; in vivo; interest; intrahepatic; liver function; liver transplantation; mouse model; overexpression; paracrine; polycystic kidney disease 1 protein; polycystic liver disease; prevent; protein function; public health relevance; receptor; repaired; response; young adult

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.

描述（由申请人提供）：我们研究的更广泛的目标是了解上皮对损害的反应，尤其是胆道上皮在修复和再生肝脏中的作用。肝内胆道树（“胆管病”）的疾病是严重的慢性衰弱肝病，影响了儿科和年轻人。多囊肝疾病是一组遗传胆管病，其特征是胆道上皮的进行性囊性扩张，可能导致需要肝移植的并发症。这些疾病具有科学的兴趣，因为它们与原发性纤毛上蛋白质的功能发生了变化。成年多囊性肾脏疾病（ADPKD）是由多囊1或-2中的遗传传播缺陷引起的。这些蛋白质是机械构的，并且参与了调节细胞分化和上皮形态发生的信号通路。显示上皮血管生成信号传导，尤其是VEGF和血管生成素-1，显示在ADPKD的胆道上皮细胞（胆管细胞）中被上调，并可能在肝病的发病机理中起作用。该提案中解决的假设是，源自胆道上皮的自分泌和旁分泌血管生成信号是负责ADPKD肝囊肿生长和疾病进展的机制之一。该假设将进行测试，将三个特定的目的测试：1）检查ADPKD患者胆道上皮中血管生成信号传导上调之间的关系； 2）研究参与自分泌VEGF和血管生成1的细胞内途径介导的胆管细胞生长和生存的刺激； 3）研究血管生成信号的阻滞是否会减少ADPKD小鼠模型中体内肝囊肿的生长。这些问题将在polycystin-1或多囊蛋白的条件失活的情况下在体外和体内解决。这些研究将a）提高我们对分泌性上皮的VEGF调节和信号传导的理解，b）更好地阐明VEGF/Angiopoietin signing在liver中的作用，以提供重要的疾病c的重要信息。抗血管生成疗法控制ADPKD中肝脏和肾脏囊肿的生长的概念。 公共卫生相关性：多囊性肝脏疾病是一组遗传疾病，其特征是胆管管的细胞异常发育。这导致形成多个胆道微汉术，逐渐扩张至散布在整个肝脏中的宏观囊肿。尽管肝功能通常在这些疾病中保存下来，但可能会发展出严重的囊肿并发症（质量作用，出血，感染或破裂），并且需要紧急肝移植，因为目前尚无治疗形式的治疗形式来防止胆道囊肿扩大。通过异常过表达这些疾病的血管生长因子刺激胆管细胞的生长可能是导致肝脏疾病严重并发症的囊肿增大。在此应用中，我们的目的是使用具有遗传缺陷的动物，这些动物可再现这种疾病，以了解其原因并开发新的方法来治疗其并发症。具体而言，我们将测试抗血管生成策略。预计为肝脏设计的治疗策​​略也可能在肾脏中有效，功能障碍会导致这些患者的发病率。此外，阻止疾病进展的能力不仅会使这些患者受益，而且可以避免器官移植他人。