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.

红细胞活性氧在衰老过程中对血栓形成的调节作用 摘要： 70%的中年（老年）成年人已经被诊断出患有至少一种慢性疾病。 条件因此，静脉血栓形成/血栓栓塞（VT/E）在55岁以上的成年人中高达7倍 与年轻人相比，VT/E每年影响超过一百万美国人。根据一项 随着预期寿命的增加，慢性病的发展将成为一个更大的卫生保健问题。 尽管如此，导致老年人患慢性病风险增加的主要风险因素 成年人还不清楚。因此，确定药物靶向致病机制至关重要， 老年人发展慢性疾病，以减少这些风险。氧化应激是 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 由于血管系统中的应激，氧化应激在诱发VT/E的RBC中的作用被忽视。 我们现在提供了一个独特的激活致病机制内在的红细胞的初步证据 可以启动老年人的血栓前通路。来自老年人（58-68岁）的RBC显示 过量活性氧（ROS）介导体外粘附和血栓形成过程 与年轻人（21-30岁）的RBC相比。增加的RBC ROS产生于 NADPH氧化酶（Noxs），并参与红细胞GRK 2活化。这表明，衰老 通过GRK 2/Nox/ROS改变RBC粘附和促血栓形成的潜力。我们还发现 来自Rpl 13 a基因座的小的非编码核仁RNA（snoRNA）调节RBC ROS介导的 体内老年小鼠模型中的血栓形成。我们假设红细胞GRK 2/Nox/ROS通路 在老年人中激活RBC粘附和血栓形成前表型， 可能发生在老年人身上。我们进一步假设，这种ROS途径是由红细胞调节的。 Rpl 13 a snoRNA，并且该途径的抑制可以减少粘附和促凝血过程。 为了验证我们的假设，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）成年人和与人年龄相当的老年小鼠模型，并确定： RBC GRK 2/Nox参与了VT可能在衰老中发生的分子和细胞基础， 并且靶向GRK 2/Nox激酶和基因将减少RBC粘附， 促血栓形成潜力; SA 2）Rpl 13 a snoRNA调节RBC ROS途径和下游 SA 3）转录组学变化使RBC ROS水平失调， 促凝血途径在衰老中的作用我们的研究将为RBC的确切机制提供新的见解 有助于促血栓通路老化，并可能确定新的靶向红细胞异常， 阻止血栓前级联激活，从而为更合理的治疗奠定基础 更好地降低中年阶段氧化应激过度成年人VT/E风险的策略。