Nlrp3 inflammasome activation in early diabetic retinopathy

早期糖尿病视网膜病变中 Nlrp3 炎性体激活

• 批准号: 10626060
• 负责人: Jayakrishna Ambati
• 金额: $ 47.28万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-01 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10626060
• 关键词: Ablation; Acute; Address; Affect; Age related macular degeneration; Alzheimer' s Disease; Animal Model; Apoptosis; Atherosclerosis; Blindness; Blood Vessels; Blood-Retinal Barrier; CASP1 gene; Cell Death; Cell model; Cells; Chronic; Clinical; Complex; Complication; Defect; Diabetes Mellitus; Diabetic Retinopathy; Diabetic mouse; Dimensions; Disease; Dose; Exhibits; Eye diseases; Functional disorder; Genetic; Genetic Recombination; Glucose; Goals; Hemorrhage; Human; Immune; Immune signaling; In Situ; Individual; Inflammasome; Inflammatory; Insulin-Dependent Diabetes Mellitus; Intervention; Knock-out; Knowledge; Leukostasis; Lytic; Measures; Medical; Methods; Microvascular Dysfunction; Mitochondria; Modeling; Molecular Biology Techniques; Mus; Myeloid Cells; Nerve Degeneration; Neuroglia; Neurons; Nonesterified Fatty Acids; Pathogenesis; Pathologic; Pathologic Processes; Pathology; Pathway interactions; Patients; Peptide Hydrolases; Persons; Phenotype; Pre-Clinical Model; Process; Production; Reactive Oxygen Species; Reporter Genes; Research; Retina; Retinal Diseases; Rheumatoid Arthritis; Risk; Role; Sampling; Signal Transduction; Source; Streptozocin; Streptozocin Diabetes; Testing; Therapeutic; Transgenic Organisms; Vision; cell type; cytokine; diabetes management; diabetic; efficacy evaluation; efficacy testing; endothelial dysfunction; inhibitor; insight; islet amyloid polypeptide; mouse model; neural; neural model; neurovascular; pathogen; pharmacologic; pre-clinical; prevent; promoter; recruit; response; stressor

Abstract/Summary 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.

摘要/总结 糖尿病视网膜病变 (DR) 的标志性病理过程包括神经和神经胶质功能障碍、 炎症细胞、内皮功能障碍、血管闭塞和血视网膜屏障丧失。 炎症小体是先天免疫信号平台，与对外来病原体的急性反应有关 以及许多慢性神经退行性和炎症相关疾病。炎症小体阻断是 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、 年龄相关性黄斑变性和类风湿性关节炎。临床和临床前证据表明 炎症小体活动也可能通过促进产生 炎症细胞因子、白细胞停滞和微血管完整性丧失。尽管有这些证据，但在 关于炎症小体的时间、细胞来源和病理影响的知识仍然存在 糖尿病视网膜病变背景下的激活。该提案的总体假设是 NLRP3 循环免疫细胞和驻留神经胶质细胞中的炎症小体激活驱动神经元和微血管 糖尿病视网膜病变的功能障碍。我们将在三个具体目标中检验这一假设：1）我们寻求识别细胞 在 1 型糖尿病动物模型中表现出炎症体激活的类型及其时间； 2）我们 寻求确定核心炎性体成分对标志性病理表型的贡献 糖尿病引起的视网膜病变的动物模型。为了实现这一目标，我们将利用全局和细胞特定的 糖尿病模型中炎症小体成分的基因敲除； 3）我们试图测试其功效 药理学炎症小体抑制剂在神经、免疫和血管缺陷临床前模型中的应用 糖尿病。总的来说，这些主题相关但独立的目标将建立以下贡献： 视网膜糖尿病病理过程中的炎症小体。这些研究可能因此开启新的 针对这种普遍致盲情况的介入途径。