Sirtuins in Lung Aging and Fibrosis

Sirtuins 在肺衰老和纤维化中的作用

基本信息

  • 批准号:
    9210543
  • 负责人:
  • 金额:
    --
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2016
  • 资助国家:
    美国
  • 起止时间:
    2016-01-01 至 2019-12-31
  • 项目状态:
    已结题

项目摘要

 DESCRIPTION (provided by applicant) Idiopathic pulmonary fibrosis (IPF) is a disease of aging. IPF carries a high morbidity and mortality, with a median survival rate of less than three years. The incidence and prevalence of IPF increase drastically with age; however, despite this strong association, cellular/molecular mechanisms that account for the aging predilection to fibrotic disease have not been elucidated. Recent studies from our laboratory have identified a reactive oxygen species (ROS)-generating enzyme, NADPH oxidase-4 (Nox4), in mediating differentiation of fibroblasts (Fbs) to myofibroblasts (MFbs), key effectors of fibrogenesis, and in in-vivo lung fibrosis in murine models of lung injury. Our preliminary studies indicate that the biological actions of Nox4 may be modulated by the expression of SIRT3, a mitochondrial sirtuin. Both cellular senescence and TGF-β1 mediate suppression of SIRT3; our preliminary studies support a role for epigenetic silencing of SIRT3 involving both DNA methylation and histone modification. Decreased expression of SIRT3 promotes a senescent and pro-fibrotic Fb phenotype. TGF-β1-induced down-regulation of SIRT3 is associated with hyper-acetylation of mitochondrial proteins, supporting a role for altered mitochondrial bioenergetics in MFbs. Human subjects with IPF express low levels of SIRT3 in myofibroblastic foci (by immunohistochemistry), as well as in ex-vivo Fbs isolated from IPF lungs. We have developed a novel aging model of non-resolving fibrosis in mice; fibrosis in young mice (2 months) resolves by >50% by 4 months post-bleomycin, whereas aged mice (18 months) show persistent fibrotic response. While SIRT3 levels decrease during the fibrogenic phase in both groups, young mice demonstrate a capacity to recover SIRT3 levels during resolution; in contrast, aged mice manifest sustained down-regulation of SIRT3. The central hypothesis to be tested in this grant proposal is that, in the context of aging, lung injury results in sustained, epigenetically-regulated SIRT3 silencing that leads to mitochondrial dysfunction, MFb senescence and apoptosis resistance, leading to persistent fibrosis with aging. Our specific aims are to: (1) determine epigenetic mechanisms for SIRT3 down-regulation with cellular senescence and with TGF-β1 signaling in lung Fbs; (2) determine the role of SIRT3 in regulating mitochondrial bioenergetics, Fb senescence and apoptosis resistance; (3) determine whether whole-animal SIRT3 knockout and/or conditional genetic deletion of SIRT3 in collagen-producing/mesenchymal cells induce(s) persistent fibrosis in young mice. The completion of the Aims in this proposal will: (a) elucidate epigenetic mechanisms that control SIRT3 expression with cellular senescence/aging; (b) provide mechanistic insights into the role of SIRT3 in maintenance of mitochondrial bioenergetics and cellular plasticity/fate; (c) provide proof-of-concept that SIRT3 induction in the context of age-associated fibrosis facilitates fibrosis resolution, uncovering a novel therapeutic approach to non-resolving fibrotic disorders such as IPF.
 描述(由申请人提供) 特发性肺纤维化(IPF)是一种衰老性疾病。IPF的发病率和死亡率较高,中位生存率不到3年。IPF的发病率和患病率随着年龄的增长而急剧增加;然而,尽管存在这种强烈的相关性,但尚未阐明导致纤维化疾病的衰老易感性的细胞/分子机制。 我们实验室最近的研究已经鉴定了活性氧(ROS)生成酶NADPH氧化酶-4(Nox 4),其在介导成纤维细胞(Fbs)向肌成纤维细胞(MFbs)分化中,肌成纤维细胞(MFbs)是纤维发生的关键效应物,并且在肺损伤的鼠模型中在体内肺纤维化中。我们的初步研究表明,Nox 4的生物学作用可能是由SIRT 3,线粒体sirtuin的表达调节。细胞衰老和TGF-β1都介导SIRT 3的抑制;我们的初步研究支持SIRT 3的表观遗传沉默的作用,涉及DNA甲基化和组蛋白修饰。SIRT 3的表达减少促进衰老和促纤维化Fb表型。TGF-β1诱导的SIRT 3下调与线粒体蛋白的超乙酰化相关,支持MFbs中线粒体生物能量学改变的作用。患有IPF的人类受试者在成肌纤维细胞灶中(通过免疫组织化学)以及在从IPF肺分离的离体Fbs中表达低水平的SIRT 3。我们已经开发了一种新的小鼠非消退性纤维化衰老模型;年轻小鼠(2个月)的纤维化在博来霉素后4个月消退>50%,而老年小鼠(18个月)显示出持续的纤维化反应。虽然SIRT 3水平在两组的纤维化阶段下降,但年轻小鼠表现出在消退期间恢复SIRT 3水平的能力;相反,老年小鼠表现出SIRT 3的持续下调。 在该资助提案中要测试的中心假设是,在衰老的背景下,肺损伤导致持续的、表观遗传调节的SIRT 3沉默,其导致线粒体功能障碍、MFb衰老和凋亡抗性,导致随着衰老的持续纤维化。 我们的具体目标是:(1)确定SIRT 3下调与细胞衰老和肺Fbs中TGF-β1信号传导的表观遗传机制;(2)确定SIRT 3在调节线粒体生物能量学、Fb衰老和凋亡抗性中的作用;(3)确定全动物SIRT 3敲除和/或胶原产生/间充质细胞中SIRT 3的条件性遗传缺失是否诱导幼龄小鼠中的持续纤维化。 完成本提案中的目标将:(a)阐明控制SIRT 3表达与细胞衰老/老化的表观遗传机制;(B)提供SIRT 3在维持线粒体生物能量学和细胞可塑性/命运中的作用的机制见解;(c)提供在年龄相关性纤维化的背景下SIRT 3诱导促进纤维化消退的概念验证,揭示了一种新的治疗方法,以解决非解决纤维化疾病,如IPF。

项目成果

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Victor J. Thannickal其他文献

Long noncoding RNA Malat1 regulates differential activation of macrophage and response to lung injury
长非编码 RNA Malat1 调节巨噬细胞的差异激活和对肺损伤的反应
  • DOI:
  • 发表时间:
    2019
  • 期刊:
  • 影响因子:
    8
  • 作者:
    Huachun Cui;Sami Banerjee;Sijia Guo;Na Xie;Jing Ge;Dingyuan Jiang;Martin Zörnig;Victor J. Thannickal;Gang Liu
  • 通讯作者:
    Gang Liu

Victor J. Thannickal的其他文献

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{{ truncateString('Victor J. Thannickal', 18)}}的其他基金

AMPK in the Development and Resolution of Lung Fibrosis
AMPK 在肺纤维化的发展和解决中的作用
  • 批准号:
    10320917
  • 财政年份:
    2019
  • 资助金额:
    --
  • 项目类别:
AMPK in the Development and Resolution of Lung Fibrosis
AMPK 在肺纤维化的发展和解决中的作用
  • 批准号:
    10083647
  • 财政年份:
    2019
  • 资助金额:
    --
  • 项目类别:
Sirtuins in Lung Aging and Fibrosis
Sirtuins 在肺衰老和纤维化中的作用
  • 批准号:
    10513291
  • 财政年份:
    2016
  • 资助金额:
    --
  • 项目类别:
Sirtuins in Lung Aging and Fibrosis
Sirtuins 在肺衰老和纤维化中的作用
  • 批准号:
    10610127
  • 财政年份:
    2016
  • 资助金额:
    --
  • 项目类别:
Myofibroblast Senescence in Pulmonary Fibrosis
肺纤维化中的肌成纤维细胞衰老
  • 批准号:
    8916533
  • 财政年份:
    2014
  • 资助金额:
    --
  • 项目类别:
Myofibroblast Senescence in Pulmonary Fibrosis
肺纤维化中的肌成纤维细胞衰老
  • 批准号:
    8786336
  • 财政年份:
    2014
  • 资助金额:
    --
  • 项目类别:
Therapeutic Targeting of the Myofibroblast in Fibrotic Lung Disease
纤维化肺病中肌成纤维细胞的治疗靶向
  • 批准号:
    10218247
  • 财政年份:
    2013
  • 资助金额:
    --
  • 项目类别:
Administrative and Biostatistical Core
行政和生物统计核心
  • 批准号:
    10218248
  • 财政年份:
    2013
  • 资助金额:
    --
  • 项目类别:
Therapeutic Targeting of the Myofibroblast in Fibrotic Lung Disease
纤维化肺病中肌成纤维细胞的治疗靶向
  • 批准号:
    9980973
  • 财政年份:
    2013
  • 资助金额:
    --
  • 项目类别:
Therapeutic Targeting of the Myofibroblast in Fibrotic Lung Disease
纤维化肺病中肌成纤维细胞的治疗靶向
  • 批准号:
    8735177
  • 财政年份:
    2013
  • 资助金额:
    --
  • 项目类别:

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