Inflammasome components NLRP3/ASC in epithelial cells and resident dendritic cells of the kidney

肾脏上皮细胞和常驻树突状细胞中的炎症小体成分 NLRP3/ASC

• 批准号: 416495184
• 负责人: Professor Dr. Hans-Joachim Anders
• 金额: --
• 依托单位: Medizinische Klinik und Poliklinik IV
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2018
• 资助国家: 德国
• 起止时间: 2017-12-31 至 2022-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/416495184?language=en
• 关键词: Inflammasome; components; NLRP3; ASC; epithelial

The NLRP3/ASC inflammasome is an intracellular signaling platform integrating multiple danger signals and activating local and systemic inflammation into proelolytic activation of IL-1beta and IL-18. During the last 10 years the functional importance of the NLRP3/ASC inflammasome has been well-documented for multiple acute and chronic disease states. We contributed to this effort by characterizing the roles of NLRP3 in kidney diseases. There is a broad consensus on ist role in dendritic cells and macrophages but NLRP3/ASC are also expressed by renal epithelial cell, i.e. podocytes and tubular cells. However, little is known on their functional roles there. Unpublished preliminary data support pro-fibrotic and anti-inflammatory effects of NLRP3/ASC, which shall be dissected in detail in this project. To do so, we will use transgeneic mice with selective de- or overactivation of NLRP3/ASC specifically in podocytes, tubular cells, and resident dendritic cells. First, we will characterize their spontaneous phenotypes and second, we will challenge them with metabolic and toxic stress to unravel their respective cell type-specific roles in kidney disease. These studies will characterize previously unknown or underrecognized functions of NLRP3/ASC and will help to better define and critically evaluate NLRP3/ASC as a potential therapeutic target.

NLRP 3/ASC炎性体是一个细胞内信号平台，整合多种危险信号并激活局部和全身炎症，使其成为IL-1 β和IL-18的蛋白溶解激活。在过去的10年中，NLRP 3/ASC炎性体的功能重要性已被充分记录用于多种急性和慢性疾病状态。我们通过描述NLRP 3在肾脏疾病中的作用来为这一努力做出贡献。关于其在树突状细胞和巨噬细胞中的作用存在广泛共识，但NLRP 3/ASC也由肾上皮细胞（即足细胞和肾小管细胞）表达。然而，人们对他们在那里的职能作用知之甚少。未发表的初步数据支持NLRP 3/ASC的促纤维化和抗炎作用，本项目将对其进行详细剖析。为此，我们将使用在足细胞、肾小管细胞和常驻树突状细胞中特异性地选择性去活化或过度活化NLRP 3/ASC的转基因小鼠。首先，我们将描述它们的自发表型，其次，我们将用代谢和毒性应激来挑战它们，以揭示它们各自的细胞类型在肾脏疾病中的特异性作用。这些研究将表征NLRP 3/ASC以前未知或未被充分认识的功能，并将有助于更好地定义和严格评估NLRP 3/ASC作为潜在的治疗靶点。