The Role of Vitamin D Receptor in Liver Fibrosis

简介（由申请人提供）：初级研究员，在肝星状细胞（HSCs）、肝纤维化、基因调控等方面有丰富的研究经验。然而，要转变为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 K01奖将使候选人能够通过结合学术课程、教学培训、专题讨论会/会议和实施拟议的研究项目来实现这一目标。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活力和鼓舞人心的科学环境，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，造血干细胞已被认为是肝纤维化的关键调节因子，然而，它们在肝纤维化过程中介导促炎反应的作用仍不明确。最近的报道发现造血干细胞中的维生素D受体（VDR）是肝脏伤口愈合反应的内分泌检查点，VDR敲除小鼠会发生自发性肝脏炎症和纤维化。初步研究表明，VDR是造血干细胞促炎反应的重要调节剂。配体激活的VDR通过与NF-κ b的直接基因组串音抑制造血干细胞中一系列促炎基因的表达，而VDR缺陷的造血干细胞表现出自发的促炎反应。该建议的总体假设是VDR通过调节造血干细胞的促炎反应在肝纤维化中发挥作用。功能基因组学、生化、遗传学和药理学方法将用于确定VDR在调节肝星状细胞促炎通路中的作用，这是肝纤维化和相关慢性肝病的发病和进展的基础。目的1将描述VDR信号在调节肝星状细胞（HSCs）促炎反应中的作用。目的2将研究VDR信号在肝纤维化过程中调节促炎反应中的作用。目的3将研究VDR信号在慢性肝病（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，并有可能开发与维生素d相关的疾病治疗方法。

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.