The Role of Vitamin D Receptor in Liver Fibrosis

维生素 D 受体在肝纤维化中的作用

• 批准号: 8911018
• 负责人: Ning Ding
• 金额: $ 9.45万
• 依托单位: SALK INSTITUTE FOR BIOLOGICAL STUDIES
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-05-01 至 2015-06-15
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8911018
• 关键词: Affect; Animal Model; Animals; Anti-Inflammatory Agents; Anti-inflammatory; Automobile Driving; Binding Sites; Biochemical Genetics; Biological; Cells; ChIP-seq; Chromatin; Chronic; Cirrhosis; Control Animal; Coupled; Cues; Development; Disease; Disease Progression; Disease model; Drug Targeting; Endocrine; Environment; Epigenetic Process; Exhibits; Fibrosis; Functional disorder; Future; Gene Expression; Gene Expression Regulation; Genes; Genetic Recombination; Genomics; Goals; Health; Hepatic; Hepatic Fibrogenesis; Hepatic Stellate Cell; IRF3 gene; In Vitro; Inflammation; Inflammatory; Inflammatory Response; Institutes; Investigation; Knockout Mice; Kupffer Cells; Laboratories; Ligands; Liver; Liver Fibrosis; Liver diseases; Mediating; Mediator of activation protein; Mentored Research Scientist Development Award; Modeling; Mus; National Institute of Diabetes and Digestive and Kidney Diseases; Nuclear Hormone Receptors; Pathogenesis; Pathologic Processes; Pathway interactions; Patients; Play; Property; Receptor Signaling; Reporting; Research Personnel; Research Project Grants; Role; Severity of illness; Technology; Therapeutic; Therapeutic Effect; Time; Tissues; Training; Transcription Factor AP-1; Transforming Growth Factor beta; United States; Vitamin D; Vitamin D Deficiency; Vitamin D3 Receptor; Wound Healing; base; chromatin immunoprecipitation; chronic liver disease; deep sequencing; experience; functional genomics; gene repression; genome-wide; histone modification; human disease; in vivo; insight; jun Oncogene; knowledge base; liver inflammation; liver injury; mortality; mouse model; non-alcoholic fatty liver; nonalcoholic steatohepatitis; novel; p65; research facility; response; stellate cell; symposium; targeted treatment

DESCRIPTION (provided by applicant): The candidate is a junior researcher with considerable experience in studying hepatic stellate cells (HSCs), liver fibrosis and gene regulation. However, to transition into a completely independent translational investigator, the candidate needs a period of additional supervised training. The NIDDK K01 award will enable the candidate to achieve this objective through a combination of academic coursework, didactic training, focused symposiums/conferences, and implementation of the proposed research project. The project will be carried out in the Gene Expression Laboratory at the Salk Institute for Biological Studies which provides a scientifically vibrant and inspiring environment and well-established state-of-the-art research facilities ideally suited to study human disease such as tissue fibrosis. In this regard, HSCs have been recognized as a pivotal regulator of liver fibrosis However, their role in mediating pro-inflammatory response during liver fibrosis remains poorly defined. Recent reports identified vitamin D receptor (VDR) in HSCs as an endocrine checkpoint for wound healing response in liver and VDR knockout mice develop spontaneous liver inflammation and fibrosis. Preliminary studies indicate that VDR is an important modulator of pro-inflammatory response in HSCs. Ligand-activated VDR represses a wide array of pro-inflammatory gene expression in HSCs through the direct genomic crosstalk with NF-κB and Vdr-deficient HSCs exhibit a spontaneous pro- inflammatory response. The overall hypothesis of this proposal is that VDR plays a role in liver fibrosis by modulating pro-inflammatory response in HSCs. Functional genomics, biochemical, genetic, and pharmacological approaches will be used to determine the roles of VDR in modulating pro-inflammatory pathways in HSCs, which underlie the pathogenesis and progression of liver fibrosis and related chronic liver diseases: Aim 1 will characterize the role of VDR signaling in modulating pro-inflammatory response in hepatic stellate cells (HSCs). Aim 2 will examine the role of VDR signaling in modulating pro-inflammatory response during liver fibrosis. Aim 3 will examine the role of VDR signaling in chronic liver diseases such as non- alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH). The ultimate goal of these investigations is to gain novel insights into the pathophysiology of HSCs to better understand the mechanisms of how VDR regulates the pathogenesis and progression of chronic liver disease, with the potential to develop vitamin D-related approaches for the treatment of disease.

职位描述（由申请人提供）：候选人是一名初级研究员，在研究肝星状细胞（HSC）、肝纤维化和基因调控方面具有丰富的经验。然而，要过渡到一个完全独立的翻译研究者，候选人需要一段时间的额外监督培训。NIDDK K 01奖将使候选人能够通过学术课程，教学培训，重点研讨会/会议和拟议研究项目的实施相结合来实现这一目标。该项目将在索尔克生物研究所的基因表达实验室进行，该实验室提供了一个充满科学活力和鼓舞人心的环境以及完善的最先进的研究设施，非常适合研究组织纤维化等人类疾病。在这方面，HSC已被认为是肝纤维化的关键调节因子，然而，它们在肝纤维化期间介导促炎反应的作用仍然不清楚。最近的报道将HSC中的维生素D受体（VDR）鉴定为肝脏中伤口愈合反应的内分泌检查点，并且VDR敲除小鼠发展自发性肝脏炎症和纤维化。初步研究表明，VDR是HSC中促炎反应的重要调节剂。配体激活的VDR通过与NF-κB的直接基因组串扰抑制HSC中多种促炎基因表达，并且VDR缺陷的HSC表现出自发的促炎反应。该提议的总体假设是VDR通过调节HSC中的促炎反应在肝纤维化中起作用。功能基因组学、生物化学、遗传学和药理学方法将用于确定VDR在调节HSC中促炎通路中的作用，这是肝纤维化和相关慢性肝病的发病机制和进展的基础：目的1将表征VDR信号传导在调节肝星状细胞（HSC）中促炎反应中的作用。目的2研究VDR信号在肝纤维化过程中对促炎反应的调节作用。目的3将检查VDR信号传导在慢性肝病如非酒精性脂肪性肝病（NAFLD）和非酒精性脂肪性肝炎（NASH）中的作用。这些研究的最终目标是获得对HSC病理生理学的新见解，以更好地了解VDR如何调节慢性肝病的发病机制和进展，并有可能开发用于治疗疾病的维生素D相关方法。