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Administrative Supplement to: Cell Autonomous and Non-Autonomous Mechanisms of Aging

Administrative Supplement to: Cell Autonomous and Non-Autonomous Mechanisms of Aging
行政补充:细胞自主和非自主衰老机制
批准号:
9914531
负责人:
Paul D. Robbins
金额:
$30.84万
依托单位:
依托单位国家:
美国
项目类别:
财政年份:
2019
资助国家:
美国
项目状态:
已结题
起止时间:
2019-05-01 至 2020-04-30

项目摘要

项目成果

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中文摘要
翻译
进展总体总结:在前一个资助期,我们发现细胞或 组织驱动新陈代谢改变,激活核因子-B、FOXO3a和UPRmit,增加活性氧 物种和衰老。这清楚地表明了细胞自主机制对内源激素的反应 DNA损伤。这项工作在很大程度上依赖于报告老鼠的品系。此外,使用组织特异性突变体 我们发现,在某些情况下,但不是所有情况下,内源性DNA损伤增加的细胞或组织 会导致组织动态平衡的丧失和其他未受损组织的衰老。我们的初步工作表明 受损的免疫细胞通过细胞非自主机制最有效地推动衰老。 人们投入了大量的精力和资源来开发这些独特的转基因小鼠,使我们能够 向下钻取并发现随机性在哪里、何时以及如何自发地随时间积累 损坏会导致衰老。在之前的资助期间,我们开发了85种独特的转基因小鼠 其中DNA修复复合体ERCC1-XPF被系统或组织特异性地耗尽或敲除/- 用来测量衰老标记物、自噬或应激反应激活的各种报告结构 寿命/健康的关键调控因子(如mTOR、过氧化氢酶、NRF2、核因子-B、ATM、p53、p21Cip1或 P16INK4a)。
英文摘要
Overall Summary of Progress: In the previous funding period, we found that DNA damage in cells or tissues drives altered metabolism, activation of NF- B, FOXO3a, and UPRmit, an increase in reactive oxygen species and senescence. This clearly demonstrates cell autonomous mechanisms in response to endogenous DNA damage. This work relied heavily on reporter mouse strains. In addition, using tissue-specific mutant mice, we discovered that in some but not all cases, cells or tissues with increased endogenous DNA damage can drive loss of tissue homeostasis and aging in other non-damaged tissues. Our preliminary work indicates that damaged immune cells are the most potent in driving aging via cell non-autonomous mechanisms. Considerable effort and resources were dedicated to developing these unique transgenic mice that enable us to drill down and discover where, when and how spontaneous time-dependent accumulation of stochastic damage drives aging. During the previous funding period, we developed 85 unique strains of transgenic mice in which the DNA repair complex ERCC1-XPF is depleted or knocked-out systemically or tissue-specifically +/- a variety of reporter constructs to measure senescence markers, autophagy, or stress response activation +/- mutation of key regulators of lifespan/healthspan (e.g., mTOR, catalase, NRF2, NF- B, ATM, p53, p21Cip1 or p16Ink4a).
期刊论文(11)
专著(0)
科研奖励(0)
会议论文
DOI: 10.1002/cpcy.38
发表时间: 2018-10
期刊: Current protocols in cytometry
影响因子: --
作者: [Muntifering M, Castranova D, Gibson GA, Meyer E, Kofron M, Watson AM]
通讯作者: Watson AM
DOI: 10.21037/sci.2017.12.03
发表时间: 2017-01-01
期刊: Stem cell investigation
影响因子: --
作者: [Robbins, Paul D]
通讯作者: Robbins, Paul D
Involvement of ERCC1 in the pathogenesis of osteoarthritis through the modulation of apoptosis and cellular senescence.
ERCC1 通过调节细胞凋亡和细胞衰老参与骨关节炎的发病机制。
DOI: 10.1002/jor.22656
发表时间: 2014-10
期刊: JOURNAL OF ORTHOPAEDIC RESEARCH
影响因子: 2.8
作者: [Takayama, Koji, Kawakami, Yohei, Lee, Sahnghoon, Greco, Nick, Lavasani, Mitra, Mifune, Yutaka, Cummins, James H., Yurube, Takashi, Kuroda, Ryosuke, Kurosaka, Masahiro, Fu, Freddie H., Huard, Johnny]
通讯作者: Huard, Johnny
DOI: 10.1371/journal.pone.0179270
发表时间: 2017
期刊: PloS one
影响因子: 3.7
作者: [Proto JD, Lu A, Dorronsoro A, Scibetta A, Robbins PD, Niedernhofer LJ, Huard J]
通讯作者: Huard J
Biological Analysis Core
  • 批准号:
    10385165
  • 项目类别:
  • 资助金额:
    $82.8万
  • 财政年份:
    2021
  • 负责人:
    Paul D. Robbins
  • 依托单位:
Biological Analysis Core
  • 批准号:
    10682555
  • 项目类别:
  • 资助金额:
    $76.65万
  • 财政年份:
    2021
  • 负责人:
    Paul D. Robbins
  • 依托单位:
Drug Discovery and Development
  • 批准号:
    10349482
  • 项目类别:
  • 资助金额:
    $52.15万
  • 财政年份:
    2019
  • 负责人:
    Paul D. Robbins
  • 依托单位:
Drug Discovery and Development
  • 批准号:
    10561623
  • 项目类别:
  • 资助金额:
    $53.44万
  • 财政年份:
    2019
  • 负责人:
    Paul D. Robbins
  • 依托单位:
海外基金