Leukadherins as novel compounds for treating restenosis

项目摘要 经皮冠状动脉介入治疗（PCI）是解除动脉粥样硬化的主要治疗手段。尽管 PCI的显著技术进步，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CD11b/CD18、CR3和 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。当使用anti-Mac-1 阻滞剂在人体临床试验中取得了有限的成功，在这个项目中，我们提出了一种替代的创新 通过用一类新化合物激活而非阻断Mac-1治疗血管损伤的方法 我们称之为白细胞粘附素。我们证明了令人惊讶的发现，白细胞粘附素显着 促进大鼠动脉球囊损伤后内皮再生，防止新生内膜增生。我们 总体假设是Mac-1受体通过白细胞粘附素的激活足以防止白细胞 血管内皮细胞的增殖、迁移和活化，减少血管炎症和新生内膜形成。我们还假设 白细胞粘附素在受损脉管系统的修复过程中抑制白细胞的炎性活化。 我们提出了三个具体目标（SA）来验证我们的假设。在SA1中，我们将寻找分子连接 血管损伤后Mac-1激活和白细胞失活之间的关系。我们将研究 炎症抑制因子Akt和Syk对白细胞粘附素抗炎作用的影响。在SA2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 促进局部内皮细胞生长超过内皮祖细胞募集，加速血管重建 内皮化。最后，在SA3中，我们将确定白细胞粘附素减少白细胞粘附素的体内机制。 支架内再狭窄临床相关模型中的新生内膜增生。我们会比较我们的领先优势 白细胞粘附素激动剂LA1与M1/70 mAb（拮抗剂）在兔支架内再狭窄模型中的联合应用， 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：呼吸暂停是冠状动脉介入治疗后的主要并发症，占30亿美元 仅在美国，每年的医疗支出就高达300万美元。在本研究中，我们将帮助定义是否以及如何 整合素Mac-1的药理学活化具有预防再狭窄的治疗潜力。这将 为未来发现治疗PCI后再狭窄以及其他疾病的新型治疗药物铺平了道路。 血管炎性疾病。

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.