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：
8372976
负责人：
VINEET GUPTA
金额：
$ 38.25万
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/8372976
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

DESCRIPTION (provided by applicant): 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 vasculr 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 sufficien 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. PUBLIC HEALTH RELEVANCE: Percutaneous coronary interventions (PCI) including stent placement by catheters are the most effective way to unblock coronary arteries and facilitate coronary revascularization. Despite all of the technological and pharmacological advances in PCI, vascular re-occlusion (restenosis) remains the major complication accounting for billions of dollars in medical expenditures annually in the US alone. This study will demonstrate how a novel class of anti-inflammatory compounds, leukadherins, prevents inflammation, accelerates vascular healing, and halts the re-occlusion of coronary arteries after PCI, resulting in outcomes that may represent new strategies and alternative therapies to accelerate endothelial healing and reduce the occurrence of restenosis, ultimately saving lives.

描述（由申请人提供）：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，尽管 PCI 技术取得了显着的进步，但继发于新生内膜增生的再狭窄（再狭窄）仍然是发病和死亡的重要原因。 PCI 后局部和全身炎症的发生与再狭窄的程度高度相关整合素 Mac-1（也称为 CD11b/CD18， CR3 和 ¿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，正如使用抗 Mac-1 阻滞剂的方法一样，Mac-1 介导白细胞粘附、迁移和募集。尽管在人体临床试验中取得的成功有限，但在该项目中，我们提出了一种治疗血管损伤的替代创新方法，即用一类新型化合物激活而不是阻断 Mac-1，我们将其称为白细胞粘附素。证明了白细胞粘着素在大鼠动脉球囊损伤后显着促进内皮再生长并预防新内膜增生的惊人发现我们的总体假设是通过白细胞粘着素激活Mac-1受体足以防止白细胞迁移和活化，减少血管炎症和。我们还参与了白细胞粘附素在受损脉管系统修复过程中抑制白细胞炎症活化的研究。 (SA) 来检验我们的假设。在 SA1 中，我们将寻找血管损伤后 Mac-1 激活和白细胞失活之间的分子联系。在 SA2 中，我们将研究炎症抑制因子 Akt 和 Syk 的抗炎作用。我们将确定白细胞粘附素促进内皮恢复的体内机制我们将评估白细胞粘附素如何促进局部内皮细胞生长而不是内皮祖细胞募集以加速血管。最后，在 SA3 中，我们将在临床相关的支架内再狭窄模型中确定白细胞粘附素减少新内膜增生的体内机制，我们将比较我们的主要白细胞粘附素激动剂 LA1 与 M1/70 mAb（拮抗剂）。在支架内再狭窄的兔子模型中，将为在大型动物（猪）中进行临床前研究提供基础，并最终相关性：再狭窄是冠状动脉介入治疗后的主要并发症，仅在美国每年就造成 30 亿美元的医疗支出。在这项研究中，我们将帮助确定整合素 Mac-1 的药理激活是否以及如何具有治疗潜力。这将为未来发现治疗 PCI 后再狭窄以及其他血管炎症性疾病的新型治疗药物铺平道路。公共卫生相关性：经皮冠状动脉介入治疗（PCI），包括导管支架置入术，是疏通动脉和促进冠状动脉血运重建的最有效方法，尽管 PCI 技术和药理学取得了诸多进步，但血管再闭塞（再狭窄）仍然是主要的治疗方法。仅在美国，这种并发症每年就造成数十亿美元的医疗支出。这项研究将展示一类新型抗炎化合物——白细胞粘附素——如何预防炎症、加速炎症。血管愈合，并阻止 PCI 后冠状动脉的重新闭塞，所产生的结果可能代表加速内皮愈合和减少再狭窄发生的新策略和替代疗法，最终挽救生命。