Inflammasome Activity as a Potential Contributor to Uremic Cardiomyopathy

项目总结 慢性肾脏疾病是亚临床左心室收缩功能不全的重要危险因素 心力衰竭，但这些关系的机制仍然不完全清楚。《炎症室》 通过激活炎症细胞因子白介素1β和白介素18促进肾和心脏炎症 和焦链蛋白Gasdermin-D。在患有收缩性心力衰竭或冠心病的患者中， 药物性白介素1β阻断改善左心室收缩功能和最大运动能力 并与心力衰竭住院人数减少的趋势有关。外源性白介素18 野生型小鼠给药后左室收缩功能受损，而阻断白细胞介素18 实验性心肌梗死可保护左心室收缩功能。此外，白细胞介素1β的S 心脏抑制作用部分是由白介素18介导的，这表明同时阻断两者 除了单独针对任何一种细胞因子外，细胞因子还会带来额外的好处。这样做的总体目标是 申请是为了让首席研究员Leo Buckley PharmD博士为独立职业生涯做好准备， 以患者为导向的研究心血管药理学的研究员，对预防和治疗心血管疾病特别感兴趣。 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……里面 除了专注于课程和研讨会，巴克利博士还将完成一系列以病人为中心的研究 在专家指导委员会的指导下，测试炎症小体活动的假说 通过促进左心室收缩增加成人慢性肾病患者发生心力衰竭的风险 功能障碍。他将谈到两个具体目标：(1)炎症小体活动增加与左翼 老年人的心脏收缩功能障碍和发生心力衰竭的风险增加；以及(2)测试 秋水仙碱改善左心室收缩功能和减少炎症体活动的假说 尿毒症心肌病患者。这些研究将提高我们对这一问题的认识，并推动进一步的调查 炎性细胞因子在亚临床左心功能不全和心脏发病机制中的作用 失败了。到颁奖结束时，巴克利博士将建立一个独立的、以患者为导向的 心血管药理研究计划。

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.