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

基本信息

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
项目类别：
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

项目摘要

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.

项目概要/摘要慢性肝病和肝癌是发病率和死亡率的重要来源，占估计每年有 200 万人死亡。非酒精性脂肪肝（NAFLD）是一个相关的公共卫生问题威胁，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 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、体内平衡和疾病的信号通路。我们发现胚胎肝脏发育过程中维生素 D 受体 (Vdr) 的活性对于正常肝脏生长，并且 Vdr 刺激在早期调节脂质代谢效应子的转录肝脏的形成。 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 VDR 信号在肝脏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脏中 Vdr 活性的细胞和分子功能发育并评估 Vdr 在成人肝脏稳态和代谢应激中的功能。在目标 1 中，我们将利用 Vdr 活性的化学和遗传调节来确定 Vdr 信号传导对肝脏的影响祖细胞扩张和肝脏生长。我们将研究突变株系来表征结果 vdr 缺乏和维生素 D 代谢受损对肝脏生长的影响。根据初步的RNA-seq数据，我们将研究维生素 D 中 PI3K/mTOR 信号传导和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。在目标 2，我们将利用组织学和方法来表征成人肝脏稳态过程中 Vdr 活性的功能。转录组分析，重点关注肝脏脂肪积累和脂质代谢。此外，我们将确定斑马鱼肝细胞特异性 Vdr 损伤的影响胆固醇饮食挑战。由于 Vdr 损伤与 NAFLD 相关，我们预计 Vdr 损伤在高脂肪高胆固醇饮食挑战后，会使成年鱼对 NAFLD 发病机制敏感。这部作品将为 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/或治疗慢性肝病策略的潜力疾病。