The Role of RBC Reactive Oxygen Species in Regulating Thrombotic Events During Aging

红细胞活性氧在调节衰老过程中血栓事件中的作用

• 批准号: 10293939
• 负责人: Rahima Zennadi
• 金额: $ 44.36万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-15 至 2026-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10293939
• 关键词: ADRBK1 gene; Adhesives; Adult; Advanced Development; Affect; Age; Age-Years; Aging; American; Blood specimen; Cardiovascular system; Cell Adhesion; Cessation of life; Chemicals; Chronic; Chronic Disease; Coagulation Process; Data; Development; Diagnosis; Drug Targeting; Elderly; Erythrocytes; Erythroid; Event; Foundations; G-Protein-Coupled Receptors; Genetic; Genetic Translation; Goals; Healthcare; Human; Hydrogen Peroxide; In Vitro; Incidence; Knockout Mice; Life Expectancy; Light; Mediating; Messenger RNA; Methylation; Molecular; Mus; NADPH Oxidase; Oxidation-Reduction; Oxidative Stress; Pathogenicity; Pathway interactions; Patients; Peroxidases; Pharmacology; Phenotype; Population; Process; Production; Proteins; RNA; Reactive Oxygen Species; Risk; Risk Factors; Role; Sampling; Signal Transduction; Small Nucleolar RNA; Source; Testing; Therapeutic; Thromboembolism; Thrombosis; Thrombus; Time; Untranslated RNA; Venous Thrombosis; aged; aging population; base; cohort; effective therapy; erythroid differentiation; genomic locus; heme a; high risk; human old age (65+); in vivo; in vivo Model; insight; mRNA Expression; middle age; mouse model; neglect; novel; peroxidasin; prevent; progenitor; targeted treatment; thrombotic; transcriptomics; young adult

The Role of RBC Reactive Oxygen Species in Regulating Thrombotic Events During Aging Abstract: Seventy percent of mid-life stage (older) adults have already been diagnosed with at least one chronic condition. As such, venous thrombosis/thromboembolism (VT/E) is up to 7 times higher in adults over 55 years old, compared to a younger cohort. VT/E affect over one million Americans per year. In light of an increasing life expectancy, development of chronic diseases will become a greater health care issue. Despite this, the key risk factors contributing to increased risks for developing chronic diseases in older adults remain unclear. Thus, it is critical to identify drug-targetable causative mechanisms predisposing older adults to develop chronic diseases to reduce these risks. Oxidative stress is one of the hallmarks of aging, and a critical contributor to VT/E. In aging, while studies have extensively focused on oxidative stress in the vasculature, the role of oxidative stress in RBCs predisposing to VT/E has been neglected. We now provide preliminary evidence for a unique activated pathogenic mechanism intrinsic to RBCs that can initiate prothrombotic pathways in older adults. RBCs from older (58-68 years old) adults show excessive reactive oxygen species (ROS) mediating adhesive and prothrombotic processes in vitro compared to RBCs from younger (21-30 years old) adults. Increased RBC ROS were generated by NADPH oxidases (Noxs), and involved RBC GRK2 activation. This suggests that aging adversely modifies RBC adhesive and prothrombotic potentials through GRK2/Nox/ROS . We also discovered that small non-coding nucleolar RNAs (snoRNAs) from the Rpl13a gene locus regulate RBC ROS-mediated thrombus formation in aged mouse models in vivo. We hypothesize that RBC GRK2/Nox/ROS pathway in older adults activates RBC adhesive and prothrombotic phenotypes, by which venous thrombosis (VT) may occur in the aging population. We further hypothesize that this ROS pathway is regulated by RBC Rpl13a snoRNAs, and that inhibition of this pathway can reduce adhesive and procoagulant processes. To test our hypotheses, we propose to use blood samples from older (55-65 years old) and younger (21- 30 years old) adults, and aged mouse models with the equivalent of human ages, and determine: SA1) that RBC GRK2/Nox are involved in the molecular and cellular bases by which VT may occur in aging, and that targeting GRK2/Nox pharmacologically and genetically will reduce RBC adhesive and prothrombotic potentials; SA2) that Rpl13a snoRNAs regulate RBC ROS pathway and downstream events in aging; and SA3) the transcriptomic changes dysregulating RBC ROS levels triggering procoagulant pathway in aging. Our studies will provide novel insights into the exact RBC mechanisms contributing to prothrombotic pathway in aging, and may identify novel targetable RBC anomalies to prevent prothrombotic cascade activation, thus laying the foundation for more rational therapeutic strategies that better reduce the risks for VT/E in mid-life stage adults with exaggerated oxidative stress.

红细胞活性氧在调节衰老过程中血栓事件中的作用 抽象的： 百分之七十的中年（老年）成年人已被诊断患有至少一种慢性病 健康）状况。因此，55 岁以上成年人的静脉血栓形成/血栓栓塞 (VT/E) 最高可达 7 倍 岁，与年轻群体相比。 VT/E 每年影响超过一百万美国人。鉴于 预期寿命的增加、慢性病的发展将成为更大的医疗保健问题。 尽管如此，导致老年人患慢性病风险增加的关键风险因素 成年人仍不清楚。因此，确定药物靶向的诱发机制至关重要 老年人患慢性病以减少这些风险。氧化应激是氧化应激的标志之一 老化，也是 VT/E 的关键因素。在衰老过程中，虽然研究广泛关注氧化 由于血管系统应激，红细胞氧化应激在诱发 VT/E 中的作用一直被忽视。 我们现在为红细胞固有的独特激活致病机制提供初步证据 可以启动老年人的血栓形成途径。老年人（58-68 岁）的红细胞显示 过量的活性氧（ROS）介导体外粘附和血栓形成过程 与年轻（21-30 岁）成年人的红细胞相比。红细胞 ROS 增加的原因是 NADPH 氧化酶 (Noxs)，并参与红细胞 GRK2 激活。这表明衰老对 通过 GRK2/Nox/ROS 改变红细胞粘附和促血栓电位。我们还发现 来自 Rpl13a 基因座的小非编码核仁 RNA (snoRNA) 调节红细胞 ROS 介导 老年小鼠模型体内血栓形成。我们假设 RBC GRK2/Nox/ROS 通路 老年人激活红细胞粘附和促血栓表型，从而导致静脉血栓 (VT) 可能会发生在人口老龄化时期。我们进一步假设该 ROS 途径受 RBC 调节 Rpl13a snoRNA，抑制该途径可以减少粘附和促凝血过程。 为了检验我们的假设，我们建议使用老年人（55-65 岁）和年轻人（21-65 岁）的血液样本。 30岁）成人，与人类年龄相当的老年小鼠模型，并测定：SA1） RBC GRK2/Nox 参与衰老过程中发生 VT 的分子和细胞基础， 药理学和基因靶向 GRK2/Nox 将减少红细胞粘附和 促血栓形成潜力； SA2) Rpl13a snoRNA 调节红细胞 ROS 通路及其下游 衰老事件；和 SA3) 转录组变化导致红细胞 ROS 水平失调 衰老过程中的促凝血途径。我们的研究将为红细胞的确切机制提供新的见解 有助于衰老过程中的血栓形成途径，并可能识别新的可靶向红细胞异常 防止血栓前级联激活，从而为更合理的治疗奠定基础 更好地降低氧化应激过度的中年成年人发生 VT/E 风险的策略。