TLR4-MEDIATED EPIGENETIC AND SENESCENCE MECHANISMS IN EMPHYSEMA

TLR4 介导的肺气肿表观遗传和衰老机制

• 批准号: 10013285
• 负责人: PATTY J LEE
• 金额: $ 29.13万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-15 至 2022-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10013285
• 关键词: Age; Aging; Alveolar; Antioxidants; CDKN2A gene; Cause of Death; Cell Survival; Cells; Cellular Structures; Chronic Obstructive Airway Disease; Chronic lung disease; DNA; DNA Modification Methylases; DNA Modification Process; DNMT3a; Data; Development; Elderly; Endothelial Cells; Enzymes; Epigenetic Process; Epithelial; Epithelium; Exhibits; Experimental Models; Future; Gases; Gene Expression; Genes; Genetic; Genetic Transcription; Goals; HDAC2 gene; Histones; Human; Immune; Immune system; Immunologic Receptors; Impairment; Infection; Inflammatory; Inhalation; Injury; Knock-in Mouse; Knockout Mice; Life; Link; Longevity; Luciferases; Lung; Lung Capacity; Lung diseases; Maintenance; Mediating; Methylation; Molecular; Molecular Target; Mus; Natural Immunity; Outcome; Pathway interactions; Post-Translational Protein Processing; Predisposition; Prevention; Process; Proteins; Pulmonary Emphysema; Recording of previous events; Regulation; Reporting; Risk Factors; Role; Source; Structure; TLR4 gene; Testing; Tetanus Helper Peptide; Therapeutic; Toxic Environmental Substances; Toxin; adaptive immune response; age related; aged; antimicrobial; cell type; cigarette smoke; cigarette smoking; clinically relevant; design; effective therapy; exposed human population; exposure to cigarette smoke; genetic manipulation; histone deacetylase 2; in vivo; inflammatory marker; innate immune pathways; innovation; insight; mortality; mouse toll-like receptor 4; new therapeutic target; novel; oxidant stress; prevent; response; senescence; stressor

PROJECT SUMMARY COPD is now the 3rd leading cause of death worldwide. Emphysema, characterized by airspace enlargement and impaired gas exchange, is a major subtype of COPD. The cumulative effects of cigarette smoke exposure (CS) and environmental toxins across the lifespan are important contributing factors to the development of emphysema. Yet very little is known about the underlying mechanisms, which limits therapies. Our overall goals are to understand the molecular mechanisms of how our lungs maintain normal structural integrity and how they protect against inhaled toxins, such as CS. We identified a critical role for an innate immune receptor, Toll-like receptor 4 (TLR4), in lung maintenance and in preventing inappropriate activation of aging and injury pathways. Unfortunately, age and CS, two of the most common risk factors for COPD, result in inadequate levels of TLR4, thus predisposing to emphysema. Our studies will fill current gaps in our understanding of how the immune system, in specific lung cells, can impact lung-protective responses even in the absence of infection, thereby offering potential new therapeutic targets. Using TLR4-deficiency and CS as clinically relevant experimental models of emphysema, we identified mechanistic roles for the senescence molecule, p16INK4A, and DNA-modifying enzymes, HDAC2, Dnmt3a and Tet2, in emphysema. In addition, we offer the first in vivo evidence that increased p16INK4A contributes to emphysema. Our overall hypothesis is that structural cell TLR4 is required to maintain normal lung integrity, at baseline and after CS, by inhibiting p16INK4A via HDAC2-Dnmt3a-Tet2-mediated mechanisms. We will use a combination of age- and CS- exposed human and mouse lungs/cells as well as innovative gene manipulations to test this hypothesis in the following Aims: 1) Identify mechanisms of decreased TLR4 expression with aging and CS and the contribution of TLR4 in specific structural cells to emphysema. 2) Determine the mechanisms of decreased HDAC2 in TLR4-deficient and CS-exposed cells. 3) Identify HDAC2 and Dnmt3a / Tet2 -mediated mechanisms of p16INK4A induction and the contribution of p16INK4A in specific structural cells to emphysema. Our studies will expand our basic understanding of the molecular drivers of emphysema, establish previously unrecognized interactions amongst innate immunity, senescence and DNA modifications and inform future preventative or therapeutic approaches to a range of age- and CS-related lung diseases.

项目摘要 COPD现在是全球第三大死亡原因。肺气肿，以气腔扩大为特征 和受损的气体交换是COPD的主要亚型。香烟烟雾暴露的累积效应 (CS)和环境毒素是发展的重要因素， 肺气肿然而，人们对潜在的机制知之甚少，这限制了治疗。我们的整体 目标是了解我们的肺如何维持正常结构完整性的分子机制， 它们是如何防止吸入毒素的，比如CS。我们确定了先天免疫受体的关键作用， Toll样受体4（TLR 4），在肺维护和防止老化和损伤的不适当激活中 途径。不幸的是，年龄和CS是COPD最常见的两个危险因素， TLR 4水平，从而诱发肺气肿。我们的研究将填补目前的空白，在我们的理解如何 免疫系统，在特定的肺细胞，可以影响肺保护性反应，即使在没有 感染，从而提供潜在的新的治疗靶点。使用TLR 4缺陷和CS作为临床 在肺气肿的相关实验模型中，我们确定了衰老分子的机械作用， p16 INK 4A和DNA修饰酶HDAC 2、Dnmt 3a和Tet 2在肺气肿中的作用。此外，我们还提供 第一个体内证据表明p16 INK 4A增加有助于肺气肿。我们的总体假设是 在基线和CS后，需要结构细胞TLR 4通过抑制 p16 INK 4A通过HDAC 2-Dnmt 3a-Tet 2介导的机制。我们将使用年龄和CS的组合- 暴露的人类和小鼠肺/细胞以及创新的基因操作来测试这一假设， 以下目的：1）确定衰老和CS降低TLR 4表达的机制， TLR 4在特定结构细胞中对肺气肿的作用。2)确定降低的机制 TLR 4缺陷和CS暴露细胞中的HDAC 2。3)确定HDAC 2和Dnmt 3a/Tet 2介导的机制 p16 INK 4A的诱导和p16 INK 4A在肺气肿的特定结构细胞中的作用。我们的研究将 扩展我们对肺气肿分子驱动因素的基本理解，建立以前未被认识的 先天免疫，衰老和DNA修饰之间的相互作用，并为未来的预防或 一系列年龄和CS相关肺部疾病的治疗方法。