Role of Amphiregulin in kidney fibrosis

双调蛋白在肾纤维化中的作用

• 批准号: 10018030
• 负责人: Andreas Herrlich
• 金额: $ 41.98万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-15 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10018030
• 关键词: Acute Renal Failure with Renal Papillary Necrosis; Affect; Amphiregulin; Ancillary Study; Bilateral; Biological Markers; Biopsy; Boston; Cell surface; Cells; Chemicals; Chronic Kidney Failure; Chronic Kidney Insufficiency; Cleaved cell; Cohort Studies; Collaborations; Creatinine; DTR gene; Data; Detection; Development; Disease Outcome; Disease Progression; Disintegrins; EGF gene; Epidermal Growth Factor Receptor; Fibrosis; Genes; Genetic; Genetic Transcription; Glomerulonephritis; Goals; Health Expenditures; Human; Hyperoxaluria; Immunity; In Vitro; Inflammatory; Injections; Injury; Injury to Kidney; Kidney; Knock-out; Knockout Mice; Lead; Ligands; Link; Measurement; Messenger RNA; Metalloproteases; Mission; Molecular; Monitor; Morbidity - disease rate; Mus; National Institute of Diabetes and Digestive and Kidney Diseases; Nephrectomy; Outcome; Patients; Phenotype; Play; Prevention; Process; Proteins; Proteinuria; Receptor Activation; Receptor Signaling; Recovery; Renal function; Reperfusion Injury; Reporting; Research; Research Personnel; Role; Sampling; Serum; Severities; Source; Structure; Technology; Testing; Therapeutic Uses; Time; Transforming Growth Factor beta; Up-Regulation; Ureteral obstruction; Urine; base; cohort; cytokine; diabetic; in vivo; injured; injury and repair; innovation; insight; kidney biopsy; kidney fibrosis; macrophage; mortality; nephrogenesis; new therapeutic target; novel; novel therapeutics; prevent; repaired; targeted biomarker; technology development; therapeutic target

PROJECT SUMMARY ABSTRACT The overall goal of our research is to develop novel therapeutic and detection/monitoring strategies to prevent progression of chronic kidney disease (CKD) and fibrosis. Acute kidney injury (AKI) due to ischemia reperfusion injury (IRI) or unilateral ureteral obstruction (UUO) in mice induces sustained EGFR activation and kidney fibrosis which is prevented by EGFR chemical inhibition or its genetic deletion in proximal tubule cells (PTCs). The specific EGFR ligand(s) involved remain unknown. We showed that A-disintegrin-and-metalloprotease-17 (ADAM17) proximal tubule knockout protects against injury-induced fibrosis, identifying the source of pro-fibrotic EGFR ligands to PTCs. In the injured mouse kidney, the EGFR ligand pro-Amphiregulin (pro-AREG) was very strongly upregulated and in humans sAREG was very significantly elevated in the urine of AKI and CKD patients, as well as fibrotic CKD kidney biopsies. In vitro, in human proximal tubule cells (HPTCs), sAREG induced sustained EGFR activation and pro-fibrotic targets. (Kefalogianni JCI Insight 2016). The objective of this application is to determine the role of sAREG in early vs. late injury-repair stages after AKI and to firmly link sAREG in human patient samples to kidney fibrosis and to CKD progression. Our central hypothesis is that Amphiregulin (sAREG) is the key epidermal growth factor receptor (EGFR) ligand that is responsible for inducing and amplifying pro-fibrotic EGFR signals in kidney injury. We base this on preliminary data including: (1) sAREG is sufficient and necessary to induce fibrosis after kidney injury in mice, based on sAREG injection and PTC-KO studies in mice (2) sAREG is significantly elevated in serum samples of a nephrectomy cohort of patients with CKD and its levels correlate negatively with kidney function parameters. The rationale for this project is that completion will identify sAREG as a novel therapeutic target and biomarker in CKD/fibrosis, and identify molecular mechanisms involved. We plan to test our central hypothesis with two specific aims: AIM1: Determine whether AREG is necessary for early renal recovery and/or the development of kidney fibrosis after IRI injury. AIM2: To link sAREG to degree of kidney fibrosis and stage of CKD in humans in the Boston Kidney Biopsy Cohort (BKBC, n=770) and to CKD progression in the Chronic-Renal-Insufficiency-Cohort (CRIC, n=3889). Here we will correlate sAREG serum/urine levels to kidney fibrosis on biopsy and CKD progression, and compare this to correlation with currently used kidney biomarkers (Creatinine, proteinuria). As outcomes, we expect that AREG proximal tubule knockout protects against injury-induced fibrosis and that sAREG levels correlate with CKD outcomes and perform better than current biomarkers (creatinine, proteinuria). This contribution is significant because it is expected to have impact on CKD/fibrosis detection, prevention and treatment. Our research is innovative, in our opinion, because, it would for the first time identify a kidney fibrosis biomarker that is directly mechanistically connected to the fibrotic process and could be used for therapeutic targeting and monitoring.

项目摘要摘要 我们研究的总体目标是制定新颖的治疗和检测/监测策略以防止 慢性肾脏疾病（CKD）和纤维化的进展。由于缺血再灌注而引起的急性肾脏损伤（AKI） 小鼠的损伤（IRI）或单侧输尿管阻塞（UUO）诱导EGFR激活和肾纤维化 EGFR化学抑制作用或其在近端小管细胞（PTC）中的遗传缺失阻止的。这 涉及的特定EGFR配体仍然未知。我们证明了a-二脑蛋白和甲甲基蛋白酶17 （ADAM17）近端小管敲除可预防损伤诱导的纤维化，鉴定了促纤维化的来源 EGFR配体到PTC。在受伤的小鼠肾脏中，EGFR配体Pro-Amphiregulin（Pro-Areg）非常 在AKI和CKD患者的尿液中，强烈上调，人类的sareg升高非常明显。 以及纤维化的CKD肾脏活检。体外，在人近端小管细胞（HPTC）中，SAREG诱导 持续的EGFR激活和促纤维化靶标。 （Kefalogianni JCI Insight 2016）。这个目的 应用是确定SAREG在早期与后期伤害修复阶段的作用，并牢固链接 人类患者样品中的sareg到肾脏纤维化和CKD进展。我们的中心假设是 两极蛋白（SAREG）是负责诱导的关键表皮生长因子受体（EGFR）配体 并在肾脏损伤中扩增促纤维性EGFR信号。我们基于初步数据，包括：（1）sareg 基于SAREG注射和PTC-KO，足以诱导小鼠肾脏损伤后纤维化的必要 在小鼠（2）的研究中，sareg的研究显着升高 CKD及其水平与肾功能参数负相关。这个项目的理由是 完成将识别出SAREG是CKD/纤维化中的新型治疗靶标和生物标志物，并识别 涉及的分子机制。我们计划以两个具体的目的测试中心假设：AIM1：确定 IRI受伤后的肾纤维化是否需要早期肾脏恢复和/或发展。 AIM2：将SAREG与波士顿肾脏活检中人类的肾脏纤维化程度和CKD阶段联系起来 队列（BKBC，n = 770）和慢性肾脏不适 - 霍特（Cric，n = 3889）中的CKD进展。这里 我们将在活检和CKD进展的肾脏纤维化和肾脏纤维化方面相关联 与当前使用的肾脏生物标志物（肌酐，蛋白尿）相关。作为结果，我们希望AREG 近端小管敲除可预防损伤引起的纤维化，而sareg水平与CKD相关 结果和表现更好，比目前的生物标志物（肌酐，蛋白尿）。这项贡献很重要 因为预计它会对CKD/纤维化检测，预防和治疗产生影响。我们的研究是 在我们看来，创新性，因为它首次确定了直接的肾脏纤维化生物标志物 机械上连接到纤维化过程，可用于治疗靶向和监测。