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 该项目的目标是揭示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症（HGPS）模型这种毁灭性的加速衰老疾病。 是由截短的核纤层蛋白 A 蛋白“早老蛋白”的产生引起的，该蛋白会损害核结构， 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。 与正常衰老有许多相似之处，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），最终导致患者在第二个十年死亡。 高龄个体和心肌病患者也会产生早老素。 驱动 HGPS 代谢功能障碍的分子机制可能会解开背后的一些谜团 正常衰老过程中的代谢问题。 我们最近报道，携带人类 HGPS 突变 (LmnaG609G/G609G) 的小鼠死于代谢性 给这些小鼠喂食高脂肪饮食可以延长健康寿命和寿命，从而释放出病人般的能力。 此外，来自 HGPS 患者和小鼠以及早衰蛋白的细胞。 可诱导的培养细胞，表现出衰老细胞典型的代谢改变特征，包括线粒体 功能障碍、AMPK 激活以及糖酵解和自噬增加。 伴随着细胞核和线粒体损伤，细胞质中自身DNA（cytDNA）的积累，以及 激活无菌炎症途径，例如 DNA 感应 cGAS-STING 途径及其下游 重要的是，我们的初步数据表明，STAT1-ISG（干扰素刺激基因）反应会减少。 STING 和 STAT1 的活性可改善早老蛋白表达细胞的代谢表型和适应性。 鉴于新出现的证据表明无菌性炎症与代谢功能障碍和心血管疾病有关，我们的工作模型 HGPS 的代谢表型是对核和线粒体适应不良反应的结果 DNA 损伤/泄漏，引发持续且未解决的无菌炎症/ISG 反应， 我们将测试 cytDNA 触发代谢改变的假设。 通过 cGAS-STING 通路（目标 1）和 STAT1:ISG15 反应（目标 2）抑制早衰，促进 细胞/组织退化和生物衰老，以及针对细胞 DNA 传感/信号通路的研究 HGPS 的治疗益处（目标 3） 衰老过程中自身 DNA 在细胞质中积累的危险是。 不被理解，这个问题与人类健康越来越相关。 通过先进的生化、生理学和组学方法，互补的专业知识将测试 变革性的想法并定义了将无菌性炎症和代谢缺陷联系起来的新机制 早衰/衰老。