Regulation of inflammasome activation in diabetic nephropathy

糖尿病肾病炎症小体激活的调控

• 批准号: 280167011
• 负责人: Dr. Khurrum Shahzad
• 金额: --
• 依托单位: Institut für Laboratoriumsmedizin, Klinische Chemie und Molekulare Diagnostik
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2015
• 资助国家: 德国
• 起止时间: 2014-12-31 至 2019-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/280167011?language=en
• 关键词: Regulation; inflammasome; activation; diabetic; nephropathy

Recent data demonstrated that glomerular cells express inflammasome regulators. In addition, non-myeloid derived cells within the kidney contribute to the disease course of diabetic nephropathy. However, unambiguous evidence supporting a pathogenetic role of the inflammasome in glomerular cells is still lacking. Likewise, the functional consequence of the inflammasome in glomerular cells, including the potential role of the non-canonical inflammasome and pyroptosis, are unknown. Furthermore, the mechanisms controlling inflammasome activation in glomerular cells are not known hitherto. Based on preliminary data we hypothesis that inflammasome activation glomerular cells, including in particular podocytes, contributes to glomerulopathy in diabetic nephropathy. We propose that pyroptosis, which is associated with sterile inflammation, is the primordial form of cell death in the context of diabetic nephropathy. Based on preliminary data we postulate that signalling via coagulation proteases, the ER-stress response, mTOR, autophagy, and mitochondrial dysfunction with increased ROS generation controls inflammasome activation in podocytes. Furthermore, based on preliminary data we hypothesize that persistent induction of the inflammasome, potential by epigenetic mechanism, contributes to the metabolic memory, generating a pro-inflammatory micromilieu in the renal glomeruli. To evaluate these hypotheses we will evaluate the following goals: To Goal 1: Defining the cell-autonomous effects of inflammasome activation in podocytes. Within this aim we will use cultured podocytes, in single and mixed cultures, to define the cell-autonomous function of inflammasome regulators in cells of the glomerular filtration barrier. These studies will be combined with in vivo studies using mice with targeted inactivation of inflammasome regulators. To Goal 2: Define the mechanism through which coagulation proteases regulate inflammasome activation in diabetic nephropathy.Within this aim we aim to define the mechanism controlling inflammasome activation in podocytes, focusing on coagulation proteases, their receptors, and potential intracellular signalling via p66Shc or the ER, mTOR, and autophagy. In vitro studies will be combined with in vivo studies. To Goal 3: Characterize the relevance of epigenetic gene induction for persistent inflammasome activation in dNP.Using a combination of in vivo and in vitro approaches we aim to define the relevance and the mechanism of sustained inflammasome activation in the context of diabetic nephropathy.

最近的数据表明，肾小球细胞表达炎性体调节剂。此外，肾脏内的非髓源性细胞有助于糖尿病肾病的病程。然而，明确的证据支持炎症小体在肾小球细胞中的致病作用仍然缺乏。同样，肾小球细胞中炎性小体的功能后果，包括非典型炎性小体和焦亡的潜在作用，也是未知的。此外，控制肾小球细胞中炎性小体活化的机制迄今尚不清楚。基于初步数据，我们假设炎症小体激活肾小球细胞，特别是足细胞，有助于糖尿病肾病的肾小球病变。我们认为，与无菌炎症相关的细胞火灾是糖尿病肾病背景下细胞死亡的原始形式。基于初步的数据，我们推测，通过凝血蛋白酶，ER-应激反应，mTOR，自噬和线粒体功能障碍与ROS生成增加的信号控制足细胞中的炎性小体激活。此外，基于初步数据，我们假设持续诱导的炎性小体，潜在的表观遗传机制，有助于代谢记忆，在肾小球中产生促炎性微环境。为了评估这些假设，我们将评估以下目标：目标1：定义足细胞中炎性小体激活的细胞自主效应。在这个目标内，我们将使用培养的足细胞，在单一和混合的文化，以确定肾小球滤过屏障细胞中的炎性小体调节剂的细胞自主功能。这些研究将与使用炎性体调节剂靶向失活的小鼠的体内研究相结合。 目标2：明确凝血蛋白酶调节糖尿病肾病炎症小体激活的机制。在此目标下，我们旨在明确足细胞炎症小体激活的控制机制，重点关注凝血蛋白酶及其受体，以及通过p66 Shc或ER、mTOR和自噬的潜在细胞内信号传导。体外研究将与体内研究相结合。目标3：表征表观遗传基因诱导与dNP中持续炎性小体激活的相关性。使用体内和体外方法的组合，我们的目标是定义糖尿病肾病背景下持续炎性小体激活的相关性和机制。