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

基本信息

批准号：
10456622
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
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-08-01 至 2024-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10456622
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 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 male member mouse model neutrophil novel oxidation pathogen postnatal prevent receptor repaired research clinical testing sensor therapeutically effective tissue repair

项目摘要

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.

抽象的胸主动脉瘤和夹层 (TAAD)，特别是 A 型夹层，是一种毁灭性的疾病，尽管升主动脉瘤和夹层 (AAD) 可能导致院内死亡率高达 25%。由于遗传因素，70%以上的病例是散发性的，目前，手术修复是唯一的方法。由于治疗效果不佳，药物预防剂的开发仍然是一项具有挑战性的任务。我们已经了解了 AAD 发病机制的细胞和分子机制。报道称，出生后平滑肌细胞（SMC）转化生长因子-β I 型受体缺失 (Tgfbr1iko) 诱导雄性小鼠形成 AAD 最近，我们开发了一种新型 X 连锁 Cre 系，可驱动 AAD 形成。与亲代 Y 连锁小鼠相比，雌性小鼠中 Tgfbr1iko 和 AAD 的形成具有相似的效率和严重程度 myh11-CreERTM 菌株 AAD 的组织学特征之一是慢性炎症，其特征是渐进的 SMC 耗竭、免疫细胞浸润和基质降解这些事件创造了完美的结果。具体来说，死亡的 SMC 产生的分子可以发挥作用。作为损伤相关分子模式，通过自分泌激活病原体识别受体（PRR）和/或旁分泌信号传导，目前正在对其他情况进行严格的实验和临床评估因此，我们探索了 AAD 模型中先天免疫的激活并获得了结果。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 而非正常主动脉来源的 RNA 引发炎症反应。 3) 更重要的是，用抑制内体 TLR 的试剂治疗小鼠可减弱 AAD。这些新的发现得出了我们的总体假设：自身 RNA 会引发 TLR7 介导的危险。促进 TAAD 发展的信号将通过两个相互关联的具体目标进行检验。具体目标 1 将确定自身 RNA 对先天免疫损伤和 AAD 激活的贡献该目标下的研究将解决三个关键问题：1）什么使自身 RNA 致病？自身RNA调节RIPK3/pMLKL通路诱导SMCs坏死性凋亡？ 3) 坏死性凋亡的作用是什么？ SMC 在 AAD 形成中的作用？特定目标 2 将识别感知自身 RNA 的 PRR 以促进 AAD 形成。具体目标 2 下提出的实验将回答两个关键问题：1) 自身 RNA 是否被感知。不同物种的不同类型细胞中存在相同的内体 TLR 成员（即小鼠与人类） 2) 是遗传的吗？或对负责的 RNA 感应 TLR 进行药物抑制，足以改变 AAD 的进程我们的新型 AAD 小鼠模型使我们处于解决这些问题的独特地位完成该项目将有助于更好地理解该机制。在 AAD 形成过程中滋养慢性炎症，并可能为 AAD 的发展带来新的方向针对 AAD 发生和进展的药物预防。