Molecular Mechanisms of Liver Fibrosis

肝纤维化的分子机制

基本信息

  • 批准号:
    10407227
  • 负责人:
  • 金额:
    $ 35.78万
  • 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:
    2022-05-01 至 2027-04-30
  • 项目状态:
    未结题

项目摘要

Hepatic stellate cell (HSC) activation encompasses aphenotype that includes enhanced migration, proliferation, and matrix deposition. Migration is critical for coordinately situating HSC for matrix deposition and development of cirrhosis. Our Long-Term Objectives are to understand the molecular underpinnings of HSC biology that lead to cirrhosis with the goal of identifying therapeutic targets. Recently,we identified a critical role of synectin in the process of HSC migration and fibrosis. Synectin is a cytosolic protein that mediates signal transduction, vesicle trafficking, and ultimately gene expression. Synectin is chosen for this proposal as a significant protein warranting detailed investigation because, as we demonstrate, it is upregulated in human cirrhosis and is required for murine fibrogenesis. Mechanistically, we implicate synectin inHSC migration through both short term receptor signaling as well as longer term epigenetic regulation of gene expression networks. Our preliminary data show that depletion of HSC synectin reduces migration signaling downstream of the receptor tyrosine kinase, platelet derived growth factor receptor alpha (PDGFRα); attenuates transcription of a set of HSC activation genes including one that encodes the multifunctional signaling protein, IGFBP3 (insulin growth factor binding protein-3); and abrogates murine fibrosis in vivo. These important observations have led us to propose the central hypothesis that synectin increases HSC migration and fibrosis by promoting PDGFRα signaling and by regulating a network of genes that include IGFBP3. This hypothesis leads to the following Specific Aims: 1) Synectin promotes HSC migration by regulating PDGFRα targeting and signal activation. Aim 1a will determine how synectin recruits and binds specific vesicle trafficking proteins that maintain PDGFRα protein levels, target the protein to endosomes and activate migration signaling. Aim 1b will uncover how disruption of synectin function leads to autophagic degradation of PDGFRα and attenuated HSC migration. 2) Synectin epigenetically controls IGFBP3 gene expression to promote HSC migration. Aim 2a will identify how synectin regulates a specific histone methyl transferase, EZH2 and how this governs IGFBP3 gene expressionthrough histone methylation. Aim 2b will determine how IGFBP3 production stimulates HSC migration. 3) Synectin regulates fibrosis in vivo. Aim 3a will use a novel fibrosis regression model in mice with HSC selective modifications to synectin and PDGFRα to further ascertain the proposed role of these proteins in vivo. Aim 3b will use a synectin neutralizing peptide that selectively targets HSC in coordination with magnetic resonance elastography (MRE) imaging, and mice with genetic deletion of IGFBP3 to elucidate how synectin promotes fibrosis in vivo. In total, this proposal will utilize conceptually and technically innovative approaches and concepts to test a novel hypothesis pertaining to synectin as a “master regulator” of HSC signals that lead to migration and fibrosis. RELEVANCE (See instructions): Liver injury from alcohol and other etiologies can culminate in cirrhosis with significant associated morbidity and mortality.
肝星状细胞(HSC)活化包括表型,包括增强的迁移, 增殖和基质沉积。迁移对于HSC在基质沉积中的协调定位至关重要 发展成肝硬化我们的长期目标是了解 HSC生物学导致肝硬化,目的是确定治疗靶点。最近,我们发现了一个 synectin在HSC迁移和纤维化过程中的关键作用。Synectin是一种细胞溶质蛋白, 介导信号转导、囊泡运输和最终基因表达。Synectin被选中用于此目的 建议作为一个重要的蛋白质澄清详细的调查,因为,正如我们所证明的,它是 在人肝硬化中上调,并且是鼠纤维化所必需的。从机制上讲,我们认为连接蛋白 通过短期受体信号传导以及长期表观遗传调节的inHSC迁移 基因表达网络我们的初步数据显示,HSC连接蛋白的缺失减少了迁移 受体酪氨酸激酶、血小板衍生生长因子受体α的下游信号传导 (PDGFRα);减弱一组HSC激活基因的转录,包括编码PDGFR α的基因。 多功能信号传导蛋白IGFBP 3(胰岛素生长因子结合蛋白-3);并消除鼠 体内纤维化。这些重要的观察结果使我们提出了一个中心假设, 通过促进PDGFRα信号传导和调节基因网络增加HSC迁移和纤维化 包括IGFBP 3。这一假说导致以下具体目的:1)Synectin促进HSC 通过调节PDGFRα靶向和信号激活来迁移。目标1a将决定synectin如何招募 并结合维持PDGFRα蛋白水平的特异性囊泡运输蛋白,靶向该蛋白, 内体并激活迁移信号。目的1b将揭示粘连蛋白功能的破坏如何导致 PDGFRα自噬降解和HSC迁移减弱。2)Synectin表观遗传控制 IGFBP 3基因表达促进HSC迁移。目的2a将确定连接蛋白如何调节一个特定的 组蛋白甲基转移酶EZH 2及其如何通过组蛋白调控IGFBP 3基因表达 甲基化目的2b将确定IGFBP 3的产生如何刺激HSC迁移。3)Synectin调节 体内纤维化。目标3a将在具有HSC选择性修饰的小鼠中使用一种新型纤维化消退模型, synectin和PDGFRα,以进一步确定这些蛋白在体内的作用。Aim 3B将使用 与磁共振协同选择性靶向HSC的连接蛋白中和肽 弹性成像(MRE)成像,以及IGFBP 3基因缺失的小鼠,以阐明粘连蛋白如何促进 体内纤维化。总之,本提案将利用概念和技术上的创新办法, 概念来测试一种新的假设,该假设涉及连接蛋白作为HSC信号的“主调节器”, 迁移和纤维化。 相关性(参见说明): 酒精和其他病因引起的肝损伤可最终导致肝硬化,并伴有显著的相关发病率 and mortality.

项目成果

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VIJAY H. SHAH其他文献

VIJAY H. SHAH的其他文献

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{{ truncateString('VIJAY H. SHAH', 18)}}的其他基金

Molecular Mechanisms of Liver Fibrosis
肝纤维化的分子机制
  • 批准号:
    10612941
  • 财政年份:
    2022
  • 资助金额:
    $ 35.78万
  • 项目类别:
Liver Cirrhosis Network: Clinical Research Center - Mayo Clinic
肝硬化网络:临床研究中心 - 梅奥诊所
  • 批准号:
    10487453
  • 财政年份:
    2021
  • 资助金额:
    $ 35.78万
  • 项目类别:
Liver Cirrhosis Network: Clinical Research Center - Mayo Clinic
肝硬化网络:临床研究中心 - 梅奥诊所
  • 批准号:
    10310667
  • 财政年份:
    2021
  • 资助金额:
    $ 35.78万
  • 项目类别:
Liver Cirrhosis Network: Clinical Research Center - Mayo Clinic
肝硬化网络:临床研究中心 - 梅奥诊所
  • 批准号:
    10700154
  • 财政年份:
    2021
  • 资助金额:
    $ 35.78万
  • 项目类别:
Assessment of Alcoholic Hepatitis with Multiparametric Magnetic Resonance Elastography
多参数磁共振弹性成像评估酒精性肝炎
  • 批准号:
    10459414
  • 财政年份:
    2018
  • 资助金额:
    $ 35.78万
  • 项目类别:
Randomized Placebo Controlled Pilot Trial to determine the efficacy of an IL22 agonist (F-652) in patients with Alcoholic Hepatitis
随机安慰剂对照预试验以确定 IL22 激动剂 (F-652) 对酒精性肝炎患者的疗效
  • 批准号:
    10202402
  • 财政年份:
    2018
  • 资助金额:
    $ 35.78万
  • 项目类别:
Assessment of Alcoholic Hepatitis with Multiparametric Magnetic Resonance Elastography
多参数磁共振弹性成像评估酒精性肝炎
  • 批准号:
    10205237
  • 财政年份:
    2018
  • 资助金额:
    $ 35.78万
  • 项目类别:
Randomized Placebo Controlled Pilot Trial to determine the efficacy of an IL22 agonist (F-652) in patients with Alcoholic Hepatitis
随机安慰剂对照预试验以确定 IL22 激动剂 (F-652) 对酒精性肝炎患者的疗效
  • 批准号:
    9791141
  • 财政年份:
    2018
  • 资助金额:
    $ 35.78万
  • 项目类别:
Randomized Placebo Controlled Pilot Trial to determine the efficacy of an IL22 agonist (F-652) in patients with Alcoholic Hepatitis
随机安慰剂对照预试验以确定 IL22 激动剂 (F-652) 对酒精性肝炎患者的疗效
  • 批准号:
    10449219
  • 财政年份:
    2018
  • 资助金额:
    $ 35.78万
  • 项目类别:
Assessment of Alcoholic Hepatitis with Multiparametric Magnetic Resonance Elastography
多参数磁共振弹性成像评估酒精性肝炎
  • 批准号:
    9791139
  • 财政年份:
    2018
  • 资助金额:
    $ 35.78万
  • 项目类别:

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