Role of Amphiregulin in kidney fibrosis

双调蛋白在肾纤维化中的作用

基本信息

批准号：
10683349
负责人：
Andreas Herrlich
金额：
$ 40.33万
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
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/10683349
关键词：
Acute Renal Failure with Renal Papillary Necrosis Affect Amphiregulin Ancillary Study Bilateral Biological Markers Biopsy Boston Cell Separation Cell surface Cells Chemicals Chronic Kidney Failure Chronic Kidney Insufficiency Cohort Studies Collaborations Creatinine DTR gene Data Detection Development Disease Outcome Disease Progression Disintegrins EGF gene Epidermal Growth Factor Receptor Exclusion 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 Ligands Link Macrophage 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 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 mortality nephrogenesis new therapeutic target novel novel therapeutics prevent profibrotic cytokine repaired technology development therapeutic biomarker therapeutic target

项目摘要

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.

项目概要摘要我们研究的总体目标是开发新的治疗和检测/监测策略来预防慢性肾脏病（CKD）和纤维化的进展。缺血再灌注引起的急性肾损伤（AKI）小鼠损伤 (IRI) 或单侧输尿管梗阻 (UUO) 诱导持续 EGFR 激活和肾纤维化这是通过 EGFR 化学抑制或其近端小管细胞 (PTC) 中的基因缺失来预防的。这所涉及的具体 EGFR 配体仍然未知。我们证明了 A-解整合素和金属蛋白酶-17 (ADAM17) 近端小管敲除可防止损伤诱导的纤维化，确定促纤维化的来源 PTC 的 EGFR 配体。在受伤的小鼠肾脏中，EGFR 配体双调蛋白原 (pro-AREG) 非常活跃。强烈上调，在人类中，AKI 和 CKD 患者尿液中的 sAREG 显着升高，以及纤维化 CKD 肾活检。体外，在人近曲小管细胞 (HPTC) 中，sAREG 诱导持续的 EGFR 激活和促纤维化靶点。（Kefalogianni JCI Insight 2016）。此举的目的应用的目的是确定 sAREG 在 AKI 后早期和晚期损伤修复阶段的作用，并牢固地联系起来人类患者样本中的 sAREG 与肾纤维化和 CKD 进展有关。我们的中心假设是双调蛋白 (sAREG) 是关键的表皮生长因子受体 (EGFR) 配体，负责诱导并放大肾损伤中的促纤维化 EGFR 信号。我们基于初步数据，包括：(1) sAREG 基于 sAREG 注射和 PTC-KO，在小鼠肾损伤后诱导纤维化是充分且必要的小鼠研究 (2) 肾切除术患者队列的血清样本中 sAREG 显着升高 CKD 及其水平与肾功能参数呈负相关。该项目的理由是完成后将确定 sAREG 作为 CKD/纤维化的新治疗靶点和生物标志物，并确定涉及的分子机制。我们计划通过两个具体目标来检验我们的中心假设： AIM1：确定 AREG 对于 IRI 损伤后早期肾脏恢复和/或肾纤维化的发展是否是必要的。目标 2：在波士顿肾活检中将 sAREG 与人类肾纤维化程度和 CKD 分期联系起来队列（BKBC，n=770）和慢性肾功能不全队列（CRIC，n=3889）中的 CKD 进展。这里我们将把 sAREG 血清/尿液水平与活检中的肾纤维化和 CKD 进展相关联，并进行比较与目前使用的肾脏生物标志物（肌酐、蛋白尿）相关。作为结果，我们期望 AREG 近端小管敲除可防止损伤引起的纤维化，并且 sAREG 水平与 CKD 相关结果和表现优于当前的生物标志物（肌酐、蛋白尿）。这个贡献意义重大因为它预计会对 CKD/纤维化的检测、预防和治疗产生影响。我们的研究是我们认为这是创新的，因为它将首次识别出直接影响肾脏纤维化的生物标志物。在机制上与纤维化过程相关，可用于治疗靶向和监测。