Epithelial Angiogenic Signaling in Biliary Pathophysiology and in Polycystic Dise

胆道病理生理学和多囊疾病中的上皮血管生成信号传导

• 批准号: 8882404
• 负责人: Mario Strazzabosco
• 金额: $ 36.21万
• 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 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8882404
• 关键词: Address; Adult; Autosomal Dominant Polycystic Kidney; Biliary; Blood Vessels; Cell Differentiation process; Cells; Cyclic AMP; Cyclic AMP-Dependent Protein Kinases; Cyst; Defect; Disease; Disease model; Epithelial; Epithelial Cells; Epithelium; Functional disorder; Funding; Genetic; Goals; Growth; Growth Factor; Health; Homeostasis; Inflammation; Inflammatory; Inherited; Link; Liver; Liver Regeneration; Liver diseases; MAPK3 gene; Mediating; Mesenchymal; Modeling; Morbidity - disease rate; Morphogenesis; Mutate; Mutation; PKD2 protein; Pathogenesis; Pathway interactions; Patients; Physiological; Play; Production; Proliferating; Proprotein Convertase 1; Proteins; Ras/Raf; Regulation; Role; Signal Pathway; Signal Transduction; Stimulus; Testing; Vascular Endothelial Growth Factor Receptor-2; Vascular Endothelial Growth Factors; Work; autocrine; base; cholangiocyte; cytokine; human FRAP1 protein; liver function; liver injury; liver repair; mortality; mouse model; notch protein; novel; paracrine; polycystic liver disease; receptor; repaired; response; stressor

DESCRIPTION (provided by applicant): The long-term goal of our studies is to understand the role of biliary epithelium in the repair and regeneration of the liver after damage. Inherited cholangiopathies with identified genetic defects serve as model diseases to elucidate the fundamental pathophysiological mechanisms. The previously funded proposal focused on polycystic liver disease associated to Adult Dominant Polycystic Kidney Disease (PLD-ADPKD) as a paradigm for the role of angiogenic signaling in biliary diseases. We uncovered mechanisms that may be relevant for the pathogenesis of other congenital and acquired liver diseases. In fact, using mice models with inducible defects of polycystins, we found that: 1) the cystic epithelium produces VEGF and expresses its cognate receptor VEGFR2; 2) VEGF-mediated stimulation of VEGFR2 results in increased ERK1/2-dependent proliferation of the cystic epithelium, 3) PC2-defective cystic cholangiocytes, altered cellular Ca2+ homeostasis and a cAMP- dependent increase in PKA/Ras/Raf/ERK signaling results in mTOR/HIF-1�-mediated stimulation of VEGF production, 4) in response to stimuli able to deplete ER Ca2+ stores, PC2 participates in store-operated Ca2+ entry (SOCE); 5) if PC2 is defective, an alternative pathway is activated (store-operated cAMP production - SOcAMP), leading to an inappropriate overproduction of cAMP; 6) VEGF/VEGFR2 play a key role on cyst growth and expansion through paracrine effects on pericystic vascular cells, and autocrine stimulation of the cystic epithelium proliferation. These findings are the basis of this new proposal which main hypothesis is that the mechanism linking PC2 to VEGF secretion and VEGFR2 expression identified in PLD-ADPKD is of general relevance in biliary pathophysiology. We will address this hypothesis through three specific aims: 1) to better understand the interactions between PC2 function store-operated Ca2+ entry and inappropriate production of cAMP, 2) to study if PC2 expression in WT cholangiocytes can be modulated by cell stressors, thereby reproducing the changes seen in PC2-defective cells; 3) to study the mechanisms leading to VEGFR2 expression in cystic and reactive cholangiocytes, and to elucidate the role of VEGF in the branching morphogenesis of the biliary epithelium during liver repair. These studies will address the novel idea that PC2 play a pivotal role in the regulation of cholangiocyte response to biliary damage acquired cholangiopathies, and that VEGF secreted by reactive cholangiocytes is a major factor in liver repair. Furthermore, our studies will increase understanding of VEGF/VEGFR2 signaling in epithelia and will address a fundamental mechanism in congenital and acquired cholangiopathies. Understanding the pathophysiology of cholangiopathies is a fundamental step for preserving liver function and prolonging the survival of patients

描述（由适用提供）：我们的研究的长期目标是了解胆汁上皮在损害后肝脏修复和再生中的作用。遗传性的胆管病变具有鉴定的遗传缺陷作为模型疾病，以阐明基本的病理生理机制。先前资助的提案着重于与成年占主导地位多囊性肾脏疾病（PLD-ADPKD）相关的多囊性肝病，作为血管生成信号在胆道疾病中的作用的范式。我们发现了可能与其他先天性疾病的发病机理有关的机制。实际上，使用具有诱导型多囊蛋白缺陷的小鼠模型，我们发现：1）囊性上皮产生VEGF并表达其同源受体VEGFR2； 2）VEGF介导的VEGFR2的模拟导致ERK1/2依赖性囊性上皮增殖增加，3）PC2缺陷性囊性胆管细胞，细胞Ca2+稳态的改变，cAMP依赖性的cAMP依赖性在PKA/RAS/RAS/RAS/RAS/RAF/RAF/RARK信号中的产生4）ver ty in ver in ver in n inf inf inf inf inf inf inf inf inf inf inf inf inf inf inf inf ras/raf/raf/raf。能够复制ER Ca2+商店的刺激，在商店经营的Ca2+进入（SOCE）中的PC2参与者； 5）如果PC2有缺陷，则可以激活替代途径（商店经营的营地生产 - SOCAMP），从而导致营地不当生产； 6）VEGF/VEGFR2通过对周气血管细胞的影响以及对囊性上皮增殖的自分泌刺激在囊肿生长和扩张中起关键作用。这些发现是这一新建议的基础，主要假设是将PC2与VEGF分泌的机制和PLD-ADPKD中鉴定的VEGFR2表达联系起来在胆道病理生理学中具有一般相关性。我们将通过三个特定目的解决这一假设：1）更好地了解PC2功能储存的Ca2+进入和不适当的CAMP的相互作用，2） 3）研究导致囊性和反应性胆管细胞中VEGFR2表达的机制，并阐明VEGF在肝修复过程中VEGF在胆汁上皮的分支形态发生中的作用。这些研究将解决以下新想法，即PC2在调节胆管细胞对胆道损伤的反应中起关键作用，而被反应性胆管细胞分泌的VEGF是肝修复的主要因素。此外，我们的研究将增加对上皮中VEGF/VEGFR2信号传导的了解，并将解决先天性和获得性胆管疾病的基本机制。了解胆管疾病的病理生理学是保持肝功能并延长患者存活的基本步骤