Purinergic modulation of the autoimmune vascular phenotype

自身免疫血管表型的嘌呤能调节

基本信息

批准号：
10581346
负责人：
Jason Knight
金额：
$ 36.12万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-01-01 至 2027-12-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10581346
关键词：
ADORA2A gene Adenosine Adjuvant Agonist Animal Model Anti-Inflammatory Agents Antibodies Anticoagulants Anticoagulation Antiphospholipid Antibodies Antiphospholipid Syndrome Area Autoimmune Bioenergetics Blood Platelets Blood Vessels Blood coagulation COVID-19 Cell Respiration Cell Surface Receptors Cells Chromatin Chronic Clinic Clinical Coagulation Process Communication Cyclic AMP Cyclic AMP Receptors Cyclic AMP-Dependent Protein Kinases Data Deterioration Disease Enzymes Event Functional disorder Glucose Glycogen Goals Grant Homeostasis Hyperactivity Immune In Vitro Inflammation Intervention Knockout Mice Lupus Mass Spectrum Analysis Measurement Mediating Metabolic Metabolism Modeling Mus Myelogenous Neurofibrillary Tangles Neutrophil Activation Organ Patients Pentosephosphate Pathway Phenotype Phosphorylation Play Pregnancy loss Proteins Purine Nucleotides Purinergic P1 Receptors Research Personnel Resistance Role Signal Transduction Surface System Therapeutic Thrombosis Time Work blood damage cohort combat coronavirus disease dietary dietary manipulation disease phenotype drug candidate ecto-nucleotidase experience experimental study extracellular glucose metabolism immunothrombosis microbicide neutrophil platelet function protective pathway receptor restraint thrombotic

项目摘要

PROJECT SUMMARY/ABSTRACT This proposed renewal of “Purinergic modulation of the autoimmune vascular phenotype” builds upon 4 years of discovery by an early stage investigator in the areas of lupus, COVID-19, and antiphospholipid syndrome (APS). Despite the routine use of traditional anticoagulants in the latter disease, 1 in 5 APS patients is still expected to experience a breakthrough thrombotic event. Furthermore, anticoagulants do little to mitigate the chronic occlusive microangiopathy that damages APS organs over time. How to combat anticoagulant- resistant manifestations of APS is unknown. This project now endeavors to use a deeply-phenotyped patient cohort, selected in vitro systems, and the most relevant animal models to identify adjuvant therapeutic approaches for the APS clinic. Its successful completion will shed additional light on neutrophil phenotypes in APS and will provide a new understanding of the role that purinergic signaling, neutrophil-platelet interactions, and neutrophil metabolism play in thrombotic events. The goal is that by the next cycle of this grant, we will have identified the 1-2 most promising drug candidates for repurposing in our APS clinic. APS is a leading acquired cause of both thrombosis and late-term pregnancy loss. In pursuit of a mechanistic understanding of immunothrombosis in APS, our group was the first to show that neutrophil extracellular traps (NETs, tangles of chromatin and microbicidal proteins expelled from activated neutrophils via “NETosis”) are required for APS-associated thrombosis. Since our last competitive submission, we have found that extracellular adenosine generated by the ectonucleotidase CD73 restrains NET release by activating surface adenosine A2A receptors (A2AR) and thereby boosting intracellular cAMP. Key preliminary data that inform this renewal demonstrate (i) restraint of platelet-mediated neutrophil activation by the CD73-A2AR axis; (ii) exaggerated thrombosis in myeloid lineage-specific A2AR knockout mice; (iii) hyperactive glucose metabolism in APS neutrophils that normalizes with A2AR agonists; and (iv) mitigation of thrombosis in APS mice by metabolism-focused interventions. The hypothesis is that manipulation of the CD73-A2AR-cAMP axis will restore neutrophil homeostasis in APS. Specific Aim 1 will define mechanisms by which purinergic signaling influences neutrophil and platelet function in APS. This Aim will define for the first time the purinergic landscape of a thrombophilic disorder, elucidate mechanisms by which purinergic signaling regulates neutrophil-platelet communication, and potentially identify the subset of APS patients most likely to benefit from antiplatelet and/or adenosine receptor-modulating therapies. Specific Aim 2 will determine the extent to which purinergic signaling can be leveraged to normalize neutrophil metabolism in APS. This Aim is expected to provide a new understanding of the metabolic requirements of NETosis, elucidate strategies for manipulating neutrophil metabolism, and identify the subset of APS patients most likely to benefit from those strategies.

项目概要/摘要这项“自身免疫血管表型的嘌呤能调节”的更新是在 4 年的基础上提出的狼疮、COVID-19 和抗磷脂综合征领域早期研究人员的发现 (APS) 尽管在该疾病中常规使用传统抗凝剂，但五分之一的 APS 后者患者仍然患有这种疾病。此外，抗凝剂对缓解血栓事件几乎没有作用。随着时间的推移会损害 APS 器官的慢性闭塞性微血管病如何对抗抗凝剂。 APS 的耐药表现尚不清楚，该项目现在致力于使用深度表型的患者。队列、选定的体外系统和最相关的动物模型来确定辅助治疗 APS 诊所的成功完成将为中性粒细胞表型提供更多线索。 APS 将为嘌呤能信号传导、中性粒细胞-血小板相互作用、和中性粒细胞代谢在血栓事件中的作用，我们的目标是在下一个资助周期中，我们将实现这一目标。已确定 1-2 种最有希望在我们的 APS 诊所重新利用的候选药物。 APS 是血栓形成和晚期妊娠流产的主要原因。为了了解 APS 中的免疫血栓形成，我们小组首先证明了中性粒细胞胞外陷阱（NET，通过“NETosis”从激活的中性粒细胞中排出的染色质缠结和杀菌蛋白）自从我们上次竞争性提交以来，我们发现 APS 相关血栓形成所需的。核酸外切酶 CD73 产生的细胞外腺苷通过激活表面抑制 NET 释放腺苷 A2A 受体 (A2AR) 并由此增强细胞内 cAMP 的关键初步数据。更新证明 (i) CD73-A2AR 轴抑制血小板介导的中性粒细胞激活；骨髓谱系特异性 A2AR 敲除小鼠中血栓形成过度；(iii) 葡萄糖代谢亢进； APS 中性粒细胞通过 A2AR 激动剂恢复正常；以及 (iv) 通过以下方式减轻 APS 小鼠的血栓形成：假设以代谢为重点的干预措施会影响 CD73-A2AR-cAMP 轴。恢复 APS 中的中性粒细胞稳态。具体目标 1 将定义嘌呤能信号传导的机制。影响 APS 中的中性粒细胞和血小板功能。该目标将首次定义嘌呤能。血栓形成性疾病的景观，阐明嘌呤能信号调节的机制中性粒细胞-血小板通讯，并可能确定最有可能从中受益的 APS 患者亚群抗血小板和/或腺苷受体调节疗法将决定具体目标2。嘌呤能信号传导可用于使 APS 中的中性粒细胞代谢正常化。提供对 NETosis 代谢要求的新认识，阐明操纵策略中性粒细胞代谢，并确定最有可能从这些策略中受益的 APS 患者子集。