Role of self-DNA and sterile inflammation driving age/progeria-related metabolic defects

自身 DNA 和无菌炎症驱动年龄/早衰相关代谢缺陷的作用

基本信息

  • 批准号:
    10688319
  • 负责人:
  • 金额:
    $ 31.04万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2022
  • 资助国家:
    美国
  • 起止时间:
    2022-09-30 至 2024-08-31
  • 项目状态:
    已结题

项目摘要

Abstract The goal of this project is to unravel mechanisms of metabolic dysfunction and tissue degeneration during aging through the Hutchinson Gilford Progeria Syndrome (HGPS) model. This devastating accelerated aging disease is caused by the production of a truncated lamin A protein “ progerin” that compromises nuclear architecture, genome function and stability, and mitochondrial function, eliciting cellular toxicity and early senescence. HGPS holds many similarities with normal aging, including alopecia, bone and joint defects, severe metabolic problems, and cardiovascular disease (CVD), which ultimately causes patients’ death in the second decade. Interestingly, progerin is also produced in advanced age individuals and in patients with cardiomyopathies. Understanding the molecular mechanisms driving metabolic dysfunction in HGPS will likely unravel some of the mysteries behind metabolic problems in normal aging. We recently reported that mice with the human HGPS mutation (LmnaG609G/G609G) succumb to metabolic dysfunction. Feeding a high-fat diet to these mice extends healthspan and lifespan, unleashing patient-like severe tissue degenerative phenotypes. In addition, cells from HGPS patients and mice, and from progerin- inducible cultured cells, exhibit traits of metabolic alterations typical of senescent cells, including mitochondrial dysfunction, AMPK activation, and increased glycolysis and autophagy. These metabolic changes are accompanied by nuclear and mitochondrial damage, accumulation of self-DNA in the cytoplasm (cytDNA), and activation of sterile inflammation pathways such as the DNA-sensing cGAS-STING pathway and the downstream STAT1-ISG (interferon stimulated gene) response. Importantly, our preliminary data show that reducing the activity of STING and STAT1 improves the metabolic phenotypes and the fitness of progerin-expressing cells. Given the emerging evidence linking sterile inflammation with metabolic dysfunction and CVD, our working model is that the metabolic phenotype of HGPS is the result of a maladaptive response to nuclear and mitochondrial DNA damage/leakage, which triggers a sustained and unresolved sterile inflammation/ISG response that impacts key metabolic pathways. We will test the hypotheses that cytDNA triggers metabolic alterations in progeria through the cGAS-STING pathway (Aim 1) and the STAT1:ISG15 response (Aim 2), promoting cell/tissue degeneration and organismal aging, and that targeting cytDNA sensing/signaling pathways has therapeutic benefits for HGPS (Aim 3). The danger of accumulating self-DNA in the cytoplasm during aging is not understood and this issue is becoming increasingly relevant to human health. We have gathered a team with complementary expertise that via advanced biochemical, physiological, and -omics methods, will test transformative ideas and define novel mechanisms linking sterile inflammation and metabolic defects in progeria/aging.
摘要 这个项目的目标是阐明衰老过程中代谢功能障碍和组织退化的机制 通过哈钦森吉尔福德早衰综合征(HGPS)模型。这种毁灭性的加速衰老疾病 是由一种截短的核纤层蛋白A蛋白“progerin”的产生引起的, 基因组功能和稳定性,以及线粒体功能,引起细胞毒性和早期衰老。HGPS 与正常衰老有许多相似之处,包括脱发,骨和关节缺陷,严重的代谢问题, 和心血管疾病(CVD),最终导致患者在第二个十年死亡。有趣的是, 早老蛋白也在高龄个体和心肌病患者中产生。了解 在HGPS中驱动代谢功能障碍的分子机制可能会解开一些背后的谜团。 正常衰老的代谢问题。 我们最近报道了携带人类HGPS突变(LmnaG 609 G/G609 G)的小鼠死于代谢性疾病, 功能障碍给这些小鼠喂食高脂肪饮食可以延长健康寿命和寿命,释放出患者般的症状 严重的组织退化表型。此外,来自HGPS患者和小鼠的细胞,以及来自progerin- 诱导培养的细胞,表现出衰老细胞典型的代谢改变的特征,包括线粒体 功能障碍、AMPK活化以及糖酵解和自噬增加。这些代谢变化是 伴有细胞核和线粒体损伤,细胞质中自身DNA的积累(cytDNA),以及 激活无菌炎症途径,如DNA敏感cGAS-STING途径和下游的 STAT 1-ISG(干扰素刺激基因)应答。重要的是,我们的初步数据表明,减少 STING和STAT 1的活性改善了代谢表型和表达早老蛋白的细胞的适应性。 考虑到无菌性炎症与代谢功能障碍和CVD之间的联系,我们的工作模型 HGPS的代谢表型是对细胞核和线粒体的适应不良反应的结果, DNA损伤/泄漏,引发持续和未解决的无菌炎症/ISG反应, 影响关键的代谢途径。我们将检验cytDNA触发代谢改变的假设, 通过cGAS-STING途径(Aim 1)和STAT 1:ISG 15反应(Aim 2),促进 细胞/组织退化和生物体老化,靶向细胞DNA传感/信号传导途径具有 HGPS的治疗益处(目标3)。衰老过程中细胞质中自身DNA积累的危险是 人们对这一问题还不了解,而这一问题与人类健康的关系正变得越来越密切。我们召集了一支队伍 通过先进的生物化学、生理学和组学方法, 变革性的想法,并定义新的机制连接无菌炎症和代谢缺陷, 早老症/衰老。

项目成果

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Angel Baldan其他文献

Angel Baldan的其他文献

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{{ truncateString('Angel Baldan', 18)}}的其他基金

Role of cytosolic DNA-induced sterile inflammation driving cellular and organismal progeria/aging hallmarks
细胞质 DNA 诱导的无菌炎症在驱动细胞和机体早衰/衰老标志中的作用
  • 批准号:
    10901042
  • 财政年份:
    2023
  • 资助金额:
    $ 31.04万
  • 项目类别:
The role of FSP27b on dietary lipid absorption, lipoprotein secretion, and oxidative metabolism
FSP27b 对膳食脂质吸收、脂蛋白分泌和氧化代谢的作用
  • 批准号:
    10337294
  • 财政年份:
    2020
  • 资助金额:
    $ 31.04万
  • 项目类别:
The role of FSP27b on dietary lipid absorption, lipoprotein secretion, and oxidative metabolism
FSP27b 对膳食脂质吸收、脂蛋白分泌和氧化代谢的作用
  • 批准号:
    10552559
  • 财政年份:
    2020
  • 资助金额:
    $ 31.04万
  • 项目类别:
Control of Sterol and Lipoprotein Homeostasis by miRNA
miRNA 对甾醇和脂蛋白稳态的控制
  • 批准号:
    8254375
  • 财政年份:
    2011
  • 资助金额:
    $ 31.04万
  • 项目类别:
Control of Sterol and Lipoprotein Homeostasis by miRNA
miRNA 对甾醇和脂蛋白稳态的控制
  • 批准号:
    8644305
  • 财政年份:
    2011
  • 资助金额:
    $ 31.04万
  • 项目类别:
Control of Sterol and Lipoprotein Homeostasis by miRNA
miRNA 对甾醇和脂蛋白稳态的控制
  • 批准号:
    8444487
  • 财政年份:
    2011
  • 资助金额:
    $ 31.04万
  • 项目类别:
Control of Sterol and Lipoprotein Homeostasis by miRNA
miRNA 对甾醇和脂蛋白稳态的控制
  • 批准号:
    8816115
  • 财政年份:
    2011
  • 资助金额:
    $ 31.04万
  • 项目类别:
Control Sterol and Lipoprotein Homeostasis by miRNA
通过 miRNA 控制甾醇和脂蛋白稳态
  • 批准号:
    9106554
  • 财政年份:
    2011
  • 资助金额:
    $ 31.04万
  • 项目类别:
Control of Sterol and Lipoprotein Homeostasis by miRNA
miRNA 对甾醇和脂蛋白稳态的控制
  • 批准号:
    8087156
  • 财政年份:
    2011
  • 资助金额:
    $ 31.04万
  • 项目类别:

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