Leukadherins as novel compounds for treating restenosis

白粘附素作为治疗再狭窄的新型化合物

基本信息

批准号：
8499414
负责人：
VINEET GUPTA
金额：
$ 36.41万
依托单位：
UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-07-01 至 2016-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8499414
关键词：
Ablation Accounting Adhesions Affinity Agonist Alternative Therapies Animals Anti-Inflammatory Agents Anti-inflammatory Antibodies Arteries Balloon Angioplasty Blocking Antibodies Blood Platelets Blood Vessels Carotid Stenosis Catheters Cell Adhesion Cell Proliferation Cells Cellular Structures Cessation of life Chronic Clinical Trials Complication Coronary Coronary Restenosis Coronary artery Data Dialysis procedure Disease Endothelial Cells Endothelium Expenditure Extracellular Matrix Family suidae Freezing Functional disorder Future Genetic Growth Healed Human Hyperplasia ITGAM gene ITGB2 gene Incidence Infiltration Inflammation Inflammatory Inflammatory Response Injury Integrins Intervention Lead Leukocytes Macrophage-1 Antigen Mediating Medical Modeling Molecular Molecular Conformation Morbidity - disease rate Oryctolagus cuniculus Outcome Phosphotransferases Play Prevention Property Proto-Oncogene Proteins c-akt Publishing Rattus Recovery Recruitment Activity Reporting Role Secondary to Severities Side Smooth Muscle Stem cells Stents Surface Testing Therapeutic Therapeutic Agents allograft rejection base cell growth clinically relevant cytokine healing in vivo injured innovation intercellular cell adhesion molecule leukocyte activation migration monocyte neointima formation novel novel strategies novel therapeutics percutaneous coronary intervention pre-clinical preclinical study prevent receptor repaired restenosis success vascular inflammation

项目摘要

PROJECT SUMMARY Percutaneous coronary intervention (PCI) is the mainstay treatment to unblock atherosclerotic arteries. Despite significant technological advances in PCI, restenosis (re-narrowing) secondary to neointimal hyperplasia remains an important cause of morbidity and death. The extent of local and systemic inflammation after PCI highly correlates with the extent of restenosis. The integrin Mac-1 (also known as CD11b/CD18, CR3, and ¿M¿2), which is primarily expressed on leukocytes, plays a key role in vascular injury and inflammation. Mac-1 mediates leukocyte adhesion, migration, and recruitment after vascular injury. As approaches using anti-Mac-1 blockers have had limited success in human clinical trials, in this project, we propose an alternative innovative approach for treating vascular injury by activating instead of blocking Mac-1 with a novel class of compounds that we have termed leukadherins. We demonstrate the surprising discovery that leukadherins significantly promote endothelial re-growth and prevent neointimal hyperplasia after arterial balloon injury in rats. Our overall hypothesis is that activation of the Mac-1 receptor via leukadherins is sufficient to prevent leukocyte transmigration and activation, decreasing vascular inflammation and neointima formation. We also hypothesize that leukadherin suppress the inflammatory activation of leukocytes during the repair of the injured vasculature. We propose three Specific Aims (SA) to test our hypotheses. In SA1, we will search for molecular connections between Mac-1 activation and leukocyte deactivation after vascular injury. We will investigate the role of inflammation suppressors Akt and Syk on leukadherin's anti-inflammatory effects. In SA2, we will identify the in vivo mechanism by which leukadherins promote endothelial recovery. We will assess how leukadherins promote local endothelial cell growth over endothelial progenitor cell recruitment to accelerate vascular re- endothelialization. Finally, in SA3 we will identify the in vivo mechanisms by which leukadherins reduce neointimal hyperplasia in a clinically relevant model of in-stent restenosis. We will compare our lead leukadherin agonist, LA1, with M1/70 mAb (antagonist) in a rabbit model of in-stent restenosis, and will provide a basis for progressing to preclinical studies in larger animals (pigs) and, eventually, to clinical trials. RELEVANCE: Restenosis is the major complication after coronary interventions, accounting for $3 billion dollars in medical expenditures annually in the US alone. In this study, we will help define whether and how pharmacologic activation of integrin Mac-1 has therapeutic potential for the prevention of restenosis. This will pave the way for the future discovery of novel therapeutic agents to treat restenosis after PCI as well as other vascular inflammatory diseases.

项目概要经皮冠状动脉介入治疗（PCI）是疏通动脉粥样硬化动脉的主要治疗方法。 PCI、新生内膜增生继发的再狭窄（再狭窄）方面的重大技术进步 PCI 术后局部和全身炎症的程度仍然是发病和死亡的重要原因。与再狭窄程度高度相关。整合素 Mac-1（也称为 CD11b/CD18、CR3 和）。 ¿米克2) 主要在白细胞上表达，在血管损伤和炎症中发挥关键作用。 As 使用抗 Mac-1 方法介导血管损伤后白细胞粘附、迁移和募集。阻滞剂在人体临床试验中取得的成功有限，在这个项目中，我们提出了一种替代创新通过用一类新型化合物激活而不是阻断 Mac-1 来治疗血管损伤的方法我们证明了一个令人惊讶的发现，即白细胞粘着素具有显着的作用。促进大鼠动脉球囊损伤后内皮再生并预防新内膜增生。总体假设是，通过白细胞粘附素激活 Mac-1 受体足以阻止白细胞迁移和激活，减少血管炎症和新内膜形成。白细胞粘附素在受损脉管系统修复过程中抑制白细胞的炎症激活。我们提出了三个具体目标（SA）来检验我们的假设。在 SA1 中，我们将寻找分子联系。我们将研究血管损伤后 Mac-1 激活和白细胞失活之间的作用。炎症抑制因子 Akt 和 Syk 对白细胞粘附素的抗炎作用的影响在 SA2 中，我们将鉴定其中的作用。白粘蛋白促进内皮恢复的体内机制我们将评估白粘蛋白如何促进内皮恢复。促进局部内皮细胞生长超过内皮祖细胞募集，加速血管再生最后，在 SA3 中，我们将确定白细胞粘附素减少的体内机制。我们将比较我们的领先优势。在支架内再狭窄的兔模型中使用白细胞粘附素激动剂 LA1 与 M1/70 mAb（拮抗剂），并将提供为在大型动物（猪）中进行临床前研究并最终进行临床试验奠定了基础。相关性：再狭窄是冠状动脉介入治疗后的主要并发症，造成 30 亿美元的损失仅在美国每年的医疗支出就高达 100 美元。在这项研究中，我们将帮助确定是否以及如何进行。整合素 Mac-1 的药理激活具有预防再狭窄的治疗潜力。为未来发现治疗 PCI 及其他疾病后再狭窄的新型治疗药物铺平道路血管炎症性疾病。