Inflammasome Activity as a Potential Contributor to Uremic Cardiomyopathy

项目摘要 慢性肾脏疾病是亚临床左心室收缩功能障碍的一个重要危险因素， 心力衰竭，但这些关系的机制仍不完全清楚。炎性体 通过激活炎性细胞因子白细胞介素-1 β和白细胞介素-18驱动肾脏和心脏炎症 和致热蛋白gasdermin-D。在患有收缩性心力衰竭或冠状动脉疾病的患者中， 药物性白细胞介素-1 β阻滞剂改善左心室收缩功能和最大运动能力 并且与更少的心力衰竭住院治疗的趋势相关。外源性白细胞介素18 对野生型小鼠给药损害左心室收缩功能，而在给药后阻断白细胞介素-18， 实验性心肌梗死保留了左心室收缩功能。此外，白细胞介素-1 β 白细胞介素-18部分介导了心血管效应，这表明同时阻断两者 细胞因子将赋予超出单独靶向任一细胞因子的额外益处。这个广泛的目标 申请是准备主要研究者，利奥巴克利博士药学博士，作为一个独立的职业生涯， 以患者为导向的研究人员，研究心血管药理学，对预防和 通过识别和靶向调节心肌结构和功能的途径来治疗心力衰竭。在 除了重点课程和研讨会，巴克利博士将完成一系列以病人为导向的研究 在专家指导委员会的指导下， 通过促进左心室收缩功能， 功能障碍他将解决两个具体的目标：（1）增加炎性小体活动与左 老年人心室收缩功能障碍和心力衰竭风险增加;（2）检测 假设秋水仙碱改善左心室收缩功能并降低炎性小体活性， 尿毒症性心肌病患者。这些研究将提高我们对这一问题的认识，并促进进一步的研究。 研究炎症因子在亚临床左室功能不全和心脏病发病机制中的作用， 失败在颁奖结束时，巴克利博士将建立一个独立的，以病人为导向的 心血管药理学研究计划。

PROJECT SUMMARY Chronic kidney disease is a powerful risk factor for subclinical left ventricular systolic dysfunction and incident heart failure, but the mechanisms of these relationships remain incompletely understood. The inflammasome drives renal and cardiac inflammation by activating the inflammatory cytokines interleukin-1β and interleukin-18 and the pyroptotic protein gasdermin-D. In patients with systolic heart failure or coronary artery disease, pharmacologic interleukin-1β blockade improves left ventricular systolic function and maximal exercise capacity and is associated with a trend towards fewer heart failure hospitalizations. Exogenous interleukin-18 administration to wild-type mice impairs left ventricular systolic function whereas blocking interleukin-18 after experimental myocardial infarction preserves left ventricular systolic function. Furthermore, interleukin-1β’s cardiodepressant effects are mediated in part by interleukin-18, suggesting that simultaneous blockade of both cytokines would confer additional benefit beyond targeting either cytokine alone. The broad goal of this application is to prepare the principal investigator, Dr. Leo Buckley PharmD, for a career as an independent, patient-oriented researcher who studies cardiovascular pharmacology with a specific interest in preventing and treating heart failure by identifying and targeting pathways that regulate myocardial structure and function. In addition to focused coursework and seminars, Dr. Buckley will complete a series of patient-oriented studies under the guidance of an expert mentoring committee to test the hypothesis that inflammasome activity contributes to incident heart failure risk in adults with chronic kidney disease by promoting left ventricular systolic dysfunction. He will address two specific aims: (1) that increased inflammasome activity associates with left ventricular systolic dysfunction and increased risk of incident heart failure in older adults; and (2) To test the hypothesis that colchicine improves left ventricular systolic function and reduces inflammasome activity in patients with uremic cardiomyopathy. These studies will improve our knowledge of and spur further investigations into the role of inflammatory cytokines in the pathogenesis of subclinical left ventricular dysfunction and heart failure. By the conclusion of the award, Dr. Buckley will have established an independent, patient-oriented cardiovascular pharmacology research program.