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调节血栓形成事件中的作用 摘要： 70%的中年(老年)成年人已经被诊断出至少患有一种慢性病 条件。因此，55岁以上的成年人静脉血栓形成/血栓栓塞症(VT/E)的发病率高达7倍 与更年轻的同龄人相比，年龄更大。VT/E每年影响100多万美国人。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，确定易感的药物靶向致病机制至关重要。 老年人罹患慢性病以降低这些风险。氧化应激是高血压的标志之一 衰老，是VT/E的关键因素。在衰老方面，研究广泛地集中在氧化 在血管系统中，氧化应激在易患VT/E的红细胞中的作用被忽视。 我们现在为红细胞固有的一种独特的激活致病机制提供初步证据。 这可能会在老年人中启动血栓前通路。来自老年人(58-68岁)的红细胞显示 过量的ROS在体外介导粘连和血栓形成过程 与年轻人(21-30岁)的红细胞相比。增加的RBC RO是由 NADPH氧化酶(NOxs)，并参与RBC GRK2的活化。这表明，衰老是不利的。 通过GRK2/NOx/ROS修饰RBC黏附和血栓前状态。我们还发现， Rpl13a基因座的非编码核仁小RNA(SnoRNAs)调节RBC ROS介导 体内老龄小鼠模型血栓的形成。我们推测RBC GRK2/NOx/ROS通路 老年人激活红细胞黏附和血栓前表型，从而导致静脉血栓形成(VT) 可能发生在老龄化的人口中。我们进一步假设ROS途径是由RBC调节的 Rpl13a snoRNAs，抑制这一途径可以减少粘连和促凝过程。 为了检验我们的假设，我们建议使用年龄较大(55-65岁)和较年轻(21-65岁)的血液样本。 30岁)成人和相当于人类年龄的老龄小鼠模型，并确定：SA1) RBC GRK2/NOx参与VT发生的分子和细胞基础， 从药物和基因上靶向GRK2/NOx将减少RBC黏附和 Rpl13a snoRNAs调节RBC ROS途径及其下游的血栓形成潜能 衰老中的事件；以及SA3)转录水平失调引发的RBC ROS水平 衰老过程中的促凝血途径。我们的研究将为RBC的确切机制提供新的见解 有助于衰老中的血栓前途径，并可能识别新的靶向RBC异常 预防血栓前级联激活，从而为更合理的治疗奠定基础 更好地降低患有过氧化应激的中年成年人VT/E风险的策略。