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).

进度的总体摘要：在上一个资金期间，我们发现细胞中的DNA损害或 组织驱动新陈代谢改变，NF-B，FOXO3A和UPRMIT的激活，反应性氧气增加 物种和衰老。这清楚地表明了响应内源性的细胞自主机制 DNA损伤。这项工作很大程度上取决于记者的小鼠菌株。另外，使用组织特异性突变体 小鼠，我们发现内源性DNA损伤增加但并非所有情况，细胞或组织 可以驱动组织稳态的损失和其他未损害的组织中的衰老。我们的初步工作表明 受损的免疫细胞通过细胞通过非自主机制驱动衰老最有效。 巨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 向下钻并发现随机时间的自发时间依赖性积累 损害驱动衰老。在上一个资金期间，我们开发了85种独特的转基因小鼠菌株 其中DNA修复复合物ERCC1-XPF被全身或组织特定地耗尽或敲除+/- 多种记者构造，用于测量衰老标记，自噬或应力反应激活+/- 寿命/健康范围关键调节剂的突变（例如MTOR，CETALASE，NRF2，NF-B，ATM，ATM，P53，P21CIP1或 p16ink4a）。

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

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

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