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: 10198038
• 负责人: Salim Hayek
• 金额: $ 54.76万
• 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/10198038
• 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; 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.

项目概要 慢性肾病 (CKD) 患者占美国人口的 15% 以上， 由于未得到充分重视的原因，他们承受着不成比例的高心血管疾病（CVD）负担 炎症代表了动脉粥样硬化和动脉粥样硬化的主要病理生理过程。 最近，发现了一种将 CVD 和 CKD 与骨髓联系起来的新炎症途径。 产生循环信号分子的骨髓细胞：可溶性尿激酶纤溶酶原激活剂受体 (suPAR) 是由未成熟的骨髓细胞针对环境暴露和 CVD 风险而释放的。 在循环中，suPAR 会改变肾小球和肾小管功能，长期暴露会导致肾小球和肾小管功能改变。 实验模型中suPAR的药理学抑制可预防肾功能障碍。 SuPAR 水平还可以独立于肾功能预测不良心血管结局，以及 优于公认的 CVD 风险标志物，例如冠状动脉钙、C 反应蛋白、高灵敏度 这些令人信服的数据揭示了 suPAR 不仅作为一种药物的潜力。 suPAR 在 CVD 中的作用是极好的风险生物标志物，而且也是一个有前途的治疗靶点。 该提案的总体目标是阐明 suPAR 在该问题中的潜在因果作用。 我们将通过流行病学的见解来了解动脉粥样硬化的进展及其与肾功能下降的关系。 通过利用对心血管科学最重要的三个贡献来实现这一目标： 具有里程碑意义的动脉粥样硬化多种族研究 (MESA)；一项由 NIH 资助的前瞻性队列研究，其中参与者 JUPITER 试验对动脉粥样硬化的亚临床标志物进行了系列测量，其中 C 反应蛋白水平高的参与者被随机分配到他汀类药物或安慰剂，英国生物银行 (UK Biobank) 将在 MESA 的 5,620 名参与者中测量超过 500,000 名志愿者的 SuPAR 水平。 确定水平是否与 CVD 早期标志物相关，并独立预测其进展 为了评估潜在的因果关系，一项针对 suPAR 水平的全基因关联研究。 MESA，然后是英国生物银行数据集中的孟德尔随机化分析，将连接遗传 suPAR 水平对 CVD 和 CKD 的决定因素 最后，确定 suPAR 是否是一个可改变的危险因素。 对于 CVD，将连续测量随机服用瑞舒伐他汀的 JUPITER 试验参与者的水平 (n=200) 或安慰剂 (n=200)，并且将比较组间 suPAR 的变化是否有益处。 他汀类药物依赖于 suPAR 水平，将通过比较 MESA 队列中的生存率来评估 参与者开始在 suPAR 四分位数上使用他汀类药物，并确定 suPAR 是否是 他汀类药物与结果之间的关联。拟议的研究有可能解决未满足的问题。 仅在美国就有近 5000 万 CKD 患者的需求，确定了急需的治疗方法 长期停滞不前的领域的目标和管理策略。