Innate Immunity and NLRP3 inflammasome activation in pathologic neovascularization

病理性新生血管形成中的先天免疫和 NLRP3 炎性体激活

基本信息

批准号：
9319274
负责人：
Alexander Georg Marneros
金额：
$ 19.69万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
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：
2016-08-01 至 2018-07-31
项目状态：
已结题

项目摘要

SUMMARY Pathologic neovascularization is an important aspect of the inflammatory process. NLRP3 inflammasome activation has been implicated as a major regulator of pathologic angiogenesis through secretion of proangiogenic factors (e.g. IL-1β). Targeting the NLRP3 inflammasome or its regulators may therefore represent a novel therapeutic approach to inhibit inflammation and pathologic neovascularization. For example, we could show in a novel genetic mouse model of VEGF-A-induced neovascular age-related macular degeneration (AMD) that genetic inactivation of the NLRP3 inflammasome can potently inhibit the manifestation of neovascular lesions. This mouse model of neovascular AMD serves as a particularly disease-relevant model system to assess the mechanisms through which the NLRP3 inflammasome promotes inflammation and pathologic angiogenesis. In vitro studies have suggested that autophagy and TLR-signaling pathways are important regulators of NLRP3 inflammasome activity. However, the role of these pathways for NLRP3 inflammasome activation and pathologic neovascularization in vivo remain unclear. We propose that increasing autophagy or inhibiting TLR-signaling could be utilized to control NLRP3 inflammasome activation. Here, we will use our novel genetic mouse model of neovascular AMD that allows precise quantitation of neovascular lesions as an experimental in vivo model system to determine the contributions of autophagy and TLR-signaling for NLRP3 inflammasome activation and subsequent pathologic angiogenesis using mouse genetic approaches. These experiments are likely to reveal the importance of these pathways as regulators of NLRP3 inflammasome-mediated inflammation. Moreover, our in vivo experiments have significant translational relevance and will help determine whether stimulating autophagic activity or inhibiting TLR-signaling represent promising novel therapeutic approaches to block pathologic angiogenesis in conditions such as neovascular AMD.

概括病理性新生血管形成是炎症过程的一个重要方面。炎症小体激活被认为是病理性血管生成的主要调节因子通过分泌促血管生成因子（例如 IL-1β）靶向 NLRP3 炎性体。因此或其调节剂可能代表一种抑制炎症的新治疗方法例如，我们可以在新型基因小鼠中展示。 VEGF-A诱导的新生血管性年龄相关性黄斑变性（AMD）模型 NLRP3炎症小体失活可有效抑制新生血管的表现这种新生血管AMD小鼠模型是一种与疾病特别相关的模型。评估 NLRP3 炎症小体促进机制的模型系统炎症和病理性血管生成。体外研究表明自噬和 TLR 信号通路很重要然而，这些途径对于 NLRP3 的作用。体内炎症小体激活和病理性新生血管形成仍不清楚。提出可以利用增加自噬或抑制 TLR 信号传导来控制 NLRP3 炎症体激活在这里，我们将使用我们的新型遗传小鼠模型。新生血管 AMD，可作为实验对新生血管病变进行精确定量体内模型系统，以确定自噬和 TLR 信号传导的贡献使用小鼠进行 NLRP3 炎性体激活和随后的病理性血管生成这些实验可能揭示这些途径的重要性。作为NLRP3炎症小体介导的炎症的调节剂，我们的体内。实验具有重要的转化相关性，将有助于确定是否刺激自噬活性或抑制 TLR 信号传导是有前途的新方法在新生血管等疾病中阻断病理性血管生成的治疗方法 AMD。