ConProject-001

基本信息

批准号：
10204790
负责人：
Ashish Kumar Sharma
金额：
$ 58.39万
依托单位：
UNIVERSITY OF FLORIDA
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：
2018-07-09 至 2023-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10204790
关键词：
ATP Receptors ATP phosphohydrolase Abdomen Abdominal Aortic Aneurysm Adhesions Aneurysm Angiography Animals Aortic Aneurysm Aortic Rupture Aortitis Apolipoprotein E Apyrase Attenuated Autocrine Communication Balloon Angioplasty Biological Blood Platelets Bone Marrow Caliber Catabolism Cells Chronic Clinical Clinical Trials Coculture Techniques Collagen Data Elastases Elastin Elderly Emigrations Endothelial Cells Endothelium Enzymes Erythrocytes Exposure to Family suidae Future Gelatinase A Genetic Goals HMGB1 gene Human IL2 gene Immune In Vitro Infiltration Inflammasome Inflammation Inflammation Mediators Inflammatory Interleukin-1 beta Interleukin-17 Knock-out Knockout Mice Lead Leukocytes Macrophage Activation Measures Mediating Mediator of activation protein Medical Modality Modeling Molecular Mus Nucleotides P2X-receptor P2Y2 receptor Pathogenesis Patients Peptides Perfusion Pharmacology Phenotype Population Prevention Probenecid Production Purinoceptor Reporting Reproducibility Research Personnel Risk Role Rupture Signal Transduction Smooth Muscle Actin Staining Method Smooth Muscle Myocytes Source Sudden Death TNF gene Testing Therapeutic Thinness Tissue Inhibitor of Metalloproteinases Tissues Tunica Adventitia Ultrasonography Vascular Endothelial Cell Vascular remodeling base beta Globin clinically relevant cytokine ectoATPase efficacy evaluation experimental study extracellular high risk immune activation inhibitor/antagonist innovation insight knockout animal leukocyte activation macrophage migration mortality mouse model neutrophil new therapeutic target novel porcine model pre-clinical receptor reconstitution response therapeutic target therapeutically effective tissue injury trovafloxacin vascular inflammation

项目摘要

Project Summary Aortic aneurysms (AA) represent a significant clinical problem with a high risk of aortic rupture leading to sudden death. Currently, there are no medical therapies available to treat aneurysms and a clear understanding of the pathobiology of AA formation is key to develop therapeutic pharmacological approaches. Recent studies reveal that ATP can be released by cells in a controlled manner through pannexin 1 (Panx1) channels to signal through purinergic P2X or P2Y receptors. ATP is a nucleotide released in large amounts after tissue injury such as AA and serves as a “danger signal” to mediate inflammation. Our data suggest that Panx1 on endothelial cells (ECs) is an important mediator of vascular inflammation in a murine model of abdominal AA (AAA) and can be a major source of extracellular ATP. The expression of Panx1 is highest in the arterial network especially in the aortic endothelium. The scientific premise of this proposal focuses on the crosstalk between aortic endothelium, smooth muscle cells and relevant immune cells to delineate Panx1- mediated signaling in AAA progression. Thus, this proposal will test the overall hypothesis that EC Panx1 signaling is a major, early inflammatory mediator of the signaling cascade via release of ATP resulting in smooth muscle cell activation, leukocyte infiltration and vascular inflammation. Using novel inducible cell- specific genetic knockout animals, specific pharmacological Panx1 inhibitors and P2X/P2Y antagonists, we will delineate this previously unknown mechanism of AAA pathobiology. Aim 1 will determine if EC Panx1 signaling mediates AAA via ATP release and its crosstalk with aortic smooth muscle cells as well as to determine whether the P2X7 receptor is a major determinant of AAA. We will also investigate if Panx1 inhibition can treat preformed AAAs in the murine models. Aim 2 will determine if Panx1 signaling mediates leukocyte activation and infiltration during AAA. The role of Panx1 and specific purinergic receptors on macrophages will be deciphered as well as whether Panx1 mediates neutrophil transendothelial migration. Aim 3 will determine if pharmacologic inhibition of Panx1 or specific P2 receptors will treat AAA using a chronic inflammatory, large animal porcine AAA model. Our studies will provide novel insight into mechanisms of molecular signaling interactions between aortic endothelial cells, smooth muscle cells, and immune cells (macrophages and neutrophils), to define Panx1 as a novel therapeutic target for the treatment of AAs.

项目概要主动脉瘤（AA）是一个重大的临床问题，主动脉破裂的风险很高，导致目前，没有任何药物可以治疗动脉瘤，也没有明确的治疗方法。了解 AA 形成的病理生物学是开发治疗药理学方法的关键。最近的研究表明，细胞可以通过 pannexin 1 (Panx1) 以受控方式释放 ATP 通过嘌呤能 P2X 或 P2Y 受体发出信号的通道 ATP 是大量释放的核苷酸。 AA 等组织损伤后，可作为介导炎症的“危险信号”。内皮细胞 (EC) 上的 Panx1 是小鼠模型中血管炎症的重要介质 Panx1 的表达在腹部 AA (AAA) 中最高。动脉网络，特别是主动脉内皮该提议的科学前提集中在主动脉内皮、平滑肌细胞和相关免疫细胞之间的串扰来描绘 Panx1- 因此，该提案将检验 EC Panx1 的总体假设。信号传导是信号级联的主要早期炎症介质，通过释放 ATP 导致使用新型诱导细胞激活平滑肌细胞、白细胞浸润和血管炎症。特定的基因敲除动物、特定的药理Panx1抑制剂和P2X/P2Y拮抗剂，我们将描述这一先前未知的 AAA 病理学机制，目标 1 将确定 EC Panx1 是否有效。信号传导通过 ATP 释放及其与主动脉平滑肌细胞的串扰介导 AAA 确定 P2X7 受体是否是 AAA 的主要决定因素我们还将研究 Panx1 是否是 AAA 的主要决定因素。抑制可以治疗小鼠模型中已形成的 AAA，目标 2 将确定 Panx1 信号传导是否介导。 Panx1 和特定嘌呤受体对 AAA 期间白细胞活化和浸润的作用。将破译巨噬细胞以及 Panx1 是否介导中性粒细胞跨内皮迁移。目标 3 将确定 Panx1 或特定 P2 受体的药物抑制是否可以使用慢性药物治疗 AAA 我们的研究将为大型动物 AAA 炎症机制提供新的见解。主动脉内皮细胞、平滑肌细胞和免疫细胞之间的分子信号相互作用（巨噬细胞和中性粒细胞），将 Panx1 定义为治疗 AA 的新治疗靶点。