Mechanisms of myeloperoxidase and Nox4 interactions in abdominal aortic aneurysm

腹主动脉瘤中髓过氧化物酶和 Nox4 相互作用的机制

基本信息

批准号：
9924277
负责人：
Neal L Weintraub
金额：
$ 52.67万
依托单位：
AUGUSTA UNIVERSITY
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：
2018-05-01 至 2022-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9924277
关键词：
Abdominal Aortic Aneurysm Address Agonist Alleles Aneurysm Angiotensin II Animal Model Aorta Aortic Aneurysm Biological Assay Blood Vessels Calcium Chloride Cell Surface Receptors Cells Cessation of life Coupled Data Deterioration Development Disease Dopamine D2 Receptor Drug Targeting Enzymes Genetic Hematopoietic Heterozygote Human Hydrogen Peroxide In Vitro Inflammation Inflammatory Infusion procedures Knockout Mice Knowledge Leukocytes Link Lipids Lung Mass Spectrum Analysis Mediating Medical Morbidity - disease rate Mus Neutrophil Activation Neutrophil Infiltration Nicotinic Acids Output Oxidants Oxidative Stress Pathogenesis Patients Peroxidases Pharmaceutical Preparations Pharmacology Play Prostaglandin D2 Proteins Receptor Cell Risk Factors Role Rupture Ruptured Aortic Aneurysms Signal Transduction Site Smoking Smooth Muscle Myocytes Source Structure Testing Therapeutic Tissues Treatment Efficacy United States experimental study improved outcome in vivo inhibitor/antagonist macrophage monocyte mortality neutrophil novel overexpression prevent receptor recruit repaired therapy outcome uptake

项目摘要

PROJECT SUMMARY Abdominal aortic aneurysm (AAA) disease is a frequent cause of morbidity and mortality. Roughly 25,000 AAA repairs are performed each year, and AAAs account for over 13,000 deaths annually in the United States. The underlying mechanisms of AAA formation are unknown, which has hampered development of effective medical therapies. Here, we focus on the novel hypothesis that myeloperoxidase (MPO), a leukocyte enzyme expressed primarily in neutrophils (PMNs) that utilizes H2O2 to promote oxidative stress and inflammation, plays a key role in the pathogenesis of AAA. We provide novel preliminary data showing that MPO accrues in the aorta during AAA formation, and that genetic deletion of Nox4, a unique high-output enzymatic producer of H2O2 that is highly expressed in smooth muscle cells (SMCs), blocks MPO uptake and prevents AAA. We further propose that PMN activation/MPO accrual in AAA are regulated by prostaglandin D2 (PGD2) and nicotinic acid (GPR109A) receptors, and that “repurposing” available drugs that target these inflammatory cell receptors is an attractive therapeutic strategy in AAA. Our central hypothesis is that MPO cooperates with Nox4 to promote deleterious oxidative stress in AAA, which can be therapeutically modulated by targeting PGD2 receptors and GPR109A. Three aims are proposed to test our central hypothesis: in Aim1, we will test the hypothesis that Nox4 cooperates with MPO in the pathogenesis of AAA using genetically modified mice and a newly developed mass spectrometry assay that will enable us to determine whether aortic MPO uptake and activity are dependent upon Nox4 during AAA formation. We will also determine whether overexpression of human MPO in hematopoietic cells enhances AAA formation, and if so, whether it can be overcome by SMC Nox4 deletion. In Aim 2, we will test the hypothesis that PGD2 receptors promote PMN/MPO recruitment and MPO-mediated AAA formation using genetically modified mice in which one or both alleles of DP1 or DP2 have been deleted, coupled with and pharmacologic DP receptor agonists and antagonists. In Aim 3, we will test the hypothesis that GPR109A modulates PMN activation and MPO-mediated AAA formation using GPR109A knockout mice coupled with pharmacologic approaches. A particular emphasis of Aims 2 and 3 is to identify promising therapeutic strategies that are both feasible and effective for patients with AAA. This application addresses two significant gaps in the field: i) identifying fundamental mechanisms of AAA formation and ii) using this knowledge to advance medical treatment for patients with AAA.

项目概要腹主动脉瘤（AAA）疾病是发病和死亡的常见原因。每年大约进行 25,000 例 AAA 修复，AAA 导致 13,000 多人死亡在美国，AAA 形成的基本机制尚不清楚。阻碍了有效医学疗法的发展。在这里，我们关注一个新的假设：髓过氧化物酶 (MPO)，一种主要在中性粒细胞 (PMN) 中表达的白细胞酶，利用 H2O2 促进氧化应激和炎症，在 AAA 的发病机制中起着关键作用。提供新颖的初步数据表明 MPO 在 AAA 形成期间在主动脉中积累，并且 Nox4 的基因删除，Nox4 是一种独特的高输出 H2O2 酶生产者，在平滑肌细胞 (SMC) 阻断 MPO 摄取并预防 AAA。 AAA 中的激活/MPO 累积受前列腺素 D2 (PGD2) 和烟酸 (GPR109A) 调节受体，并且“重新利用”针对这些炎症细胞受体的现有药物是一种我们的中心假设是 MPO 与 Nox4 合作来治疗 AAA。促进 AAA 中有害的氧化应激，可以通过以下方法进行治疗调节：提出了三个目标来检验我们的中心假设：目的1，我们将使用以下方法检验Nox4与MPO在AAA发病机制中合作的假设转基因小鼠和新开发的质谱分析使我们能够确定主动脉 MPO 摄取和活性是否依赖于 AAA 形成过程中的 Nox4。我们还将确定造血细胞中人 MPO 的过度表达是否会增强 AAA 如果是的话，是否可以通过删除 SMC Nox4 来克服它。在目标 2 中，我们将测试该问题。 PGD2 受体促进 PMN/MPO 募集和 MPO 介导的 AAA 形成的假设使用 DP1 或 DP2 的一个或两个等位基因已被删除的转基因小鼠，偶联在目标 3 中，我们将检验该假设。 GPR109A 使用 GPR109A 敲除来调节 PMN 激活和 MPO 介导的 AAA 形成目标 2 和 3 的一个特别重点是确定小鼠与药理学方法的结合。对于 AAA 患者来说，可行且有效的有前途的治疗策略。应用程序解决了该领域的两个重大空白：i) 确定 AAA 的基本机制 ii) 利用这些知识推进 AAA 患者的医疗治疗。