suPAR and renal fibrosis

摘要 慢性肾脏疾病(CKD)是死亡率的主要驱动因素，也是#年医疗保健的经济挑战。 美国。治疗选择是稀少的、间接的和不充分的，而慢性肾脏病正在成长为 这是我们这个时代最大的未满足的医疗需求之一。 一旦肾脏受损，疾病的进展取决于纤维化的程度，这是 不同的病人会有不同。我们和其他人已经做出了独特的观察，即可溶的 尿激酶型纤溶酶原激活物受体(UPAR)是发病和流行的危险因素 慢性肾脏病的各种肾脏疾病。SuPAR是一种三指毒素，由 骨髓中未成熟的髓样细胞，在血浆中循环，调节整合素的功能 在肾脏里。SuPAR水平升高或某些suPAR亚型的存在是因果关系 通过介导肾小球足细胞和近端肾小管上皮细胞的损伤参与CKD 与β整合素的特异性相互作用。以我们发表的和新颖的初步观察为基础 SuPAR介导的整合素激活推动了肾脏的纤维化程序，我们计划研究 SuPAR与不同β整合素在不同肾单位节段和 探讨其在促进肾小球和肾小管间质纤维化中的作用。三个独立目标 建议：首先，我们将确定翻译suPAR-αvβ3的分子机制 整合素信号在足细胞损伤和肾小球硬化中的表面等离子共振研究 检测、培养细胞实验和suPAR转基因小鼠模型。第二，我们将确定 肾小管损伤中驱动suPAR-αvβ6整合素信号转导的分子机制 通过遗传改变肾小管整合素功能的间质纤维化。第三，我们将 用基于多肽的阻断策略研究uPAR及其相关基因的治疗方法 相关的纤维化途径。这项提案中概述的实验将允许我们分离不同的 在肾脏纤维化的suPAR级联反应中的步骤，并确定最佳干预方案。因此，洞察力 这笔赠款将为预防和治疗策略提供基础，以对抗suPAR介导的 纤维化和慢性肾脏病。

Abstract Chronic kidney disease (CKD) is a major driver of mortality and a financial challenge for healthcare in the United States. Treatment options are scarce, indirect and not sufficient, whilst CKD is growing into one of the largest unmet medical needs of our time. Once the kidney is injured, progression of the disease is dependent on the degree of fibrosis, which can differ from patient to patient. We and others have made the unique observation that the soluble form of urokinase plasminogen activator receptor (uPAR) is a risk factor for incident and prevalent kidney diseases across the spectrum of CKD. suPAR is a three finger toxin that is produced by immature myeloid cells in the bone marrow and circulates in the plasma to regulate integrin function in the kidney. Elevated suPAR levels or the presence of certain suPAR isoforms are causally involved in CKD by mediating injury to both glomerular podocytes and proximal tubular cells through specific interactions with β integrins. Building on our published and novel preliminary observations that suPAR-mediated integrin activation drives fibrotic programs in the kidney, we plan to investigate the consequences of suPAR interactions with distinct β integrins in different nephron segments and explore its role in promoting both glomerular and tubulointerstitial fibrosis. Three independent aims are being proposed: First, we will determine the molecular mechanisms that translate suPAR-αvβ3 integrin signaling into podocyte injuries and glomerular sclerosis using surface plasmon resonance assays, cultured cell experiments and suPAR transgenic mouse models. Second, we will determine the molecular mechanisms that drive suPAR-αvβ6 integrin signaling in tubular injuries and tubulointerstitial fibrosis by genetically modifying the tubular integrin function. Third, we will investigate therapeutic modalities using peptide based blocking strategies for uPAR and its associated fibrotic pathways. Experiments outlined in this proposal will allow us to separate different steps in the suPAR cascade of kidney fibrosis and define best options to intervene. As such, insights from this grant will provide a basis for preventive and treatment strategies to combat suPAR mediated fibrosis and CKD.