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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

基本信息

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
项目类别：
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

项目摘要

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形成事件中的作用