Common Post-Infectious Premature Epigenetic Aging

常见的感染后表观遗传过早衰老

• 批准号: 10734590
• 负责人: Andrew R DiNardo
• 金额: $ 62.63万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-15 至 2028-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10734590
• 关键词: Acceleration; Age; Aging; Animal Model; Animals; Bacterial Pneumonia; Benchmarking; Bioinformatics; COVID-19; Cardiovascular Diseases; Cell Aging; Cells; Cessation of life; Cicatrix; Citric Acid Cycle; Clinical; DNA; DNA Methylation; Data; Enzymes; Epigenetic Process; Exclusion; Genome; Glean; Human; Hypermethylation; Immune; Immunity; In Vitro; Individual; Infection; Inflammation; Malignant Neoplasms; Metformin; Modeling; Outcome; Participant; Pathologic; Patients; Pharmaceutical Preparations; Pneumonia; Population; Premature aging syndrome; Recovery; Resolution; Risk; SDZ RAD; Sepsis; Severity of illness; Succinates; Survivors; T-Lymphocyte; Testing; Tricarboxylic Acids; United States; Viral Pneumonia; Work; alpha ketoglutarate; clinically relevant; cofactor; epigenome; epigenomics; exhaust; experimental study; follow-up; immune function; improved; in vivo; inhibitor; mortality; mortality risk; mouse model; mycobacterial; patient retention; practical application; premature; preservation; prevent; progenitor; recurrent infection; single cell sequencing; stem cells; transcriptome sequencing

Project Summary: Last year in the United States, there were 1.3 million cases of pneumonia (excluding covid19). Worldwide, last year, there were 49 million cases respectively. Even after successful therapy, pneumonia and other severe infections are associated with >3-fold increased mortality risk due to increased cardiovascular disease, cancer, and recurrent infections. Preliminary evidence by our group and others have demonstrated that these severe infections induce detrimental premature epigenetic scars that accelerate age-associated epigenetic perturbations and induce pathologic inflammation and decrease immune responsiveness. While other studies have identified post-infectious premature aging, this study will be the first to identify which post-infectious premature aging epigenetic scars are associated with post-infectious mortality, inflammation and decreased immune responsiveness. We previously identified that post-infectious detrimental epigenetic scars last at least 6 months. Studies with longer-term follow up have confirmed these epigenetic scars are still present 82 weeks after resolution of the original insult. Therefore, we will follow participants with severe pneumonia for 24-months after completion of successful therapy and make use of cutting-edge single cell sequencing to clarify how these detrimental scars are persistently propagated. Our preliminary in vitro data demonstrates that infection induced premature epigenetic aging and immune perturbations can be mitigated by drugs that inhibit the TCA cycle such as metformin, everolimus, and metformin. This study will implement mechanistic studies to explore how inhibitors of the TCA can be used to alleviate post-infectious premature epigenetic scars and restore immune responsiveness.

项目概要： 去年美国有130万例肺炎病例（不包括 新冠肺炎）。去年全球范围内分别有 4900 万例病例。即使成功后 治疗、肺炎和其他严重感染与死亡率增加 3 倍以上相关 心血管疾病、癌症和反复感染的风险增加。 我们小组和其他人的初步证据表明，这些严重的 感染会导致有害的过早表观遗传疤痕，从而加速与年龄相关的 表观遗传扰动并诱发病理性炎症并降低免疫力 反应能力。虽然其他研究已经确定了感染后过早衰老，但这项研究 将是第一个确定与哪些感染后过早衰老表观遗传疤痕相关的人 感染后死亡率、炎症和免疫反应能力下降。 我们之前发现，感染后有害的表观遗传疤痕至少持续 6 几个月。长期随访研究证实这些表观遗传疤痕仍然存在 最初的侮辱解决后 82 周出现。因此，我们将跟踪参与者 完成成功治疗后 24 个月的严重肺炎并使用 尖端单细胞测序可阐明这些有害疤痕是如何持续存在的 传播。 我们的初步体外数据表明，感染诱导过早表观遗传 衰老和免疫紊乱可以通过抑制 TCA 循环的药物来缓解，例如 二甲双胍、依维莫司和二甲双胍。本研究将进行机理研究来探索 如何使用 TCA 抑制剂来缓解感染后过早表观遗传疤痕 并恢复免疫反应能力。