Sirtuins in Lung Aging and Fibrosis

Sirtuins 在肺衰老和纤维化中的作用

基本信息

项目摘要

Human fibrotic disorders affect many organ systems including heart, blood vessels, kidney, liver and lung, accounting for excessive disease burden in the U.S., including among our Veterans Administration (VA) patient population. The most common fibrotic lung disease, idiopathic pulmonary fibrosis (IPF), is characterized by excessive scar tissue formation and irreversible destruction of the lung parenchyma, resulting in gas-exchange abnormalities and ultimately respiratory failure. Aging is strongest risk factor for IPF; however, the cellular/molecular mechanisms that account for the age-associated predilection to fibrotic disease are only beginning to be explored. Improved understanding of the role of aging in this disease will aid in the development of novel therapies with greater clinical efficacy. In support of this VA Merit Award renewal application, we have made several recent contributions to our understanding of aging mechanisms in lung injury and repair mechanisms. Human subjects with IPF express low levels of the mitochondrial sirtuin, SIRT3, in myofibroblastic foci and in ex-vivo fibroblasts isolated from IPF lungs. This down-regulation of SIRT3 is replicated in an aging model of non-resolving fibrosis in mice; while fibrosis in young mice largely resolves over 2-4 months post-bleomycin, aged mice manifest persistent fibrosis. Our data indicate that this capacity for fibrosis resolution in young mice is associated with recovery of SIRT3 levels in the late reparative phase of lung injury, while this is absent in aged mice. However, re-constitution of SIRT3 (via lung-targeted non-viral cDNA plasmid delivery) restores the capacity for fibrosis resolution in aged mice. This protective effect is associated with in-vivo activation of FoxO3a, evidenced by higher levels of nuclear FoxO3a. Both cellular senescence and the pro-fibrotic cytokine, transforming growth factor-β1 (TGF- β1) induce a down-regulation of SIRT3 and FoxO3a, events that lead to mitochondrial dysfunction, senescence and apoptosis resistance of lung fibroblasts. Our studies also support the possibility that modulation of SIRT3 in alveolar macrophages regulates fibroblast activation of FoxO3a by a paracrine mechanism. Additionally, the histone acetyltransferases, p300 and cyclic AMP-response element binding protein (CREB)-binding protein (CBP), are implicated in the epigenetic down-regulation of SIRT3 by TGF-β1 and cellular senescence. Impaired activation of the SIRT3-FoxO3a signaling axis promotes a senescent and apoptosis-resistant fibroblast phenotype, which drives persistent/non-resolving fibrosis. The central hypothesis to be tested in this grant proposal is that persistent/non-resolving fibrosis associated with aging is mediated by impaired activation of Foxo3a in fibroblasts, either by SIRT3 deficiency in fibroblasts themselves or by macrophage-derived paracrine mechanisms, contributes to mitochondrial dysfunction, senescence and apoptosis resistance of lung fibroblasts. Our specific aims are to: (1) elucidate p300/CBP-dependent epigenetic regulation of SIRT3 in lung fibroblasts and alveolar macrophages that mediate pro-resolution phenotypes; (2) investigate the role of the SIRT3-FoxO3a signaling axis in restoring mitochondrial bioenergetics and apoptosis susceptibility to senescent/fibrotic lung fibroblasts; and (3) determine whether reconstitution of SIRT3 by genetic/pharmacologic approaches promotes fibrosis resolution in aged mice via the activation of FoxO3a in lung fibroblasts. The completion of the Aims in this proposal will: (a) uncover epigenetic mechanisms that control SIRT3 expression with cellular senescence/aging; (b) provide mechanistic insights into the role of SIRT3-FoxO3a signaling in the regulation of mitochondrial bioenergetics and cellular plasticity/fate; and (c) elucidate macrophage-fibroblast crosstalk and SIRT3 regulation of pro-resolving macrophages; and (d) provide proof-of-concept that activation of the SIRT3-FoxO3a signaling pathway promotes fibrosis resolution, leading to new therapeutic approaches for progressive lung diseases.
人类的纤维化疾病影响到许多器官系统,包括心脏、血管、肾脏、肝脏和肺, 在美国,包括退伍军人管理局(VA)患者在内的疾病负担过重的原因 人口。最常见的纤维性肺疾病,特发性肺纤维化(IPF),其特征是 过多的疤痕组织形成和不可逆转的肺实质破坏,导致气体交换 异常并最终导致呼吸衰竭。老龄化是IPF的最大危险因素;然而, 解释与年龄相关的纤维性疾病倾向的细胞/分子机制只是 开始被探索。提高对衰老在这种疾病中的作用的理解将有助于 开发更具临床疗效的新疗法。 为了支持此次退伍军人荣誉奖续展申请,我们最近为我们的 了解衰老机制在肺损伤和修复机制中的作用。患有IPF Express的人体受试者 低水平线粒体sirtuin,SIRT3在肌成纤维细胞灶和体外分离的IPF成纤维细胞中的表达 肺部。SIRT3的这种下调在小鼠的未消退纤维化的衰老模型中被复制;而 年轻小鼠服用博莱霉素2-4个月后纤维化基本消退,老年小鼠表现为持续性纤维化。 我们的数据表明,幼鼠的这种纤维化消退能力与SIRT3的恢复有关 在肺损伤修复后期的水平,而这在老年小鼠中是不存在的。然而,重新组建 SIRT3(通过肺靶向非病毒cDNA质粒传递)恢复老年患者的纤维化消退能力 老鼠。这种保护作用与FOXO3a在体内的激活有关,更高水平的 核FOXO3a。细胞衰老和促纤维化细胞因子-转化生长因子-β-1(转化生长因子-1) β1)诱导SIRT3和FOXO3a下调,这两个事件导致线粒体功能障碍, 肺成纤维细胞的衰老和抗凋亡作用。我们的研究也支持这样一种可能性 旁分泌调节肺泡巨噬细胞SIRT3对成纤维细胞FOXO3a的激活 机制。此外,组蛋白乙酰转移酶、p300和环状AMP反应元件结合 蛋白(CREB)结合蛋白参与转化生长因子-β1对SIRT3的表观下调 和细胞衰老。SIRT3-FOXO3a信号轴的激活受损会促进衰老和 抗凋亡的成纤维细胞表型,它驱动持续性/非消退性纤维化。 在这项赠款提案中要检验的中心假设是持续性/非消退性纤维化 与衰老相关的是通过成纤维细胞中Foxo3a的激活受损所介导的,或者是由于SIRT3缺乏在 成纤维细胞本身或通过巨噬细胞衍生的旁分泌机制对线粒体做出贡献 肺成纤维细胞功能障碍、衰老和凋亡抵抗。 我们的具体目标是:(1)阐明肺组织中依赖p300/CBP的SIRT3的表观遗传调控 成纤维细胞和肺泡巨噬细胞介导的促分解表型;(2)研究 SIRT3-FOXO3a信号轴在恢复线粒体生物能量学和细胞凋亡易感性中的作用 衰老/纤维化的肺成纤维细胞;以及(3)确定SIRT3是否通过 遗传/药物途径通过激活FXO3a促进老年小鼠肝纤维化的消退 肺成纤维细胞。完成本提案中的目标将:(A)揭示表观遗传机制, 通过细胞衰老/衰老控制SIRT3的表达;(B)提供对SIRT3的作用的机械性见解 SIRT3-FOXO3a在线粒体生物能量学和细胞可塑性/命运调控中的信号转导; 阐明巨噬细胞-成纤维细胞串扰和SIRT3对促分解巨噬细胞的调节;和(D)提供 激活SIRT3-FOXO3a信号通路促进纤维化消退的概念验证 为治疗进行性肺部疾病提供新的治疗方法。

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:
    9210543
  • 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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激素治疗、绝经年龄、既往产次和 APOE 基因型会影响老年人的认知。
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