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

来源：
https://reporter.nih.gov/project-details/9319274
关键词：
Affect Age related macular degeneration Autophagocytosis Biological Models CASP1 gene Cells Data Disease Endothelial Cells Experimental Models Exudative age-related macular degeneration Eye Genetic Growth IL1R1 gene In Vitro Inflammasome Inflammation Inflammatory Interleukin-1 beta Lesion Lipids Mediating Mus Natural Immunity Pathologic Pathologic Neovascularization Pathology Pathway interactions Patients Play Process Reporting Role Signal Pathway Signal Transduction Structure of retinal pigment epithelium System TLR2 gene Testing Therapeutic Vascular Endothelial Growth Factors angiogenesis base cell type experimental study genetic approach in vivo in vivo Model inhibitor/antagonist mouse model neovascular neovascularization novel novel therapeutic intervention oxidation oxidative damage therapeutic target

Affect Age related macular degeneration Autophagocytosis Biological Models CASP1 gene Cells Data Disease Endothelial Cells Experimental Models Exudative age-related macular degeneration Eye Genetic Growth IL1R1 gene In Vitro Inflammasome Inflammation Inflammatory Interleukin-1 beta Lesion Lipids Mediating Mus Natural Immunity Pathologic Pathologic Neovascularization Pathology Pathway interactions Patients Play Process Reporting Role Signal Pathway Signal Transduction Structure of retinal pigment epithelium System TLR2 gene Testing Therapeutic Vascular Endothelial Growth Factors angiogenesis base cell type experimental study genetic approach in vivo in vivo Model inhibitor/antagonist mouse model neovascular neovascularization novel novel therapeutic intervention oxidation oxidative damage therapeutic target

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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.

概括病理新血管形成是炎症过程的重要方面。 nlrp3 炎性体激活已被暗示为病理血管生成的主要调节剂通过分泌促血管生成因子（例如IL-1β）。靶向NLRP3炎症体因此，其调节剂可能代表一种抑制注射的新型治疗方法和病理新生血管形成。例如，我们可以在新的遗传小鼠中显示 VEGF-A诱导的新血管年龄相关的黄斑变性（AMD）的模型 NLRP3炎性体的失活可能会抑制新生血管的表现病变。这种新生血管AMD的小鼠模型与疾病有关评估NLRP3炎性体促进的机制的模型系统炎症和病理血管生成。体外研究表明自噬和TLR信号途径很重要 NLRP3炎性体活动的调节剂。但是，这些途径在NLRP3中的作用体内炎性体激活和病理新生血管化尚不清楚。我们提议可以利用增加自噬或抑制TLR信号来控制 NLRP3炎性体激活。在这里，我们将使用我们的新型遗传鼠标模型新生血管AMD，可以精确定量新血管病变作为实验体内模型系统，以确定自噬和TLR信号的贡献 NLRP3炎性体激活和随后使用小鼠的病理血管生成遗传方法。这些实验可能揭示了这些途径的重要性作为NLRP3炎性体介导的炎症的调节剂。而且，我们的体内实验具有显着的转化相关性，将有助于确定是否是否刺激自噬活性或抑制TLR信号代表有望的新颖在新生血管中阻断病理血管生成的治疗方法 AMD。