BLR&D Research Career Scientist Award

BLR

• 批准号: 10618284
• 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/10618284
• 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; 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; Productivity; 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; United States National Institutes of Health; Veterans; Viral; afferent nerve; autocrine; bile duct; biliary tract; career; cholangiocyte; chronic liver disease; clinically relevant; editorial; end stage liver disease; graduate student; in vivo; knowledge translation; 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; therapeutically effective; 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)是胆道疾病如原发性胆管疾病的靶细胞。 胆管炎(PBC)、原发性硬化性胆管炎(PSC)和胆管癌(CCA)，它们是 以胆管细胞损伤、增殖和肿瘤性转化为特征的疾病。 这些胆汁淤积性肝病(以胆管上皮协调增殖/损伤为特征 细胞)以及其他胆管疾病是一个主要的临床挑战，因为缺乏有效的 治疗干预导致在终末期肝病期间需要肝移植。 胆管病(包括药物或病毒引起的肝损伤)的处理是主要的 退伍军人健康面临的挑战。靶向对胆汁淤积有反应的神经内分泌因子 防止组织损伤可能有助于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刺激因素及其反应的迫切需要 在胆汁淤积过程中受到损害，这将有助于识别代表可存活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 胆汁发育过程中神经内分泌因子及其信号机制的研究进展 胆汁淤积、脂肪肝和酒精性肝病，这将为这一发现提供基础 胆管病和肝病的预防和新的药物干预的特点 由肝纤维化引起。对于我目前资助的VA Merit奖，核心假设是基于 假设分泌素/分泌素受体(SCT/SR)轴信号转导是调节细胞增殖的关键。 和激活的促纤维化胆汁表型，促进肝脏脂肪变性的进展和 非酒精性脂肪性肝病/非酒精性脂肪性肝炎发病过程中的纤维化 (纳什)。此外，我的研究项目是由多个合作的NIH R01拨款资助的，这些拨款探索 神经内分泌因子对胆汁生长和肝纤维化的多方面调节 胆汁淤积、非酒精性脂肪肝和酒精性肝损伤模型中促胰液素、褪黑素、5-羟色胺和miRNAs的表达 疾病。我与多名退伍军人管理局调查人员的合作努力卓有成效，并导致 在高影响力期刊的许多出版物中。神经内分泌功能的探讨 胆管细胞将为发展对这些疾病的治疗干预提供新的途径。 疾病。我们的贡献意义重大，因为这是提供翻译知识的关键一步 胆管病治疗方法的发展。这些发现还将对以下方面产生更广泛的影响 其他以肝纤维化为特征的肝病。