Purinergic modulation of the autoimmune vascular phenotype

自身免疫血管表型的嘌呤能调节

• 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
• 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

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.

项目摘要/摘要 这项提议的“自身免疫性血管表型的嘌呤能调节”建立在4年的基础上 早期研究者在狼疮，COVID-19和抗磷脂综合征的领域发现 （APS）。尽管在后来的疾病中常规使用传统抗凝剂，但仍有1例APS患者仍在 预计会经历突破性的血栓性事件。此外，抗凝剂对减轻 随着时间的流逝，慢性闭塞微型疾病会损害APS器官。如何对抗抗凝剂 - AP的抗性表现未知。该项目现在努力使用深度型患者 队列，选择的体外系统以及最相关的动物模型，以识别调整治疗 APS诊所的方法。它的成功完成将为中性粒细胞表型提供额外的启示 APS并将提供对嘌呤能信号传导，中性粒细胞相互作用的作用的新理解， 中性粒细胞代谢在血小板事件中发挥作用。目的是，到本赠款的下一个周期，我们将 已经确定了在我们的APS诊所重新利用的1-2个最有前途的候选药物。 APS是血栓形成和晚期妊娠丧失的主要获得原因。追求机械 了解AP中的免疫骨骼，我们的小组是第一个表明中性粒细胞外陷阱的人 （通过“ Netosis”从活化的中性粒细胞中排出的染色质和染色质和微生物蛋白的网状缠结）为 与AP相关的血栓形成所必需的。自上次竞争提交以来，我们发现 Etonucleotidase CD73产生的细胞外腺苷通过激活表面限制了净释放 腺苷A2A接收器（A2AR），从而增加细胞内营地。关键的初步数据，告知此 更新证明了（i）CD73-A2AR轴对血小板介导的中性粒细胞激活的约束； （ii） 髓样谱系特异性A2AR敲除小鼠的夸大血栓形成； （iii）多动葡萄糖代谢 在与A2AR激动剂归一化的AP中性粒细胞中； （iv）通过 以代谢为重点的干预措施。假设是对CD73-A2AR锻炼轴的操作将 恢复AP中的中性粒细胞稳态。特定的目标1将定义嘌呤能信号传导的机制 影响AP中的中性粒细胞和血小板功能。这个目标将首次定义 血栓形成障碍的景观，阐明嘌呤能信号传导调节的机制 中性粒细胞 - 血小板通信，并有可能识别最有可能受益于APS患者的子集 抗血小板和/或腺苷受体调节疗法。具体目标2将确定多大程度 可以利用嘌呤能信号传导以使AP中的中性粒细胞代谢正常化。期望这个目标 对Netosis的代谢要求提供新的了解，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患者的子集。