Role of SuPAR in the Intersection between Cardiovascular and Kidney Disease

SuPAR 在心血管疾病和肾脏疾病交叉点中的作用

• 批准号: 10450750
• 负责人: Salim Hayek
• 金额: $ 54.82万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-01 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10450750
• 关键词: Address; Arterial Fatty Streak; Atherosclerosis; Biological Markers; Blood Circulation; Bone Marrow; Brain natriuretic peptide; C-reactive protein; Cardiovascular Diseases; Cardiovascular system; Cause of Death; Chronic; Chronic Kidney Failure; Data; Data Set; Development; Diffuse; Discrimination; Disease; Disease Outcome; Endothelium; Enrollment; Environmental Exposure; Epidemiology; Etiology; Experimental Models; Foundations; Functional disorder; Funding; Genes; Genetic; Genetic Determinism; Glycoproteins; Goals; Inflammation; Inflammatory; Injections; Injury; Injury to Kidney; Innate Immune System; Kidney; Kidney Diseases; Knowledge; Link; Measurement; Measures; Membrane; Mendelian randomization; Meta-Analysis; Multi-Ethnic Study of Atherosclerosis; Myeloid Cells; Outcome; PLAU gene; PLAUR gene; Participant; Pathogenicity; Pathway interactions; Patients; Persons; Pharmacology; Placebos; Plasminogen; Population; Process; Prospective Studies; Prospective cohort; Randomized; Recombinant Proteins; Renal function; Research; Risk; Risk Factors; Role; Sampling; Science; Secure; Signaling Molecule; Surface; Testing; Therapeutic Intervention; Therapeutic Studies; Troponin I; Tubular formation; United States; United States National Institutes of Health; Urokinase; Urokinase Plasminogen Activator Receptor; Virulence Factors; Work; arterial stiffness; base; biobank; cardiovascular disorder risk; cardiovascular risk factor; clinical practice; cohort; coronary artery calcium; coronary calcium scoring; cytokine; data repository; design; disorder risk; experience; experimental study; follow-up; genetic variant; genome wide association study; healthy volunteer; high risk; individualized medicine; insight; kidney dysfunction; modifiable risk; multidisciplinary; novel; overexpression; prevent; preventive intervention; randomized trial; receptor; response; rosuvastatin; therapeutic target; volunteer

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.

项目摘要 患有慢性肾脏疾病（CKD）的人，占美国人口15％以上的人 由于较差的原因 理解。炎症代表了动脉粥样硬化和 CKD。最近，发现了一种新型的炎症途径，将CVD和CKD连接到骨髓 产生循环信号分子的髓样细胞：可溶性尿激酶纤溶酶原激活剂接收器 （supar）。 SUPAR由未成熟的髓样细胞释放，以应对环境暴露和CVD风险 因素。在循环中，supar会改变肾小球和管状功能，慢性暴露导致 进步的肾脏功能障碍。在实验模型中对SUPAR的药理抑制阻止了肾脏 受伤。 SUPAR水平还独立于肾功能预测心血管不良后果，并且 CVD风险的表现优于良好的标记，例如冠状动脉钙，C反应蛋白，高灵敏度 肌钙蛋白I和B型纳地钠肽。这些引人入胜的数据揭示了Supar的潜力，不仅是 出色的风险生物标志物，也是一个有前途的治疗靶标。但是，supar在CVD中的作用是 理解不佳。该提议的总体目标是阐明Supar在 动脉粥样硬化的进展及其通过流行病学见解与肾功能下降的联系。我们将 通过利用对心血管科学的三个最重要的贡献来实现这一目标： 地标性动脉粥样硬化多民族研究（MESA）； NIH资助的潜在队列 经过了动脉粥样硬化的亚临床标记的连续测量，木星试验，其中 具有高C反应蛋白水平的参与者被随机分为他汀类药物或安慰剂，而英国生物银行则是 超过500,000名志愿者的数据存储库。 SUPAR水平将在5,620名Mesa参与者中进行测量 确定水平是否与CVD的早期标记相关并预测其进展独立于A 肾功能下降。为了评估潜在的平静，跨基因范围的supar水平研究 台面，然后在英国生物库数据集中进行孟德尔随机化分析将连接遗传 CVD和CKD的SUPAR水平的决定因素。最后，确定Supar是否是可修改的风险因素 对于CVD，将在木星试验的参与者的参与者中串行测量水平 （n = 200）或安慰剂（n = 200），以及组之间的SUPAR变化。是否有好处 他汀类药物的依赖于supar水平，将在梅萨队列中进行评估 参与者开始跨supar四分位数的他汀类药物，并确定supar是否是 他汀类药物和结果之间的关联。拟议的研究有可能解决未得到的 仅在美国，就需要近5000万患有CKD的人，确定急需的治疗 长期以来一直停滞的领域的目标和管理策略。