Hepatic insulin resistance and metabolic disease

肝脏胰岛素抵抗与代谢疾病

基本信息

  • 批准号:
    8829241
  • 负责人:
  • 金额:
    $ 45.99万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2013
  • 资助国家:
    美国
  • 起止时间:
    2013-04-01 至 2016-03-31
  • 项目状态:
    已结题

项目摘要

DESCRIPTION (provided by applicant): This is a new proposal entitled "Hepatic insulin resistance and metabolic disease" that is based upon work conducted in our laboratory during the past 5 years with LDKO (hepatic-specific Irs1-/-"Irs2-/-) and LTKO (hepatic-specific Irs1-/-"Irs2-/-"FoxO1-/-) mice. LDKO-mice display systemic metabolic dysregulation, including hepatic and peripheral insulin resistance, hyperglycemia, moderate hyperinsulinemia, and progressive NAFLD (nonalcoholic fatty liver disease). The etiology of NAFLD is rooted in insulin resistance, obesity, hyperlipidemia, and diabetes. As LTKO-mice display normal nutrient homeostasis, we posit that activated hepatic FoxO1, rather than the mere accumulation of hepatic triglyceride, promotes inflammation that progresses to life- threatening necrosis/apoptosis and cycles of regeneration that culminate with damage-characteristic of the progression of NAFLD to NASH (nonalcoholic steatohepatitis) and HCC (hepatocellular carcinoma). To investigate the underlying pathophysiology, we focus upon mitochondrial dysfunction that develops as a result of chronically activated FoxO1 that increases the expression of hundreds of genes, including hemeoxygenase- 1 (encoded by Hmox1) and cyclophilin D (encoded by Ppif). To interrogate the molecular mechanisms, we propose to use nanoparticle delivery of targeted siRNA to suppress the expression of hepatic FoxO1, Hmox1, or Ppif during initiation (10 weeks of age) and progression (10 months of age) of NAFLD. To enable this technology in our laboratory, we have formed a 'Consortium Agreement' with the Amiji group in the School of Pharmacy at Northeastern University. The mouse-based experiments will investigate the relation between FoxO1-mediated hepatic mitochondrial dysfunction and progressive NAFLD/NASH upon systemic inflammation and muscle insulin action that contributes to diabetes in the following Specific Aims: i) Investigate FoxO1-mediated mitochondrial dysfunction in LDKO-mice by modulating the expression of FoxO1, Hmox1 or Ppif to restore mitochondrial function and attenuate hepatic inflammation, NASH and its progression to HCC during persistent hepatic insulin resistance. ii) Investigate skeletal muscle insulin resistance in LDKO-mice to establish the relation between hepatic inflammation and dysregulated skeletal muscle insulin action and metabolism. iii) Quantify Ser/Thr-phosphorylation of IRS1 in muscle of LDKO-mice using a library of phosphosite-specific monoclonal antibodies before and after resolution of hepatic mitochondrial dysfunction and NAFLD by suppression of FoxO1, Hmox1 or Ppif. Since the LDKO-mice are uncomplicated by the dominant effects of hypothalamic-based obesity encountered with ob/ob-mice, our experiments focus squarely upon the relation between hepatic insulin resistance and NAFLD, and its progression to systemic insulin resistance and diabetes.
描述(由申请人提供):这是一个名为“肝脏胰岛素抵抗和代谢性疾病”的新提案,基于我们实验室过去5年对LDKO(肝脏特异性Irs1-/-“Irs2-/-”)和LTKO(肝脏特异性Irs1-/-“Irs2-/-”fox01 -/-)小鼠的研究。ldko小鼠表现出全身性代谢失调,包括肝脏和外周胰岛素抵抗、高血糖、中度高胰岛素血症和进行性NAFLD(非酒精性脂肪性肝病)。NAFLD的病因是胰岛素抵抗、肥胖、高脂血症和糖尿病。由于ltko -小鼠表现出正常的营养平衡,我们假设激活的肝脏FoxO1,而不仅仅是肝脏甘油三酯的积累,促进炎症发展为危及生命的坏死/凋亡和再生周期,最终以损伤告终,这是NAFLD发展为NASH(非酒精性脂肪性肝炎)和HCC(肝细胞癌)的特征。为了研究潜在的病理生理学,我们重点研究了长期激活FoxO1导致的线粒体功能障碍,FoxO1增加了数百个基因的表达,包括血红素加氧酶- 1(由Hmox1编码)和亲环蛋白D(由Ppif编码)。为了探究其分子机制,我们建议使用纳米颗粒递送靶向siRNA来抑制NAFLD发病(10周龄)和进展(10月龄)期间肝脏fox01、Hmox1或Ppif的表达。为了在我们的实验室中实现这项技术,我们已经与东北大学药学院的Amiji小组达成了“联盟协议”。小鼠实验将研究fox01介导的肝脏线粒体功能障碍与进行性NAFLD/NASH在全身性炎症和肌肉胰岛素作用下导致糖尿病的关系,具体目的如下:i)通过调节FoxO1、Hmox1或Ppif的表达,研究FoxO1介导的ldko小鼠线粒体功能障碍,以恢复线粒体功能,减轻肝脏炎症、NASH及其向HCC的进展。ii)研究ldko -小鼠骨骼肌胰岛素抵抗,建立肝脏炎症与骨骼肌胰岛素作用和代谢失调之间的关系。iii)在通过抑制FoxO1、Hmox1或Ppif解决肝脏线粒体功能障碍和NAFLD前后,使用磷酸位点特异性单克隆抗体文库,定量ldko -小鼠肌肉中IRS1的Ser/ thr磷酸化。由于ldko -小鼠不受ob/ob-小鼠所遇到的下丘脑肥胖的主要影响,因此我们的实验直接关注肝脏胰岛素抵抗与NAFLD之间的关系,以及其向全身性胰岛素抵抗和糖尿病的进展。

项目成果

期刊论文数量(0)
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Morris F. White其他文献

The IRS-Pathway Operates Distinctively From the Stat-Pathway in Hematopoietic Cells and Transduces Common and Distinct Signals During Engagement of the Insulin or Interferon-α Receptors
  • DOI:
    10.1182/blood.v90.7.2574
  • 发表时间:
    1997-10-01
  • 期刊:
  • 影响因子:
  • 作者:
    Shahab Uddin;Eleanor N. Fish;Dorie Sher;Concetta Gardziola;Oscar R. Colamonici;Merrill Kellum;Paula M. Pitha;Morris F. White;Leonidas C. Platanias
  • 通讯作者:
    Leonidas C. Platanias
Early biochemical events in insulin-stimulated fluid phase endocytosis
胰岛素刺激的液相内吞作用的早期生化事件
  • DOI:
  • 发表时间:
    1998
  • 期刊:
  • 影响因子:
    0
  • 作者:
    D. Pitterle;R. Sperling;M. G. Myers;Morris F. White;P. J. Blackshear
  • 通讯作者:
    P. J. Blackshear
Extreme makeover of pancreatic α-cells
胰腺α细胞的极端改造
  • DOI:
    10.1038/4641132a
  • 发表时间:
    2010-04-21
  • 期刊:
  • 影响因子:
    48.500
  • 作者:
    Kenneth S. Zaret;Morris F. White
  • 通讯作者:
    Morris F. White
Stimulation of pancreatic beta-cell proliferation by growth hormone is glucose-dependent: signal transduction via janus kinase 2 (JAK2)/signal transducer and activator of transcription 5 (STAT5) with no crosstalk to insulin receptor substrate-mediated mitogenic signalling.
生长激素对胰腺 β 细胞增殖的刺激是葡萄糖依赖性的:通过 janus 激酶 2 (JAK2)/信号转导器和转录激活剂 5 (STAT5) 进行信号转导,与胰岛素受体底物介导的有丝分裂信号传导没有串扰。
  • DOI:
  • 发表时间:
    1999
  • 期刊:
  • 影响因子:
    4.1
  • 作者:
    S. P. Cousin;S. Hügl;M. G. Myers;Morris F. White;Anne Reifel;Christopher J. Rhodes
  • 通讯作者:
    Christopher J. Rhodes
Insulin receptor substrate proteins and diabetes
  • DOI:
    10.1007/bf02980074
  • 发表时间:
    2004-04-01
  • 期刊:
  • 影响因子:
    7.500
  • 作者:
    Yong Hee Lee;Morris F. White
  • 通讯作者:
    Morris F. White

Morris F. White的其他文献

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{{ truncateString('Morris F. White', 18)}}的其他基金

Regulation of hippocampal function by central and peripheral IRS signaling
通过中枢和外周 IRS 信号调节海马功能
  • 批准号:
    10343848
  • 财政年份:
    2020
  • 资助金额:
    $ 45.99万
  • 项目类别:
Regulation of hippocampal function by central and peripheral IRS signaling
通过中枢和外周 IRS 信号调节海马功能
  • 批准号:
    10162475
  • 财政年份:
    2020
  • 资助金额:
    $ 45.99万
  • 项目类别:
Regulation of hippocampal function by central and peripheral IRS signaling
通过中枢和外周 IRS 信号调节海马功能
  • 批准号:
    10548150
  • 财政年份:
    2020
  • 资助金额:
    $ 45.99万
  • 项目类别:
Hepatic insulin resistance integrates T2D and NAFLD
肝脏胰岛素抵抗整合了 T2D 和 NAFLD
  • 批准号:
    10792348
  • 财政年份:
    2013
  • 资助金额:
    $ 45.99万
  • 项目类别:
Hepatic insulin resistance and metabolic disease
肝脏胰岛素抵抗与代谢疾病
  • 批准号:
    8482791
  • 财政年份:
    2013
  • 资助金额:
    $ 45.99万
  • 项目类别:
Hepatic insulin resistance and metabolic disease
肝脏胰岛素抵抗与代谢疾病
  • 批准号:
    8637073
  • 财政年份:
    2013
  • 资助金额:
    $ 45.99万
  • 项目类别:
Metabolic Crosstalk During Hepatic Insulin Resistance
肝脏胰岛素抵抗期间的代谢串扰
  • 批准号:
    9749986
  • 财政年份:
    2013
  • 资助金额:
    $ 45.99万
  • 项目类别:
Metabolic Crosstalk During Hepatic Insulin Resistance
肝脏胰岛素抵抗期间的代谢串扰
  • 批准号:
    9982302
  • 财政年份:
    2013
  • 资助金额:
    $ 45.99万
  • 项目类别:
Gordon Conference: Second Messengers and Phosphorylation
戈登会议:第二信使和磷酸化
  • 批准号:
    6535541
  • 财政年份:
    2002
  • 资助金额:
    $ 45.99万
  • 项目类别:
IRS2 function in beta cell physiology
IRS2 在 β 细胞生理学中的功能
  • 批准号:
    7050416
  • 财政年份:
    2000
  • 资助金额:
    $ 45.99万
  • 项目类别:

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