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

• 批准号: 10688319
• 负责人: Angel Baldan
• 金额: $ 31.04万
• 依托单位: SAINT LOUIS UNIVERSITY
• 依托单位国家: 美国
• 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
• 来源: https://reporter.nih.gov/project-details/10688319
• 关键词: Age; Aging; Alopecia; Architecture; Automobile Driving; Autophagocytosis; Biochemical; Cardiomyopathies; Cardiovascular Diseases; Cause of Death; Cell Aging; Cells; Cessation of life; Complex; Cultured Cells; Cytoplasm; DNA; DNA Damage; Data; Defect; Disease; Elderly; Enzymes; Exhibits; Extravasation; FRAP1 gene; Gene Expression; Genes; Genetic; Genome; Genome Stability; Glycolysis; Goals; Health; High Fat Diet; Human; ISG15 gene; Individual; Inflammation; Interferons; Joints; Lamin Type A; Link; Lipodystrophy; Longevity; Metabolic; Metabolic Diseases; Metabolic Pathway; Metabolic dysfunction; Metabolism; Methods; Mitochondria; Mitochondrial DNA; Modeling; Molecular; Mus; Mutation; Normal Cell; Nuclear; Nucleic Acids; Pathology; Pathway interactions; Patients; Pharmacology; Phenotype; Physiological; Production; Progeria; Proteins; Reporting; Role; STAT1 gene; Scheme; Signal Pathway; Signal Transduction; Starvation; Sterility; Stimulator of Interferon Genes; Syndrome; Testing; Therapeutic; Three Prime Repair Exonuclease 1; Tissues; Toxic effect; Up-Regulation; age related; bone; fatty acid oxidation; feeding; fitness; healthspan; improved; in vivo; insight; mTOR inhibition; metabolic phenotype; mitochondrial dysfunction; normal aging; novel; replication stress; response; senescence; therapeutic target; tissue degeneration; trait

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.

抽象的 该项目的目的是阐明衰老期间代谢功能障碍和组织变性的机制 通过Hutchinson Gilford Progeria综合征（HGPS）模型。这种毁灭性的加速衰老疾病 是由于损害核蛋白的蛋白质“孕激素”的产生，损害了核结构的蛋白质“早期” 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感应。 HGP 与正常衰老相似，包括脱发，骨骼和关节缺陷，严重的代谢问题， 和心血管疾病（CVD），最终导致第二个十年中患者的死亡。有趣的是， 早期患者和心肌病患者还会产生过程。了解 HGP中驱动代谢功能障碍的分子机制可能会揭示背后的某些奥秘 正常衰老的代谢问题。 我们最近报道了人类HGP突变（LMNAG609G/G609G）的小鼠屈服于代谢 功能障碍。向这些小鼠喂养高脂饮食会延长健康状态和寿命，从而释放患者样 严重的组织退化表型。此外，来自HGPS患者和小鼠的细胞以及促进蛋白的细胞 可诱导的培养细胞，表现出典型的感觉细胞的代谢改变的特征，包括线粒体 功能障碍，AMPK激活以及糖酵解和自噬的增加。这些代谢变化是 伴随着核和线粒体损伤，在细胞质（cytDNA）中的自动-DNA积累和 无菌注入途径的激活，例如DNA感应CGAS刺激途径和下游 STAT1-ISG（干扰素刺激基因）反应。重要的是，我们的初步数据表明，减少了 STING和STAT1的活性改善了代谢表型和表达孕激素的细胞的适应性。 考虑到将无菌注射与代谢功能障碍和CVD联系起来的新兴证据，我们的工作模型 是HGP的代谢表型是对核和线粒体的不良反应的结果 DNA损伤/泄漏，触发持续且未解决的无菌注入/ISG响应 影响关键的代谢途径。我们将测试cytdna触发代谢改变的假设 通过CGAS丁字道途径（AIM 1）和STAT1：ISG15响应（AIM 2），启动子， 细胞/组织变性和有机老化，并且靶向cytdna感应/信号通路具有 HGP的治疗益处（AIM 3）。在衰老期间积累自动-DNA的危险是 不理解，这个问题正变得越来越与人类健康相关。我们聚集了一个团队 完全专业的知识，通过先进的生化，生理和-OMICS方法，将测试 变革性思想并定义了连接无菌注入和代谢缺陷的新型机制 促进/老化。