Role of SuPAR in the Intersection between Cardiovascular and Kidney Disease

项目摘要 慢性肾病(CKD)患者占美国人口的15%以上， 心血管疾病(CVD)的负担不成比例地高，原因很差 明白了。炎症是动脉粥样硬化和糖尿病共同的主要病理生理过程。 CKD。最近发现了一种新的炎症途径，将CVD和CKD与骨髓联系起来。 产生循环信号分子的髓系细胞：可溶性尿激酶型纤溶酶原激活剂受体 (SuPAR)。未成熟的髓系细胞对环境暴露和心血管疾病风险的反应是释放suPAR 各种因素。在循环中，suPAR改变肾小球和肾小管功能，长期暴露导致 进行性肾功能障碍。SuPAR对实验性肾脏保护作用的药理抑制作用 受伤。SuPAR水平也独立于肾功能预测不良的心血管结果，并且 表现优于冠状动脉钙化、C反应蛋白、高敏感性等心血管疾病风险的成熟标志 肌钙蛋白I和B型利钠肽。这些令人信服的数据揭示了suPAR不仅作为一种 极好的风险生物标志物，但也是一个有前途的治疗靶点。然而，suPAR在心血管疾病中的作用是 人们对此知之甚少。这项建议的总体目标是阐明suPAR在 通过流行病学观察动脉粥样硬化的进展及其与肾功能下降的联系。我们会 通过利用心血管科学的三项最重要的贡献来实现这一目标： 里程碑式的动脉粥样硬化多种族研究(MESA)；NIH资助的前瞻性队列研究，参与者 对动脉粥样硬化的亚临床标志物进行了一系列测量，在Jupiter试验中 C反应蛋白水平高的参与者被随机分为他汀类药物或安慰剂，英国生物库，a 超过500,000名志愿者的数据库。将在5,620名MESA TO参与者中测量suPAR水平 确定水平是否与心血管疾病的早期标志物相关，并独立于 肾功能下降。为了评估潜在的因果关系，一项关于suPAR水平的全基因关联研究 MESA，随后在英国生物库数据集中进行孟德尔随机化分析，将遗传 SuPAR水平对CVD和CKD的决定因素。最后，要确定suPAR是否是一个可修改的风险因素 对于心血管疾病，将连续测量随机服用瑞舒伐他汀的JUPITER试验参与者的血药浓度 (n=200)或安慰剂(n=200)，并比较不同组之间suPAR的变化。是不是好处 他汀类药物依赖于suPAR水平将在MESA队列中通过比较以下患者的存活率进行评估 参与者开始服用他汀类药物，跨越suPAR四分位数，并确定suPAR是否是 他汀类药物与预后之间的关系。这项拟议的研究有可能解决未满足的问题 仅在美国就需要近5000万CKD患者，确定迫切需要的治疗方法 一个长期停滞不前的领域的目标和管理战略。

Project Summary People with chronic kidney disease (CKD), who represent over 15% of the population of the United States, suffer a disproportionately high burden of cardiovascular disease (CVD) for reasons that are poorly understood. Inflammation represents the major pathophysiologic process common to both atherosclerosis and CKD. Recently, a novel pathway of inflammation was uncovered linking both CVD and CKD to bone marrow myeloid cells which produce a circulating signaling molecule: soluble urokinase plasminogen activator receptor (suPAR). SuPAR is released by immature myeloid cells in response to environmental exposures and CVD risk factors. In circulation, suPAR alters glomerular and tubular function, with chronic exposure leading to progressive kidney dysfunction. Pharmacologic inhibition of suPAR in experimental models prevented kidney injury. SuPAR levels also predict adverse cardiovascular outcomes independently of kidney function, and outperform well-established markers of CVD risk, such as coronary calcium, C-reactive protein, high sensitivity troponin I and B-type natriuretic peptide. These compelling data reveal the potential for suPAR not only as an excellent biomarker of risk, but also as a promising therapeutic target. The role of suPAR in CVD is however poorly understood. The overall goal of this proposal is to elucidate suPAR’s potential causal role in the progression of atherosclerosis and its link to decline in kidney function through epidemiologic insights. We will achieve this goal by leveraging three of the most significant contributions to cardiovascular science: the landmark Multi-Ethnic Study of Atherosclerosis (MESA); an NIH-funded prospective cohort in which enrollees underwent serial measurements of subclinical markers of atherosclerosis, the JUPITER trial, in which participants with high C-reactive protein levels were randomized to statin or placebo, and the UK Biobank, a data repository of over 500,000 volunteers. SuPAR levels will be measured in 5,620 participants of MESA to determine whether levels correlate with early markers of CVD and predicts their progression independently of a decline in kidney function. To assess potential causality, a gene-wide association study of suPAR levels in MESA, followed by a Mendelian randomization analysis in the UK Biobank dataset will connect genetic determinants of suPAR levels to CVD and CKD. Lastly, to establish whether suPAR is a modifiable risk factor for CVD, levels will be measured serially in participants of the JUPITER trial randomized to rosuvastatin (n=200) or placebo (n=200), and the change in suPAR will be compared between groups. Whether the benefits of statins are dependent on suPAR levels will be assessed in the MESA cohort by comparing the survival of participants started on statins across suPAR quartiles, and determining whether suPAR is a modifier of the association between statins and outcomes. The proposed research has the potential to address the unmet need of close to 50 million people with CKD in the United States alone, identifying sorely needed therapeutic targets and management strategies in a field that has long been stagnant.