Vitamin D Receptor Regulation of Liver Organogenesis and Disease

维生素 D 受体对肝脏器官发生和疾病的调节

• 批准号: 10056844
• 负责人: Scott Hull Freeburg
• 金额: $ 3.32万
• 依托单位: HARVARD MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-01 至 2022-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10056844
• 关键词: Accounting; Adult; Affect; Animal Model; Apoptosis; Cell Differentiation process; Cell Lineage; Cell Proliferation; Cessation of life; Chemicals; Cholesterol; Chronic; Cirrhosis; Data; Development; Diet; Disease; Disease model; Embryo; Epidemic; Epidemiology; FRAP1 gene; Fatty acid glycerol esters; Fibrosis; Fishes; Gene Expression Profiling; Genetic Models; Genetic Transcription; Growth; Hepatic; Hepatitis; Hepatocyte; Histologic; Homeostasis; Human; Impairment; In Situ Hybridization; Inflammation; Investigation; Laboratories; Lead; Lipids; Liver; Liver Fibrosis; Liver diseases; Malignant neoplasm of liver; Metabolic; Metabolic stress; Metabolism; Microscopy; Molecular; Morbidity - disease rate; Organogenesis; Outcome; Pathogenesis; Pathology; Phenotype; Prevention; Primary Malignant Neoplasm of Liver; Primary carcinoma of the liver cells; Public Health; Receptor Signaling; Regulation; Resolution; Role; Signal Pathway; Signal Transduction; Source; Tissues; Vitamin D; Vitamin D3 Receptor; Work; Zebrafish; base; chemical genetics; chronic liver disease; experimental study; high resolution imaging; human model; immunoregulation; improved; insight; lipid metabolism; liver cell proliferation; liver development; liver function; liver metabolism; loss of function; mortality; mutant; non-alcoholic fatty liver disease; novel; prevent; progenitor; receptor function; screening; tool; transcriptome sequencing; transcriptomics; zebrafish development

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.

项目摘要/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200万人死亡。非酒精性脂肪肝病（NAFLD）是相关的公共卫生 威胁是因为它会导致代谢功能受损，肝硬化和原发性肝癌，并且会影响 到25％的美国成年人。我们的实验室利用肝发育和成人的化学和遗传调节 斑马鱼中的肝功能确定调节肝脏生长，体内平衡和疾病的信号通路。 我们发现，胚胎肝发育过程中的维生素D受体（VDR）活性对于 正常的肝脏生长，VDR刺激调节早期脂质代谢效应子的转录 肝脏形成。 VDR功能受损与NAFLD，肝纤维化，肝硬化和肝癌有关 人类和动物模型，但是VDR信号在肝发育和疾病中的功能尚不清楚。 我们的目标是表征斑马鱼肝中VDR活性的细胞和分子功能 开发并评估VDR在成人肝稳态和代谢压力中的功能。在AIM 1中，我们 将利用VDR活性的化学和遗传调制来定义VDR信号对肝脏的影响 祖细胞扩张和肝脏产物。我们将研究突变线以表征 VDR缺乏症和维生素D代谢对肝脏生长的代谢。基于初步RNA-seq数据，我们将 研究PI3K/MTOR信号传导和其他候选信号通路的功能 诱导肝脏生长。这些实验将发现肝脏形成过程中VDR信号的影响。在 AIM 2，我们将使用组织学和 转录组分析，重点是肝脂肪积累和脂质代谢。此外，我们将 确定受高脂高 - 高脂高 - 胆固醇饮食挑战。由于VDR障碍与NAFLD相关，因此我们预计VDR障碍 在高脂高脂高胆固醇饮食挑战之后，将使成年鱼对NAFLD发病机理敏感。这项工作 将提供有关VDR信号在肝发育和疾病中的功能的详细洞察力 并将阐明维生素D/VDR调制的潜力作为预防和/或治疗慢性肝脏的策略 疾病。