BLR&D Research Career Scientist Award

BLR

基本信息

批准号：
9763814
负责人：
Gianfranco D Alpini
金额：
--
依托单位：
RLR VA MEDICAL CENTER
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 2026-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/9763814
关键词：
Alcoholic Liver Diseases Angiogenic Factor Area Award Basic Science Bile Duct Epithelium Biliary Calcitonin Gene-Related Peptide Cell Aging Cells Cholangiocarcinoma Cholestasis Chronic Clinical Clinical Sciences Collaborations Cyclic AMP Data Development Diagnosis Disease Disease Progression Ductal Epithelial Cell Educational process of instructing Epithelial Cells Faculty Fatty Alcohols Fatty Liver Fibrosis Foundations Funding Gastroenterology Gastrointestinal Diseases Genes Goals Grant Grant Review Growth Health Hepatic Stellate Cell Hepatobiliary Hepatology Heterogeneity Homeostasis Human In Vitro Inflammation Injury Intervention Investigation Journals Knowledge Liver Cirrhosis Liver Failure Liver Fibrosis Liver diseases Mediating Medical Medical Students Medical center Melatonin Mentors MicroRNAs Modeling Molecular Nature Neoplastic Cell Transformation Neuropeptides Neurosecretory Systems Neurotransmitters Pathogenesis Pathway interactions Patients Pharmaceutical Preparations Pharmacologic Substance Phenotype Play Population Postdoctoral Fellow Prevention Primary biliary cirrhosis Program Development Proliferating Publications Publishing Reaction Regulation Research Research Personnel Rodent Rodent Model Role Sampling Scientist Secretin Seminal Sensory Serotonin Serum Services Signal Pathway Signal Transduction Stem cells Substance P Therapeutic Agents Therapeutic Intervention Tissues Training Treatment Efficacy United States National Institutes of Health Veterans Viral afferent nerve autocrine base bile duct biliary tract career cholangiocyte cholestatic liver disease chronic liver disease clinically relevant editorial graduate student in vivo liver injury liver transplantation meetings member neuroendocrine phenotype non-alcoholic fatty liver disease nonalcoholic steatohepatitis novel paracrine peptide P primary sclerosing cholangitis problem drinker prognostic tool programs receptor repaired response secretin receptor senescence symposium therapeutic development therapy development

项目摘要

Bile duct epithelial cells (i.e., cholangiocytes) are the target cells in cholangiopathies such as primary biliary cholangitis (PBC), primary sclerosing cholangitis (PSC), and cholangiocarcinoma (CCA), which are diseases characterized by the damage, proliferation and neoplastic transformation of cholangiocytes. These cholestatic liver diseases (characterized by coordinated proliferation/damage of biliary epithelial cells) along with other cholangiopathies represent a major clinical challenge due to the lack of effective therapeutic interventions resulting in the need for liver transplantation during end-stage liver disease. Management of cholangiopathies (including drug- or viral-induced liver injury) represents one of the major challenges for Veterans Health. Targeting the neuroendocrine factors that respond to cholestasis resulting from tissue injury may help limit inflammation and fibrosis that occur during hepatobiliary damage. There is a critical need to understand the neuroendocrine triggers of cholangiocyte growth and their responses to damage during cholestasis, which will help identify key signaling pathways that represent viable targets for the development of effective therapeutic agents. Our long-term research goal is to develop an understanding of the neuroendocrine factors and signaling mechanisms regulating biliary growth during cholestasis, fatty liver and alcohol-induced liver disease, which will provide a foundation for the discovery of prevention and new pharmaceutical interventions for cholangiopathies and liver diseases characterized by hepatic fibrosis. For my current funded VA Merit Award, the central hypothesis is based upon the postulate that the secretin/secretin receptor (Sct/SR) axis signaling is key for mediating the proliferative and activated profibrogenic biliary phenotype that contributes to the progression of hepatic steatosis and fibrosis during the pathogenesis of nonalcoholic fatty liver disease (NAFLD)/nonalcoholic steatohepatitis (NASH). In addition, my research program is funded by multiple collaborative NIH R01 grants that explore various aspects of the regulation of biliary growth and hepatic fibrosis by neuroendocrine factors such as secretin, melatonin, serotonin and miRNAs in models of cholestasis, NAFLD, and alcohol-induce liver disease. My collaborative effort with multiple VA investigators has been high productive and has resulted in many publications in high impact journals. The exploration of the neuroendocrine features of cholangiocytes will provide new avenues for the development of therapeutic interventions for these diseases. Our contribution is significant since this is a critical step to provide translational knowledge for the development of therapies for cholangiopathies. These findings will also have broader implications for other hepatic diseases characterized by hepatic fibrosis.

胆管上皮细胞（即胆管细胞）是胆管病中的靶细胞，例如原发性胆道胆管炎（PBC），原发性硬化性胆管炎（PSC）和胆管癌（CCA），它们是以胆管细胞的损伤，增殖和肿瘤转化为特征的疾病。这些胆固性肝病（以胆道上皮的协调增殖/损害为特征细胞）以及其他胆管疾病代表了由于缺乏有效的临床挑战治疗性干预措施导致在末期肝病期间需要进行肝移植。胆管疾病的治疗（包括药物或病毒诱导的肝损伤）代表了主要之一对退伍军人健康的挑战。针对对胆汁淤积反应的神经内分泌因素从组织损伤中可能有助于限制肝胆管损伤期间发生的炎症和纤维化。那里是了解胆管细胞生长及其反应的神经内分泌触发的迫切需要在胆汁淤积期间损坏，这将有助于识别代表可行目标的关键信号通路用于开发有效的治疗剂。我们的长期研究目标是开发了解调节胆道生长的神经内分泌因素和信号传导机制胆汁淤积，脂肪肝和酒精引起的肝病，这将为发现提供基础预防和新的胆管病病和肝脏疾病的药物干预措施通过肝纤维化。对于我目前的资助VA优异奖，中心假设是基于假设Systin/secralin受体（SCT/SR）轴信号是介导增殖的关键并激活的纤维化胆道表型有助于肝脂肪变性和非酒精性脂肪肝病（NAFLD）/非酒精性脂肪性肝炎的发病机理期间的纤维化（纳什）。此外，我的研究计划由多个协作NIH R01赠款资助，探索通过神经内分泌因子（例如胆汁淤积，NAFLD和酒精 - 诱导肝的模型中的Sectin，褪黑激素，5-羟色胺和miRNA 疾病。我与多个VA调查人员的合作努力的生产力很高，并导致了在高影响期刊的许多出版物中。探索神经内分泌特征胆管细胞将为这些治疗干预措施提供新的途径疾病。我们的贡献很重要，因为这是提供翻译知识的关键步骤开发胆管疾病的疗法。这些发现也将对其他以肝纤维化为特征的肝疾病。