BLR&D Research Career Scientist Award

BLR

• 批准号: 9912633
• 负责人: Gianfranco D Alpini
• 金额: --
• 依托单位: RLR VA MEDICAL CENTER
• 依托单位国家: 美国
• 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/9912633
• 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; 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; Substance P; Therapeutic Agents; Therapeutic Intervention; Training; Treatment Efficacy; United States National Institutes of Health; Veterans; Viral; afferent nerve; autocrine; base; bile duct; biliary tract; career; cell injury; 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; stem cells; symposium; therapeutic development; therapy development; tissue injury

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（如原发性胆管炎）中的靶细胞 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。 这些胆汁淤积性肝病（特征在于胆管上皮细胞的协调增殖/损伤） 沿着其他胆管病，由于缺乏有效的治疗方法， 治疗干预导致终末期肝病期间需要肝移植。 胆管疾病（包括药物或病毒引起的肝损伤）的管理是主要的 退伍军人健康的挑战。靶向对胆汁淤积产生反应的神经内分泌因子 可以帮助限制在肝胆损伤期间发生的炎症和纤维化。那里 是了解胆管细胞生长的神经内分泌触发因素及其反应的关键 这将有助于确定代表可行靶点的关键信号通路 用于开发有效的治疗剂。我们的长期研究目标是开发一种 了解调节胆汁生长的神经内分泌因子和信号机制， 胆汁淤积、脂肪肝和酒精引起的肝病，这将为这一发现提供基础 预防和新的药物干预的胆管疾病和肝脏疾病的特点 肝纤维化对于我目前资助的VA优异奖，中心假设是基于 我假设分泌素/分泌素受体（Sct/SR）轴信号转导是介导增殖性细胞凋亡的关键， 和激活的促纤维化胆汁表型，其有助于肝脂肪变性的进展， 非酒精性脂肪性肝病（NAFLD）/非酒精性脂肪性肝炎发病过程中的纤维化 （NASH）。此外，我的研究计划是由多个合作NIH R 01赠款，探索 通过神经内分泌因子调节胆汁生长和肝纤维化的各个方面， 胆汁淤积、NAFLD和酒精诱导的肝脏模型中的促胰液素、褪黑激素、5-羟色胺和miRNAs 疾病我与多个VA调查人员的合作努力一直很有成效， 在许多高影响力的期刊上发表。神经内分泌特点的探讨 胆管细胞将为这些疾病的治疗干预提供新的途径。 疾病我们的贡献是重要的，因为这是一个关键的一步，提供翻译知识， 胆管疾病治疗方法的发展这些发现还将对以下方面产生更广泛的影响： 以肝纤维化为特征的其他肝病。