Leukadherins as novel compounds for treating restenosis

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技术取得了显著进步，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术后局部和全身炎症程度与再狭窄程度高度相关。整合素Mac-1（也称为CD 11b/CD 18，CR 3和<$M <$2）主要在白细胞上表达，在血管损伤和炎症中起关键作用。Mac-1介导血管损伤后白细胞粘附、迁移和募集。由于使用抗Mac-1阻断剂的方法在人体临床试验中取得了有限的成功，在本项目中，我们提出了一种替代的创新方法，通过激活而不是阻断Mac-1与一类新的化合物，我们称之为leukadherins来治疗血管损伤。我们证明了令人惊讶的发现，白细胞粘附素显着促进内皮细胞再生和防止动脉球囊损伤后的新生内膜增生大鼠。我们的总体假设是，Mac-1受体通过白细胞粘附素的激活被抑制，以防止白细胞迁移和激活，减少血管炎症和新生内膜形成。我们还假设白细胞粘附素在损伤血管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）来验证我们的假设。在SA 1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。我们将研究炎症抑制因子Akt和Syk在白细胞粘附素抗炎作用中的作用。在SA 2中，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超过内皮祖细胞募集，以加速血管再内皮化。最后，在SA 3中，我们将确定在支架内再狭窄的临床相关模型中白细胞粘附素减少新生内膜增生的体内机制。我们将在兔支架内再狭窄模型中比较我们的主要白细胞粘附素激动剂LA 1与M1/70 mAb（拮抗剂），并将为在较大动物（猪）中进行临床前研究并最终进行临床试验提供基础。相关性：呼吸暂停是冠状动脉介入治疗后的主要并发症，仅在美国每年就占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的药理学激活是否以及如何具有预防再狭窄的治疗潜力。这将为未来发现新的治疗药物来治疗PCI后再狭窄以及其他血管炎性疾病铺平道路。 公共卫生相关性：经皮冠状动脉介入治疗（PCI）包括通过导管放置支架是疏通冠状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进步，但血管再闭塞（再狭窄）仍然是主要并发症，仅在美国每年的医疗支出就高达数十亿美元。这项研究将证明一种新型的抗炎化合物白细胞粘附素如何预防炎症，加速血管愈合，并阻止PCI后冠状动脉的再闭塞，从而产生可能代表新策略和替代疗法的结果，以加速内皮愈合并减少再狭窄的发生，最终挽救生命。

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.