Anti-inflammatory therapy during percutaneous coronary intervention

 描述(由申请人提供)： 我的长期研究目标是利用转译研究方法开发新的有效治疗策略，并改善缺血性心脏病患者的预后。这项建议的主要焦点是描述急性冠脉综合征和/或经皮冠状动脉介入治疗(PCI)后中性粒细胞激活和不良后果之间的病理生理机制。我们目前关于中性粒细胞潜在作用的大部分知识都是基于对小鼠实验模型或炎症微血管模型的观察。我建议通过详细研究中性粒细胞生物学以及中性粒细胞表型与接受临床指示的经皮冠状动脉介入治疗(一种急性血管损伤模型)患者的不良心血管结果之间的关系，来弥合目前知识上的差距。我还建议使用秋水仙碱，一种具有直接抑制中性粒细胞作用的药物，作为阐明中性粒细胞激活在急性血管损伤中的作用的工具。秋水仙碱在经皮冠状动脉介入治疗中可能特别有用，因为它起效快，在低剂量时有良好的副作用，以及它对中性粒细胞黏附分子的已知作用机制。转诊为可能接受经皮冠状动脉介入治疗的患者将以双盲方式随机服用安慰剂或秋水仙碱(在经皮冠状动脉介入治疗前1小时服用1.8毫克PO)。在这两项研究设计(介入治疗后与介入治疗前，秋水仙素与安慰剂对照)中，将检验经皮冠状动脉介入治疗和研究药物对中性粒细胞特异性生物标志物以及中性粒细胞-内皮细胞和中性粒细胞-血小板相互作用的影响。我还将探讨中性粒细胞表型与经皮冠状动脉介入治疗后不良心血管结局之间的关系，以及秋水仙碱对这些结局的影响。对急性血管损伤中性粒细胞生物学的深入描述将使 探索预防和治疗的新途径，目的是确定新的选择性靶点，在最大限度地减少全身免疫抑制的情况下产生抗炎作用。通过中性粒细胞细胞外陷阱和中性粒细胞衍生的微粒途径鉴定细胞后介质可能提供额外的新的治疗靶点。此外，在这项提议中获得的对中性粒细胞生物学的更多了解可能为2型MI人群(例如，术后环境中的需求缺血)和其他动脉粥样硬化人群(例如，外周动脉疾病)的病理提供新的见解。我在纽约大学(NYU)完成了为期5年的课程，获得了普通心脏病学和介入心脏病学的认证，以及临床调查的理学硕士学位。退伍军人管理局职业发展奖将通过支持我完成一系列课程，并为有效利用翻译方法和炎症主题的结构化教程提供受保护的时间，为我提供迈向调查独立性的垫脚石。曼哈顿退伍军人管理局及其学术附属机构、临床与翻译科学研究所和纽约大学心血管临床研究中心强大的环境和资源，将使我能够成功地执行本提案中概述的职业发展计划。这项建议以多学科方法为特色，并得到基础和临床科学方面的心脏病学和风湿学专家的支持，以减少PCI术后的不良后果。这种跨学科的合作对于有效地进行翻译研究是必要的，并将有助于我为成为一名成功的独立调查员的职业生涯做好准备。

 DESCRIPTION (provided by applicant): My long-term research goal is to leverage translational research methodologies to develop novel and effective therapeutic strategies and improve outcomes in patients with ischemic heart disease. The primary focus of this proposal is to characterize pathophysiological mechanisms linking neutrophil activation and adverse outcomes after acute coronary syndrome and/or percutaneous coronary intervention (PCI). Much of our current knowledge about the potential role of neutrophils is based on observations from experimental models in mice, or microvascular models of inflammation. I propose to bridge the current gap in knowledge through detailed study of neutrophil biology and the association between neutrophil phenotype and adverse cardiovascular outcomes in patients who undergo clinically indicated PCI, a model of acute vascular injury. I further propose to use colchicine, an agent with direct neutrophil suppressive action, as a tool to elucidate the role of neutrophil activation during acute vascular injury. Colchicine may be particularly useful in the PCI setting due to its rapid onset of action and excellent side-effect profile at low doses, as well as its known mechanisms of action on neutrophil adhesion molecules. Patients referred for possible PCI will be randomized in a double-blinded fashion to placebo or colchicine (1.8mg PO over 1 hour prior to PCI). In this two by two study design (post- versus pre-PCI and colchicine versus placebo), the effect of PCI and study drug will be examined on neutrophil-specific biomarkers and neutrophil-endothelial cell and neutrophil-platelet interactions. I will also explore the association between neutrophil phenotype and adverse cardiovascular outcomes after PCI and the effects of colchicine on these outcomes. In-depth characterization of neutrophil biology in acute vascular injury will allow for exploration of new avenues in prevention and treatment, with a goal to identify novel selective targets that induce anti-inflammatory effects with minimal systemic immunosuppression. Characterization of post-cellular mediators via neutrophil extracellular trap and neutrophil-derived microparticle pathways may provide additional novel therapeutic targets. In addition, increased understanding of neutrophil biology gained in this proposal may provide novel insight into pathology of type 2 MI populations (e.g. demand ischemia in post-operative settings) and other atherosclerosis populations (e.g. peripheral artery disease). I completed a 5- year program at New York University (NYU) resulting in certification in general and Interventional Cardiology, as well as a Master's of Science degree in Clinical Investigation. A VA Career Development Award will provide me with the stepping stone on which to advance to investigative independence, by supporting me through a series of courses and providing protected time for structured tutorials on the effective utilization of translational approaches an topics in inflammation. The strong environment and resources of the Manhattan VA and its academic affiliates, the Clinical and Translational Science Institute and the Cardiovascular Clinical Research Center at NYU, will allow me to successfully execute the career development plan outlined in this proposal. This proposal features a multi-disciplinary approach, with support from experts in cardiology and rheumatology in both basic and clinical science, to reduce adverse outcomes after PCI. Such cross-disciplinary collaboration is necessary to effectively conduct translational research and will help prepare me for my career as a successful independent investigator.