Leukadherins as novel compounds for treating restenosis

白粘附素作为治疗再狭窄的新型化合物

• 批准号: 8851715
• 负责人: VINEET GUPTA
• 金额: $ 8.6万
• 依托单位: UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 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/8851715
• 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

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.

项目总结 经皮冠状动脉介入治疗(PCI)是解除动脉粥样硬化的主要手段。尽管 冠状动脉介入治疗的重大技术进步，继发于新的内膜增生的再狭窄(再狭窄) 仍然是导致发病和死亡的重要原因。经皮冠状动脉介入治疗后局部和全身炎症的程度 与再狭窄的程度高度相关。整合素Mac-1(也称为CD11b/CD18、CR3和 主要表达在白细胞上，在血管损伤和炎症中起关键作用。MAC-1 调节血管损伤后白细胞的黏附、迁移和募集。使用反Mac-1的AS方法 阻滞剂在人体临床试验中取得的成功有限，在本项目中，我们提出了一种创新的替代方案 一类新型化合物激活而不是阻断Mac-1治疗血管损伤的研究 我们称之为白细胞粘附素。我们展示了一个令人惊讶的发现，白细胞粘附素显著 促进大鼠动脉球囊损伤后血管内皮细胞再生长，防止新生内膜增生。我们的 总体假设是，通过白细胞粘附素激活Mac-1受体足以防止白细胞 移行和激活，减少血管炎症和新生内膜的形成。我们还假设 在损伤的血管系统修复过程中，白细胞粘附素抑制白细胞的炎症激活。 我们提出了三个特定的目标(SA)来检验我们的假设。在SA1中，我们将搜索分子连接 血管损伤后Mac-1激活与白细胞失活之间的关系。我们将调查 炎症抑制剂Akt和Syk对白细胞粘附素的抗炎作用。在SA2中，我们将确定 白细胞粘附素促进内皮细胞修复的体内机制。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加速血管再通 内皮化。最后，在SA3中，我们将确定白细胞粘附素减少的体内机制 支架内再狭窄的临床相关模型中的新生内膜增生。我们将比较我们的领先优势 白细胞粘附素激动剂LA1与M1/70单抗(拮抗剂)联合应用于兔支架内再狭窄模型，并将提供 这是在较大动物(猪)上进行临床前研究并最终进入临床试验的基础。 相关性：再狭窄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美元。在这项研究中，我们将帮助定义是否以及如何 整合素Mac-1的药理激活具有预防再狭窄的治疗潜力。这将是 为未来发现新的治疗药物来治疗经皮冠状动脉介入术后再狭窄以及其他 血管炎症疾病。