Nlrp3 inflammasome activation in early diabetic retinopathy - Administrative Supplement ERG Request

项目概要/摘要 糖尿病性视网膜病变（DR）的标志性病理过程包括神经和胶质功能障碍， 炎症细胞、内皮功能障碍、血管阻塞和血视网膜屏障丧失。 炎性小体是先天性免疫信号传导平台，涉及对外来病原体的急性反应， 以及许多慢性神经变性和炎症相关疾病。炎性小体阻断是 正在探索多种复杂的神经血管疾病，包括阿尔茨海默病，动脉粥样硬化， 老年性黄斑变性和类风湿性关节炎。临床和临床前证据表明， 炎性小体活性也可能通过促进 炎性细胞因子、白细胞停滞和微血管完整性丧失。尽管有这些证据， 关于炎性小体形成的时间、细胞来源和病理学意义的知识仍然存在， 在糖尿病视网膜病变的背景下激活。该提案的总体假设是，NLRP 3 循环免疫细胞和驻留神经胶质细胞中的炎性小体激活驱动神经元和微血管 糖尿病性视网膜病变我们将在三个具体目标中测试这一假设：1）我们试图识别细胞 在1型糖尿病动物模型中表现出炎性小体活化的类型及其时机; 2）我们 试图确定核心炎性小体成分对HLA-DR中标志性病理表型的贡献， 糖尿病视网膜病变的动物模型。为了实现这一点，我们将利用全局和特定于单元的 糖尿病模型中炎性体成分的基因敲除; 3）我们试图测试 药理学炎性体抑制剂在临床前模型的神经，免疫和血管缺陷，由于 糖尿病总的来说，这些主题相关，但独立的目标将确定的贡献， 炎症小体在糖尿病视网膜病变过程中的作用。这些研究可能会开启新的 这种普遍设盲情况的干预途径。

PROJECT SUMMARY/ABSTRACT Hallmark pathologic processes of diabetic retinopathy (DR) include neural and glial dysfunction, recruitment of inflammatory cells, endothelial dysfunction, vascular occlusion, and loss of the blood retinal barrier. Inflammasomes are innate immune signaling platforms implicated in acute responses to foreign pathogens as well as numerous chronic neurodegenerative- and inflammatory-related diseases. Inflammasome blockade is being explored for multiple complex neurovascular conditions including Alzheimer's disease, atherosclerosis, age-related macular degeneration, and rheumatoid arthritis. Clinical and preclinical evidence suggest that inflammasome activity may also contribute to pathological hallmarks of DR by promoting production of inflammatory cytokines, leukostasis, and loss of microvascular integrity. Despite this evidence, major gaps in knowledge persist with respect to the timing, cellular sources, and pathological implications of inflammasome activation in the context of diabetic retinopathy. The overall hypothesis of this proposal is that NLRP3 inflammasome activation in circulating immune cells and resident neuroglia drives neuronal and microvascular dysfunction in diabetic retinopathy. We will test this hypothesis in three specific aims: 1) We seek to identify cell types that exhibit inflammasome activation and the timing thereof in an animal model of type 1 diabetes; 2) We seek to determine the contribution of core inflammasome constituents to hallmark pathological phenotypes in animal models of retinal pathologies due to diabetes. To accomplish this, we will utilize global and cell-specific genetic knockouts of inflammasome constituents in models of diabetes; 3) We seek to test the efficacy of pharmacological inflammasome inhibitors in preclinical models of neural, immune, and vascular defects due to diabetes. Collectively, these thematically related, but independent aims will establish the contribution of inflammasome in pathological processes of diabetes in the retina. These studies may thereby open new interventional avenues for this prevalent blinding condition.