Ca2+ waves in hepatocytes: Mechanisms and effects

肝细胞中的 Ca2 波:机制和作用

基本信息

  • 批准号:
    10388244
  • 负责人:
  • 金额:
    $ 51.46万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2018
  • 资助国家:
    美国
  • 起止时间:
    2018-04-01 至 2024-03-31
  • 项目状态:
    已结题

项目摘要

PROJECT SUMMARY Bile secretion is one of the principal functions of the liver. Cholestasis, or impaired bile flow, is a cardinal manifestation of liver disease. Cholestatic liver diseases are an important group of disorders, which collectively represent the most common indication for pediatric liver transplant and account for one in ten of all liver transplants. This project investigates a basic biological mechanism in epithelial biology that is directly relevant for the regulation of secretion in hepatocytes in health and disease. Calcium signals in hepatocytes are formed largely by calcium release from the inositol 1,4,5-trisphosphate (InsP3) receptor (InsP3R), which is an InsP3- gated calcium channel in the endoplasmic reticulum (ER). The type II InsP3R (InsP3R-2) is the predominant isoform in hepatocytes, constituting 80% of the total pool of InsP3Rs, and is most concentrated in a specialized region of the ER beneath the canalicular membrane. Calcium signals in hepatocytes generally begin as calcium waves that originate in this region, and the apical pool of InsP3R-2 in hepatocytes is important for mediating calcium waves and canalicular secretion. In contrast, the type I InsP3R (InsP3R-1), which constitutes the remaining 20% of the InsP3R pool in hepatocytes, preferentially localizes to a different subcellular region and does not affect secretion. The hypothesis of this project is that the factors that regulate the expression and subcellular distribution of InsP3R-2 also regulate hepatocyte secretion, so that cholestasis is mediated by these effects on InsP3R-2. In particular, we will test whether cholestatic liver diseases are due in part to impaired expression and/or peri-canalicular targeting of InsP3R-2, which in turn impairs polarized calcium waves in the cytosol and downstream events including regulation of the bile acid transporter Bsep and the organic anion transporter Mrp2. This hypothesis will be tested through the following specific aims: (1) We will determine the genetic and epigenetic factors that regulate expression of InsP3R-2 in hepatocytes. (2) We will determine the molecular basis for, and cellular effects of, targeting InsP3R-2 to the ER-canalicular membrane interface. (3) We will determine whether and how InsP3R-2 expression and/or pericanalicular targeting is impaired in hepatocytes during canalicular cholestasis. We also will determine whether the efficacy of new therapies being developed for treatment of cholestatis disorders is mediated in part by modulating InsP3R-2. Collectively, these studies will break new ground in our understanding of the ways in which signaling microdomains are established in hepatocytes, and have the potential to establish new paradigms for translating these observations into understanding the mechanistic basis for a range of clinically significant human liver diseases.
项目总结

项目成果

期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)

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MICHAEL H NATHANSON其他文献

MICHAEL H NATHANSON的其他文献

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{{ truncateString('MICHAEL H NATHANSON', 18)}}的其他基金

Yale Liver Center
耶鲁肝脏中心
  • 批准号:
    10388648
  • 财政年份:
    2021
  • 资助金额:
    $ 51.46万
  • 项目类别:
Interactions between neutrophils and cholangiocytes in alcoholic hepatitis
酒精性肝炎中中性粒细胞和胆管细胞之间的相互作用
  • 批准号:
    10298412
  • 财政年份:
    2021
  • 资助金额:
    $ 51.46万
  • 项目类别:
Interactions between neutrophils and cholangiocytes in alcoholic hepatitis
酒精性肝炎中中性粒细胞和胆管细胞之间的相互作用
  • 批准号:
    10494268
  • 财政年份:
    2021
  • 资助金额:
    $ 51.46万
  • 项目类别:
Interactions between neutrophils and cholangiocytes in alcoholic hepatitis
酒精性肝炎中中性粒细胞和胆管细胞之间的相互作用
  • 批准号:
    10617893
  • 财政年份:
    2021
  • 资助金额:
    $ 51.46万
  • 项目类别:
Interactions between neutrophils and cholangiocytes in alcoholic hepatitis
酒精性肝炎中中性粒细胞和胆管细胞之间的相互作用
  • 批准号:
    10646369
  • 财政年份:
    2021
  • 资助金额:
    $ 51.46万
  • 项目类别:
Interactions between neutrophils and cholangiocytes in alcoholic hepatitis
酒精性肝炎中中性粒细胞和胆管细胞之间的相互作用
  • 批准号:
    10874892
  • 财政年份:
    2021
  • 资助金额:
    $ 51.46万
  • 项目类别:
Ca2+ waves in hepatocytes: Mechanisms and effects
肝细胞中的 Ca2 波:机制和作用
  • 批准号:
    9902430
  • 财政年份:
    2018
  • 资助金额:
    $ 51.46万
  • 项目类别:
Molecular regulation of cholestasis in cholangiocytes
胆管细胞胆汁淤积的分子调控
  • 批准号:
    9925220
  • 财政年份:
    2018
  • 资助金额:
    $ 51.46万
  • 项目类别:
Enrichment Program
强化计划
  • 批准号:
    8916082
  • 财政年份:
    2015
  • 资助金额:
    $ 51.46万
  • 项目类别:
Trafficking of the EGF receptor to the nucleus: Mechanisms and Effects
EGF 受体转运至细胞核:机制和作用
  • 批准号:
    8152910
  • 财政年份:
    2012
  • 资助金额:
    $ 51.46万
  • 项目类别:

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