Nlrp3 inflammasome activation in early diabetic retinopathy

早期糖尿病视网膜病变中 Nlrp3 炎性体激活

基本信息

批准号：
10414049
负责人：
Jayakrishna Ambati
金额：
$ 45.86万
依托单位：
UNIVERSITY OF VIRGINIA
依托单位国家：
美国
项目类别：
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/10414049
关键词：
Ablation Acute Address Affect Age related macular degeneration Alzheimer&apos 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 Neuronal Dysfunction Neurons Nonesterified Fatty Acids Pathogenesis Pathologic Pathologic Processes Pathology Pathway interactions Patients Peptide Hydrolases Persons Pharmacology Phenotype Pre-Clinical Model Process Production Reactive Oxygen Species Reporter 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 model neurovascular pathogen pre-clinical prevent promoter recruit relating to nervous system response stressor

项目摘要

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/摘要糖尿病性视网膜病（DR）的标志性病理过程包括神经和神经胶质功能障碍，招募炎症细胞，内皮功能障碍，血管闭塞和血液视网膜屏障的丧失。炎性症是先天免疫信号平台，涉及对异物病原体的急性反应以及许多慢性神经退行性和炎症相关疾病。炎症封锁是正在针对多种复杂的神经血管疾病进行探索，包括阿尔茨海默氏病，动脉粥样硬化，与年龄相关的黄斑变性和类风湿关节炎。临床和临床前的证据表明炎性体活动也可能通过促进生产来促进DR的病理标志炎性细胞因子，白细胞和微血管完整性的丧失。尽管有这些证据，但主要差距知识在炎性体的时间，细胞来源和病理意义方面持续存在在糖尿病性视网膜病的背景下激活。该提议的总体假设是NLRP3 循环免疫细胞和常数神经胶质的炎性体激活驱动神经元和微血管糖尿病性视网膜病的功能障碍。我们将以三个特定目的测试这一假设：1）我们试图识别细胞在1型糖尿病的动物模型中表现出炎症体激活及其时间的类型； 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由于糖尿病引起的视网膜病理的动物模型。为此，我们将利用全球和细胞特定的糖尿病模型中炎性体成分的遗传敲除； 3）我们试图测试由于神经，免疫和血管缺陷的临床前模型中的药理学炎症体抑制剂糖尿病。总的来说，这些主题相关，但独立目标将确定视网膜中糖尿病病理过程中的炎症体。这些研究可能会开放新的这种普遍的盲目条件的介入途径。