Role of RNA-mediated danger signals in regulating TAAD development

RNA介导的危险信号在调节TAAD发展中的作用

• 批准号: 10218266
• 负责人: Zhihua Jiang
• 金额: $ 44.95万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-08-01 至 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10218266
• 关键词: Abdominal Aortic Aneurysm; Address; Angiotensin II; Anti-Inflammatory Agents; Aorta; Aortic Aneurysm; Attenuated; Autocrine Communication; Automobile Driving; B-Cell Activation; Binding; Bone Marrow; CXCL10 gene; Cardiovascular Diseases; Cell Line; Cell model; Cells; Chest; Chronic; Clinical; Dendritic Cells; Development; Disease; Dissection; Environment; Event; Female; Fire - disasters; Gender; Genes; Genetic; Genetic Predisposition to Disease; Growth; Histologic; Homeostasis; Hospital Mortality; Human; Hydroxychloroquine; Immune; Immune response; Immunologic Receptors; Infiltration; Inflammation; Inflammatory Response; Injury; Interferon-alpha; Interleukin-1 beta; Lead; Ligands; Link; Location; MMP2 gene; MMP9 gene; Mediating; MicroRNAs; Modeling; Molecular; Mus; Natural Immunity; Necrosis; Operative Surgical Procedures; Outcome; Paracrine Communication; Pathogenesis; Pathogenicity; Pathway interactions; Pattern; Pharmacologic Substance; Pharmacology; Play; Positioning Attribute; Prevention; Production; RIPK3 gene; RNA; Reagent; Receptor Signaling; Regulation; Reporting; Role; Severities; Signal Pathway; Signal Transduction; Smooth Muscle Myocytes; Sterility; Stress; Structure; System; T-Lymphocyte; TLR3 gene; TLR7 gene; TNF gene; Testing; Thoracic Aortic Aneurysm; Tissues; Toll-like receptors; Transforming Growth Factor beta; Transforming Growth Factors; Up-Regulation; Y Chromosome; ascending aorta; cell type; cytokine; experimental study; genetic risk factor; immune activation; improved; inhibitor/antagonist; male; member; mouse model; neutrophil; novel; oxidation; pathogen; postnatal; prevent; receptor; repaired; research clinical testing; sensor; therapeutically effective; tissue repair

ABSTRACT Thoracic aortic aneurysms and dissections (TAAD), particularly type A dissections, are a devastating disease, with an in-hospital mortality rate up to 25%. Although ascending aortic aneurysms and dissections (AADs) may result from genetic predispositions, more than 70% of cases are sporadic. Currently, surgical repair is the only available treatment. Development of pharmacological prevention agents remains a challenging task due to poor understanding of the cellular and molecular mechanisms responsible for pathogenesis of AADs. We have reported that postnatal deletion of smooth muscle cell (SMC) transforming growth factor-β type I receptors (Tgfbr1iko) induces AAD formation in male mice. Recently, we developed a novel X-linked Cre line that drives Tgfbr1iko and AAD formation in female mice with similar efficiency and severity compared to its parental Y-linked myh11-CreERTM strain. One of the histological hallmarks of AADs is chronic inflammation, characterized by progressive SMC depletion, immune cell infiltration, and matrix degradation. These events create a perfect environment for activation of the innate immunity. Specifically, molecules produced by dying SMCs can function as damage-associated molecular patterns to activate pathogen recognition receptors (PRRs) via autocrine and/or paracrine signaling, a scenario currently under rigorous experimental and clinical evaluation for other chronic conditions. Therefore, we explored activation of the innate immunity in our AAD models and obtained results as follows. 1) AAD formation was associated with RNA oxidation, upregulation of toll-like receptor (TLR)- 7, and SMC necroptosis. 2) AAD-, but not normal aorta-derived RNAs triggered inflammatory response in immune cells. 3) More importantly, treatment of mice with reagents inhibiting endosomal TLRs attenuated AAD formation. These novel findings led to our overall hypothesis that self-RNAs trigger TLR7-mediated danger signals to promote TAAD development. This hypothesis will be tested through two interrelated Specific Aims. Specific Aim 1 will determine the contribution of self-RNAs to activation of innate immune injury and AAD formation. Studies under this Aim will address three key issues. 1) What makes self-RNAs pathogenic? 2) How self-RNAs regulate the RIPK3/pMLKL pathway to induce necroptosis of SMCs? 3) What is the role of necroptosis of SMCs in AAD formation? Specific Aim 2 will identify PRR(s) that sense self-RNAs to promote AAD formation. Experiments proposed under Specific Aim 2 will answer two key questions. 1) Are self-RNAs sensed by the same endosomal TLR member(s) in different type of cells across species (i.e. mouse vs. human)? 2) Is genetic or pharmacological inhibition of the responsible RNA-sensing TLR(s) sufficient to alter the course of AAD formation? Our novel AAD mouse models have placed us in a unique position to address these issues with mouse AADs of either gender. Completion of this project will provide a better understanding of the mechanisms that nourish chronic inflammation during AAD formation and may lead to a new direction for the development of pharmacological preventions against initiation and progression of AADs.

摘要 胸主动脉瘤和夹层（TAAD），特别是A型夹层，是一种毁灭性的疾病， 住院死亡率高达25%虽然升主动脉瘤和夹层（AAD）可能 由于遗传易感性，70%以上的病例是散发的。目前，手术修复是唯一的 可用的治疗。药物预防剂的开发仍然是一项具有挑战性的任务， 了解AAD发病机制的细胞和分子机制。我们有 报道了出生后平滑肌细胞（SMC）转化生长因子-β I型受体缺失， （Tgfbr 1 iko）诱导雄性小鼠AAD形成。最近，我们开发了一种新颖的X连锁Cre线， 雌性小鼠中Tgfbr 1 iko和AAD的形成与其亲本Y连锁的小鼠相比具有相似的效率和严重程度。 myh 11-CreERTM菌株。AAD的组织学标志之一是慢性炎症，其特征在于 进行性SMC耗竭、免疫细胞浸润和基质降解。这些事件创造了一个完美的 天然免疫的激活环境。具体来说，由垂死的SMC产生的分子可以发挥作用， 作为损伤相关的分子模式，通过自分泌激活病原体识别受体（PRR） 和/或旁分泌信号，目前正在严格的实验和临床评估的情况下，其他 慢性病因此，我们在我们的AAD模型中探索了先天免疫的激活，并获得了 结果如下。1)AAD的形成与RNA氧化、Toll样受体（TLR）的上调有关。 7、SMC坏死性凋亡。2)AAD-，而不是正常的大肠杆菌衍生的RNA触发炎症反应， 免疫细胞。3)更重要的是，用抑制内体TLR的试剂治疗小鼠可减弱AAD 阵这些新的发现导致我们的总体假设，即自身RNA触发TLR 7介导的危险 促进TAAD发展的信号。这一假设将通过两个相互关联的具体目标进行检验。 特异性目标1将决定自身RNA对先天免疫损伤和AAD激活的贡献 阵根据这一目标进行的研究将涉及三个关键问题。1)是什么使自身RNA致病？2)如何 自身RNA调节RIPK 3/pMLKL通路诱导SMC坏死性凋亡？3)坏死性凋亡的作用是什么 AAD形成中的SMC？特异性目标2将鉴定感测自身RNA以促进AAD形成的PRR。 具体目标2下提出的实验将回答两个关键问题。1)自我RNA是由 在不同种属（即小鼠与人）的不同类型细胞中是否存在相同的内体TLR成员？2)是遗传 或药理学抑制负责的RNA敏感TLR，足以改变AAD的进程 阵型？我们的新型AAD小鼠模型使我们处于一个独特的位置，可以解决这些问题， 任何性别的小鼠AAD。完成这一项目将使人们更好地了解这些机制， 在AAD形成过程中滋养慢性炎症，并可能导致AAD发展的新方向。 药物预防AAD的启动和进展。