Vitamin D Receptor Regulation of Liver Organogenesis and Disease

项目总结/摘要 慢性肝病和肝癌是发病率和死亡率的重要来源， 估计每年有两百万人死亡。非酒精性脂肪性肝病（NAFLD）是一种相关的公共卫生 威胁，因为它可以导致代谢功能受损，肝硬化和原发性肝癌，它影响了 25%的美国成年人。我们的实验室利用化学和遗传调节肝脏发育和成人 斑马鱼的肝功能，以确定调节肝脏生长，稳态和疾病的信号通路。 我们发现，胚胎肝脏发育过程中的维生素D受体（Vdr）活性对于 正常的肝脏生长，并且Vdr刺激调节早期脂质代谢效应物的转录， 肝形成VDR功能受损与NAFLD、肝纤维化、肝硬化和肝癌相关， 人类和动物模型，但VDR信号传导在肝脏发育和疾病中的功能尚不清楚。 我们的目的是表征斑马鱼肝脏中Vdr活性的细胞和分子功能 探讨VDR在成人肝脏稳态和代谢应激中的作用。目标1： 将利用Vdr活性的化学和遗传调节来确定Vdr信号对肝脏的影响 祖细胞扩增和肝脏生长。我们将研究突变株系，以表征 vdr缺乏和维生素D代谢受损对肝脏生长的影响。基于初步的RNA-seq数据，我们将 研究PI 3 K/mTOR信号传导和维生素D中其他候选信号传导途径的功能 诱导肝脏生长。这些实验将揭示Vdr信号在肝脏形成过程中的影响。在 目的2，我们将利用组织学和免疫组化方法， 转录组分析，重点是肝脏脂肪积累和脂质代谢。此外，我们将 确定肝细胞特异性Vdr损伤在斑马鱼中的影响， 胆固醇饮食挑战。由于Vdr损伤与NAFLD相关，我们预计Vdr损伤 将使成鱼在高脂肪高胆固醇饮食挑战后对NAFLD发病机理敏感。这项工作 将为VDR信号在肝脏发育和疾病中的功能提供详细的机制见解 并将阐明维生素D/VDR调节作为预防和/或治疗慢性肝病的策略的潜力 疾病

PROJECT SUMMARY/ABSTRACT Chronic liver disease and liver cancer are significant sources of morbidity and mortality, accounting for an estimated 2 million deaths annually. Non-alcoholic fatty liver disease (NAFLD) is a pertinent public health threat because it can lead to impaired metabolic function, cirrhosis, and primary liver cancer, and it affects up to 25% of U.S. adults. Our laboratory utilizes chemical and genetic modulation of liver development and adult liver function in zebrafish to identify signaling pathways that regulate liver growth, homeostasis, and disease. We have found that Vitamin D Receptor (Vdr) activity during embryonic liver development is essential for normal liver growth, and that Vdr stimulation modulates transcription of lipid metabolic effectors during early liver formation. Impaired VDR function is associated with a NAFLD, liver fibrosis, cirrhosis, and liver cancer in humans and animal models, but the functions of VDR signaling in liver development and disease are unknown. Our objective is to characterize the cellular and molecular functions of Vdr activity in zebrafish liver development and to evaluate the functions of Vdr in adult liver homeostasis and metabolic stress. In Aim 1, we will utilize chemical and genetic modulation of Vdr activity to define the impact of Vdr signaling on liver progenitor expansion and liver outgrowth. We will investigate mutant lines to characterize the consequence of vdr deficiency and impaired vitamin D metabolism on liver growth. Based on preliminary RNA-seq data, we will investigate the functions of PI3K/mTOR signaling and other candidate signaling pathways in vitamin D induction of liver growth. These experiments will uncover the impacts of Vdr signaling during liver formation. In Aim 2, we will characterize the functions of Vdr activity during adult liver homeostasis using histological and transcriptomic analysis, with a focus on hepatic fat accumulation and lipid metabolism. In addition, we will determine the impact of hepatocyte-specific Vdr impairment in zebrafish subjected to a high-fat high- cholesterol diet challenge. Since Vdr impairment is associated with NAFLD, we anticipate that Vdr impairment will sensitize adult fish to NAFLD pathogenesis following a high-fat high-cholesterol diet challenge. This work will provide detailed mechanistic insight into the functions of VDR signaling in liver development and disease and will illuminate the potential of vitamin D/VDR modulation as a strategy to prevent and/or treat chronic liver disease.