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.
人体纤维化疾病影响许多器官系统,包括心脏、血管、肾脏、肝脏和肺部,

项目成果

期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ monograph.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ sciAawards.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ conferencePapers.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ patent.updateTime }}

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

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

{{ 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:

相似海外基金

Hormone therapy, age of menopause, previous parity, and APOE genotype affect cognition in aging humans.
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。
  • 批准号:
    495182
  • 财政年份:
    2023
  • 资助金额:
    --
  • 项目类别:
Investigating how alternative splicing processes affect cartilage biology from development to old age
研究选择性剪接过程如何影响从发育到老年的软骨生物学
  • 批准号:
    2601817
  • 财政年份:
    2021
  • 资助金额:
    --
  • 项目类别:
    Studentship
RAPID: Coronavirus Risk Communication: How Age and Communication Format Affect Risk Perception and Behaviors
RAPID:冠状病毒风险沟通:年龄和沟通方式如何影响风险认知和行为
  • 批准号:
    2029039
  • 财政年份:
    2020
  • 资助金额:
    --
  • 项目类别:
    Standard Grant
Neighborhood and Parent Variables Affect Low-Income Preschool Age Child Physical Activity
社区和家长变量影响低收入学龄前儿童的身体活动
  • 批准号:
    9888417
  • 财政年份:
    2019
  • 资助金额:
    --
  • 项目类别:
The affect of Age related hearing loss for cognitive function
年龄相关性听力损失对认知功能的影响
  • 批准号:
    17K11318
  • 财政年份:
    2017
  • 资助金额:
    --
  • 项目类别:
    Grant-in-Aid for Scientific Research (C)
Affect regulation and Beta Amyloid: Maturational Factors in Aging and Age-Related Pathology
影响调节和 β 淀粉样蛋白:衰老和年龄相关病理学中的成熟因素
  • 批准号:
    9320090
  • 财政年份:
    2017
  • 资助金额:
    --
  • 项目类别:
Affect regulation and Beta Amyloid: Maturational Factors in Aging and Age-Related Pathology
影响调节和 β 淀粉样蛋白:衰老和年龄相关病理学中的成熟因素
  • 批准号:
    10166936
  • 财政年份:
    2017
  • 资助金额:
    --
  • 项目类别:
Affect regulation and Beta Amyloid: Maturational Factors in Aging and Age-Related Pathology
影响调节和 β 淀粉样蛋白:衰老和年龄相关病理学中的成熟因素
  • 批准号:
    9761593
  • 财政年份:
    2017
  • 资助金额:
    --
  • 项目类别:
How age dependent molecular changes in T follicular helper cells affect their function
滤泡辅助 T 细胞的年龄依赖性分子变化如何影响其功能
  • 批准号:
    BB/M50306X/1
  • 财政年份:
    2014
  • 资助金额:
    --
  • 项目类别:
    Training Grant
Inflamm-aging: What do we know about the effect of inflammation on HIV treatment and disease as we age, and how does this affect our search for a Cure?
炎症衰老:随着年龄的增长,我们对炎症对艾滋病毒治疗和疾病的影响了解多少?这对我们寻找治愈方法有何影响?
  • 批准号:
    288272
  • 财政年份:
    2013
  • 资助金额:
    --
  • 项目类别:
    Miscellaneous Programs
{{ showInfoDetail.title }}

作者:{{ showInfoDetail.author }}

知道了