Nuclear Receptor Dysfunction Reprograms Metabolism and Cellular Proliferation in Wilson's Disease

威尔逊病中核受体功能障碍重新编程代谢和细胞增殖

基本信息

  • 批准号:
    10667593
  • 负责人:
  • 金额:
    $ 32.16万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2022
  • 资助国家:
    美国
  • 起止时间:
    2022-07-18 至 2027-05-31
  • 项目状态:
    未结题

项目摘要

PROJECT SUMMARY Wilson’s disease is an autosomal recessive disorder caused by mutations in the copper-transporting P- type ATPase, ATP7b, resulting in excessive copper accumulation primarily in the liver and brain. Elevation of free copper leads to oxidative stress and mitochondrial dysfunction, inflammation, steatosis, fibrosis, and cirrhosis. Treatments for Wilson’s disease are limited to chelation or zinc therapies and often associated with many side effects. Atp7b-/- mice exhibit hallmarks of the progressive liver pathology present in Wilson’s disease patients. By using specific nuclear receptors expressed in the liver and intestine, we will address transcriptomic and metabolomic changes to understand how copper reprograms the metabolic and cellular signaling pathways in the liver of Atp7b-/- mice. The lack of well-defined molecular mechanisms for therapeutic targeting represents a critical gap in our scientific understanding of liver disease. Our preliminary data in Atp7b-/- mice revealed decreased metabolic nuclear receptor activity and target gene expression that dynamic changes in hepatic metabolic composition. We also discovered that hepatic nodule formation in older Atp7b-/- mice is exacerbated by deletion of PXR in Atp7b-/- mice. These findings suggest that reprogrammed metabolism and cell cycle regulation contribute to the hepatic phenotype of Atp7b-/- mice, and overlap other chronic hepatic disorders. Rationale: definition of molecular targets of Cu++ toxicity will provide novel therapeutic targets for WD treatment. Our proposed studies will test the central hypothesis: Cu++-compromises PXR activities and promotes liver dysfunction in Wilson’s disease.
项目摘要 威尔逊病是一种常染色体隐性遗传疾病,由铜转运蛋白P- 型ATP酶,ATP 7 b,导致过量的铜积累,主要在肝脏和大脑。标高 游离铜导致氧化应激和线粒体功能障碍、炎症、脂肪变性、纤维化, 肝硬化威尔逊病的治疗仅限于螯合或锌疗法,并且通常与 很多副作用。Atp 7 b-/-小鼠表现出威尔逊病中存在的进行性肝脏病理学特征 患者通过使用在肝和肠中表达的特异性核受体,我们将解决转录组学问题。 和代谢组学变化,以了解铜如何重新编程代谢和细胞信号通路 在Atp 7 b-/-小鼠的肝脏中。缺乏明确的治疗靶向分子机制代表了 这是我们对肝病科学认识的一个关键空白。我们在Atp 7 b-/-小鼠中的初步数据显示, 降低代谢核受体活性和靶基因表达, 代谢组成我们还发现,老年Atp 7 b-/-小鼠的肝结节形成加剧, 通过在Atp 7 b-/-小鼠中缺失PXR。这些发现表明,重编程代谢和细胞周期 调节有助于Atp 7 b-/-小鼠的肝脏表型,并与其他慢性肝脏疾病重叠。 原理:确定Cu++毒性的分子靶点将为WD治疗提供新的治疗靶点。 我们提出的研究将验证中心假设:Cu++-损害PXR活性并促进肝脏 威尔逊氏病的症状

项目成果

期刊论文数量(0)
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Clavia Ruth Wooton-Kee其他文献

Therapeutic implications of impaired nuclear receptor function and dysregulated metabolism in Wilson's disease
威尔逊病中核受体功能受损和代谢失调的治疗意义
  • DOI:
    10.1016/j.pharmthera.2023.108529
  • 发表时间:
    2023-11-01
  • 期刊:
  • 影响因子:
    12.500
  • 作者:
    Clavia Ruth Wooton-Kee
  • 通讯作者:
    Clavia Ruth Wooton-Kee

Clavia Ruth Wooton-Kee的其他文献

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{{ truncateString('Clavia Ruth Wooton-Kee', 18)}}的其他基金

Nuclear Receptor Dysfunction Reprograms Metabolism and Cellular Proliferation in Wilson's Disease
威尔逊病中核受体功能障碍重新编程代谢和细胞增殖
  • 批准号:
    10516671
  • 财政年份:
    2022
  • 资助金额:
    $ 32.16万
  • 项目类别:
Nuclear Receptors as Novel Therapeutic Targets for Wilson’s Disease
核受体作为威尔逊病的新治疗靶点
  • 批准号:
    9437798
  • 财政年份:
    2017
  • 资助金额:
    $ 32.16万
  • 项目类别:
Excessive Copper Levels Disrupt Hepatic Nuclear Receptor Function
过量的铜水平会破坏肝核受体功能
  • 批准号:
    8059216
  • 财政年份:
    2010
  • 资助金额:
    $ 32.16万
  • 项目类别:
Excessive Copper Levels Disrupt Hepatic Nuclear Receptor Function
过量的铜水平会破坏肝核受体功能
  • 批准号:
    8205047
  • 财政年份:
    2010
  • 资助金额:
    $ 32.16万
  • 项目类别:

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