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: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-05-01 至 2020-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9914531
• 关键词: Administrative Supplement; Aging; Automobile Driving; Autophagocytosis; CDKN2A gene; Cells; DNA Damage; DNA Repair; ERCC1 gene; FRAP1 gene; Funding; Goals; Homeostasis; Immune; Knock-out; Longevity; Measures; Metabolism; Mouse Strains; Mutant Strains Mice; Mutation; Program Research Project Grants; Reactive Oxygen Species; Repair Complex; Reporter; Resources; TP53 gene; Time; Tissues; Transgenic Mice; Work; biological adaptation to stress; catalase; healthspan; mouse model; response; senescence

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).

总体进展概述：在上一个资助期，我们发现细胞中的DNA损伤或 组织驱动代谢改变，NF- B、FOXO 3a和UPRmit的活化，活性氧增加 物种与衰老这清楚地表明了细胞自主机制响应内源性 DNA损伤。这项工作在很大程度上依赖于报告小鼠品系。此外，使用组织特异性突变体 在小鼠中，我们发现在某些但不是所有情况下，内源性DNA损伤增加的细胞或组织， 可导致组织稳态的丧失和其他未受损组织的老化。我们的初步工作表明 受损的免疫细胞是通过细胞非自主机制驱动衰老的最有力的因素。 相当大的努力和资源致力于开发这些独特的转基因小鼠，使我们能够 深入挖掘，发现在哪里，何时以及如何自发的时间依赖性的随机积累， 损伤导致老化。在上一个资助期间，我们开发了85种独特的转基因小鼠 其中DNA修复复合物ERCC 1-XPF被系统性地或组织特异性地+/-缺失或敲除 多种报告构建体，以测量衰老标志物、自噬或应激反应活化+/- 寿命/健康寿命关键调节因子的突变（例如，mTOR、过氧化氢酶、NRF 2、NF- B、ATM、p53、p21 Cip 1或 p16 Ink4a）。

项目成果

Clearing for Deep Tissue Imaging.

• DOI: 10.1002/cpcy.38
• 发表时间: 2018-10
• 期刊: Current protocols in cytometry
• 作者: Muntifering M;Castranova D;Gibson GA;Meyer E;Kofron M;Watson AM
• 通讯作者: Watson AM

Extracellular vesicles and aging.

• DOI: 10.21037/sci.2017.12.03
• 发表时间: 2017-01-01
• 期刊: Stem cell investigation
• 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

Inhibition of NF-κB improves the stress resistance and myogenic differentiation of MDSPCs isolated from naturally aged mice.

• 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

Dystrophin and utrophin "double knockout" dystrophic mice exhibit a spectrum of degenerative musculoskeletal abnormalities.

• DOI: 10.1002/jor.22236
• 发表时间: 2013-03
• 期刊: JOURNAL OF ORTHOPAEDIC RESEARCH
• 影响因子: 2.8
• 作者: Isaac, Christian;Wright, Adam;Usas, Arvydas;Li, Hongshuai;Tang, Ying;Mu, Xiaodong;Greco, Nicholas;Dong, Qing;Vo, Nam;Kang, James;Wang, Bing;Huard, Johnny
• 通讯作者: Huard, Johnny