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: 8856321
• 负责人: VINEET GUPTA
• 金额: $ 46.14万
• 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 2017-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8856321
• 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; coronary artery occlusion; 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

项目成果

c-Kit suppresses atherosclerosis in hyperlipidemic mice.

c-Kit 抑制高脂血症小鼠的动脉粥样硬化。

• DOI: 10.1152/ajpheart.00062.2019
• 发表时间: 2019
• 期刊: American journal of physiology. Heart and circulatory physiology
• 作者: Song,Lei;Zigmond,ZacharyM;Martinez,Laisel;Lassance-Soares,RobertaM;Macias,AlejandroE;Velazquez,OmaidaC;Liu,Zhao-Jun;Salama,Alghidak;Webster,KeithA;Vazquez-Padron,RobertoI
• 通讯作者: Vazquez-Padron,RobertoI