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Role of ADAM17 substrates in Progressive Kidney Disease

ADAM17 底物在进行性肾病中的作用

基本信息

批准号：
9355173
负责人：
Andreas Herrlich
金额：
$ 34.31万
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-09-20 至 2020-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9355173
关键词：
Acute Renal Failure with Renal Papillary Necrosis Amphiregulin Angiotensin II Cells Chronic Chronic Kidney Failure Cleaved cell Clinical Combined Modality Therapy Data Development Dialysis procedure Disease Disease Progression Disease model Drug Targeting ERBB3 gene Epidermal Growth Factor Epidermal Growth Factor Receptor Erlotinib Etanercept Fibroblasts Fibrosis Goals Health Expenditures Heterodimerization Human Inflammation Inflammation Mediators Inflammatory Inflammatory Response Injury Ischemia Kidney Kidney Diseases Knock-out Knowledge Lead Lesion Ligands Losartan Mediating Medical Metalloproteases Mission Modeling Molecular Morbidity - disease rate Mus NRG1 gene Outcome Pathway interactions Patients Pharmaceutical Preparations Phase Phosphorylation Population Production Proteins Public Health RAS inhibition Rattus Research Role Sampling Small Interfering RNA Surface TNF gene TNFRSF1A gene Testing Therapeutic Tissue Sample Transforming Growth Factor beta Tubular formation Ubiquitination Up-Regulation Ureteral obstruction Urine base cytokine defined contribution in vivo inhibitor/antagonist injury and repair innovation knock-down mortality mouse model new therapeutic target novel prevent public health relevance repaired socioeconomics translational approach translational impact tumor necrosis factor precursor tumor necrosis factor-alpha inhibitor

项目摘要

DESCRIPTION (provided by applicant): Therapies to prevent or treat progressive kidney disease associated with fibrosis are lacking. The overall goal of this application is to evaluate the therapeutic potential of inhibition of ADAM17 or of its substrates in progressive kidney disease and to define molecular mechanisms whereby ADAM17 substrates promote kidney disease progression. Our central hypothesis is that the select proximal tubular ADAM17-cleaved substrates promote progressive kidney disease and that both pathways interact and synergize in their injurious actions. We base this hypothesis on preliminary data in ADAM17 hypomorph mice, in a mouse model with inducible proximal tubule-specific ADAM17 knockout, in human samples and in proximal tubular cells. As compared to controls, both mouse models show strongly reduced inflammation and fibrosis after severe AKI or UUO. The rationale underlying the proposed research is that completion will enable us to understand when pro-fibrotic ADAM17-dependent pathway activation occurs during injury/repair, what ADAM17 substrates and molecular mechanisms are involved, how it compares to standard therapy with RAS inhibition and whether available drugs targeting ADAM17-dependent pathways could be repurposed for the treatment of progressive kidney disease. To test this hypothesis, we propose the following three Specific Aims: Aim 1: Define the role and timing of activation of select ADAM17-dependent pathways in kidney disease progression associated with fibrosis, using severe AKI and UUO in mice as models of fibrotic disease. Here we will compare ADAM17 inhibition and inhibition of select ADAM17 pathways with AT1R blockade (current best CKD therapy) or a combination of these therapies. Aim 2: Test the role of select proximal-tubule released ADAM17 substrates in progressive kidney disease. Aim 3: Define cellular mechanisms of select ADAM17 substrate-induced pro- fibrotic EGFR-pathway activation in tubular cells and fibroblasts. It is anticipated that these Aims will yield the following outcomes: (1) We expect to establish select ADAM17 substrates as critical drivers of kidney fibrosis and highlight translational approaches to inhibit them clinically in humans. (2) We will define molecular mechanisms that allow select ADAM17 substrates to be particularly pro-fibrotic. Such results are expected to fundamentally advance our understanding of progressive kidney disease associated with fibrosis. This contribution is significant because it is expected to have a positiv translational impact because drugs for inhibition of select ADAM17 substrates or their downstream effects are already in clinical use and could be repurposed for kidney disease. The research proposed in this application is innovative, in our opinion, because it represents a new and substantive departure from the status quo - no specific fibrosis therapies available - by shifting focus to new drug targets, ADAM17 and its substrates, for the treatment of progressive kidney disease.

描述（由申请人提供）：缺乏预防或治疗与纤维化相关的进行性肾脏疾病的疗法。本申请的总体目标是评价在进行性肾病中抑制ADAM 17或其底物的治疗潜力，并确定ADAM 17底物促进肾病进展的分子机制。我们的中心假设是，选择近端肾小管ADAM 17切割底物促进进行性肾脏疾病，这两种途径相互作用，并协同其有害作用。我们基于这一假设的初步数据，在ADAM 17亚型小鼠，在小鼠模型与诱导近端小管特异性ADAM 17敲除，在人类样本和近端肾小管细胞。与对照相比，两种小鼠模型在严重阿基或UUO后均显示出炎症和纤维化的强烈减少。拟议研究的基本原理是，完成这项研究将使我们能够了解在损伤/修复过程中促纤维化的ADAM 17依赖性通路激活何时发生，涉及哪些ADAM 17底物和分子机制，如何与RAS抑制的标准治疗进行比较，以及是否可以将现有的靶向ADAM 17依赖性通路的药物重新用于治疗进行性肾脏疾病。为了验证这一假设，我们提出了以下三个具体目标：目标1：使用小鼠中的严重阿基和UUO作为纤维化疾病模型，确定选择的ADAM 17依赖性途径在与纤维化相关的肾脏疾病进展中的作用和激活时间。在这里，我们将比较ADAM 17抑制和选择ADAM 17通路的抑制与AT 1 R阻断（目前最好的CKD治疗）或这些治疗的组合。目的2：检测选择的近端小管释放的ADAM 17底物在进行性肾脏疾病中的作用。目的3：确定肾小管细胞和成纤维细胞中选择性ADAM 17底物诱导的促纤维化EGFR途径活化的细胞机制。预计这些目标将产生以下结果：（1）我们预计将选择ADAM 17底物作为肾纤维化的关键驱动因素，并强调在人类临床上抑制它们的转化方法。(2)我们将定义允许选择ADAM 17底物特别促纤维化的分子机制。这些结果有望从根本上推进我们对与纤维化相关的进行性肾脏疾病的理解。这一贡献是显著的，因为预期其具有积极的翻译影响，因为用于抑制选择的ADAM 17底物或其下游效应的药物已经在临床上使用，并且可以重新用于肾脏疾病。在我们看来，本申请中提出的研究是创新的，因为它代表了一种新的实质性偏离现状-没有特定的纤维化疗法-通过将重点转移到新的药物靶点，ADAM 17及其底物，用于治疗进行性肾脏疾病。