Role of SuPAR in the Intersection between Cardiovascular and Kidney Disease

项目摘要 慢性肾脏病（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， 明白炎症是动脉粥样硬化和动脉粥样硬化的主要共同病理生理过程。 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：可溶性尿激酶纤溶酶原激活物受体的髓样细胞 （suPAR）。SuPAR由未成熟的骨髓细胞释放，以响应环境暴露和CVD风险 因素在循环中，suPAR改变肾小球和肾小管功能，长期暴露会导致 进行性肾功能不全在实验模型中，suPAR的药理学抑制可防止肾脏 损伤SuPAR水平也可独立于肾功能预测不良心血管结局， 优于心血管疾病风险的成熟标志物，如冠状动脉钙，C反应蛋白，高敏感性 肌钙蛋白I和B型利钠肽。这些令人信服的数据揭示了suPAR的潜力，不仅是作为一种 这是一个极好的风险生物标志物，也是一个有前途的治疗靶点。然而，suPAR在CVD中的作用是 不太了解。该提案的总体目标是阐明suPAR在以下方面的潜在因果作用： 动脉粥样硬化的进展及其与肾功能下降的联系。我们将 通过利用心血管科学的三个最重要的贡献来实现这一目标： 具有里程碑意义的多种族动脉粥样硬化研究（梅萨）;一项由NIH资助的前瞻性队列研究， 进行了一系列动脉粥样硬化亚临床标志物的测量，即JUPITER试验， 高C反应蛋白水平的参与者被随机分配到他汀类药物组或安慰剂组，英国生物样本库， 超过50万名志愿者的数据库。将在5，620名梅萨参与者中测量SuPAR水平， 确定水平是否与CVD的早期标志物相关，并预测其独立于CVD的进展。 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， 梅萨，然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水平是CVD和CKD的决定因素。最后，确定suPAR是否是一个可改变的风险因素 对于CVD，将在随机接受瑞舒伐他汀的JUPITER试验受试者中连续测量水平 （n=200）或安慰剂（n=200），并且将在组之间比较suPAR的变化。的好处是否 将在梅萨队列中通过比较他汀类药物依赖于suPAR水平的患者的生存率来评估 参与者开始使用他汀类药物，并确定suPAR是否是 他汀类药物与预后的关系拟议的研究有可能解决未得到满足的问题， 仅在美国就需要近5000万CKD患者， 这是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.