The Paracrine Regulation of Mast Cells During Biliary/Cholangiocyte Repair and Damage

胆管/胆管细胞修复和损伤过程中肥大细胞的旁分泌调节

基本信息

批准号：
9980878
负责人：
Heather L Francis
金额：
$ 25.3万
依托单位：
INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-04-01 至 2022-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9980878
关键词：
Address Agonist Animal Model Apoptotic Area Biliary Cell Count Cell Line Cells Cholestasis Cromolyn Sodium Data Development Disease Duct (organ) structure Enzymes Epithelial Epithelium Goals Growth H2 gene HRH2 gene Hepatic Hepatocyte Histamine Histamine Receptor Histamine Release Histidine Decarboxylase Homeostasis Hyperplasia In Vitro Infiltration Inflammation Injury Intrahepatic bile duct Knockout Mice Liver Liver Fibrosis Mediator of activation protein MicroRNAs Modeling Mus Paracrine Communication Pathway interactions Patients Plasma Play Primary biliary cirrhosis Proliferating Proto-Oncogene Protein c-kit Rattus Regulation Role Serum Signal Pathway Source Transfection Vascular Endothelial Growth Factors Work autocrine bile duct cell motility cell type cholangiocyte cholestatic liver disease clinically relevant in vivo innovation insight liver injury liver repair mast cell neoplastic novel overexpression paracrine primary sclerosing cholangitis public health relevance receptor expression recruit repaired response treatment strategy vector

项目摘要

DESCRIPTION (provided by applicant): Cholangiopathies (Primary Biliary Cirrhosis (PBC) and Primary Sclerosing Cholangitis (PSC)) are characterized by the proliferation/loss of cholangiocytes, which are the cells that line the biliary epithelium. During cholestasis, biliary hyperplasia/damage is regulated by both autocrine/paracrine mechanisms. For example, during hyperplastic cholangiocyte proliferation bile duct mass increases and proliferating cholangiocytes release numerous factors like histamine presumably to sustain the increased bile duct mass. In ductopenic states, bile duct mass decreases and cholangiocytes are damaged and unable to maintain biliary homeostasis. We have shown that: (i) cholangiocytes express histamine receptors (HRs) and histidine decarboxylase (HDC), the key enzyme regulating histamine synthesis; (ii) cholangiocytes release histamine; and (iii) inhibition of biliry HDC decreases both hyperplastic and neoplastic cholangiocyte growth and vascular endothelial growth factor (VEGF) by autocrine pathways. Besides the autocrine regulation of cholangiocyte proliferation/loss, paracrine regulation of biliary function by neighboring hepatic cells must be considered. It has been demonstrated in patients with PBC and PSC that histamine plasma levels are higher and that there are increased numbers of hepatic mast cells in the proximity of bile ducts. When activated, hepatic mast cells release numerous factors like histamine into the microenvironment, which we propose influence cholangiocyte proliferative/apoptotic responses in cholangiopathies. In our proposal, we present preliminary data supporting the hypothesis that mast cells infiltrate the liver following damage via c-kit/SCF interaction and that mast cells alte the proliferative response of small and large cholangiocytes in models of liver damage or repair by interaction with H1 and H2 HRs and specific microRNAs. Our proposed studies are innovative and will likely provide important, clinically relevant data to add to the understanding f the regulation of biliary disorders and also offer insight into novel treatment strategies.

描述（由申请人提供）：胆管病（原发性胆汁性肝硬化（PBC）和原发性硬化性胆管炎（PSC））的特征是胆管细胞的增殖/损失，胆管细胞是胆管上皮细胞。在胆汁淤积期间，胆道增生/损伤受到自分泌/旁分泌机制的调节。例如，在增生性胆管细胞增殖期间，胆管质量增加，并且增殖的胆管细胞释放许多因子，如组胺，大概是为了维持增加的胆管质量。在胆管减少状态下，胆管质量减少，胆管细胞受损，无法维持胆道稳态。我们已经证明：（i）胆管细胞表达组胺受体（HR）和组氨酸脱羧酶（HDC），这是调节组胺合成的关键酶； (ii) 胆管细胞释放组胺； (iii)抑制胆汁HDC通过自分泌途径减少增生性和肿瘤性胆管细胞生长以及血管内皮生长因子(VEGF)。除了胆管细胞增殖/损失的自分泌调节外，还必须考虑邻近肝细胞对胆道功能的旁分泌调节。已证明 PBC 和 PSC 患者的血浆组胺水平较高，并且胆管附近的肝肥大细胞数量增加。当激活时，肝肥大细胞会向微环境中释放组胺等多种因子，我们认为这些因子会影响胆管病中胆管细胞的增殖/凋亡反应。在我们的提案中，我们提供了初步数据支持以下假设：肥大细胞在 c-kit/SCF 相互作用损伤后浸润肝脏，并且肥大细胞通过与 H1 相互作用改变肝脏损伤或修复模型中小型和大型胆管细胞的增殖反应H2 HR 和特定的 microRNA。我们提出的研究具有创新性，可能会提供重要的临床相关数据，以增进对胆道疾病调节的理解，并为新的治疗策略提供见解。