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.

抽象的胸部主动脉瘤和解剖（TAAD），尤其是A型解剖是一种毁灭性的疾病，院内死亡率高达25％。尽管升高主动脉瘤和解剖（AADS）可能由遗传易感性引起的，超过70％的病例是零星的。目前，手术修复是唯一的可用治疗。由于差，药物预防剂的开发仍然是一项挑战任务了解负责AAD发病机理的细胞和分子机制。我们有报道了平滑肌细胞（SMC）转化生长因子I型受体的产后缺失（SMC）（TGFBR1IKO）在雄性小鼠中诱导AAD形成。最近，我们开发了一种新颖的X连锁CRE系列，可以驱动与父母y连接相比 myh11-creertm菌株。 AADS的组织学标志之一是慢性炎症，其特征是进行性SMC部署，免疫细胞浸润和基质降解。这些事件创造了完美激活先天免疫的环境。具体而言，死亡SMC产生的分子可以起作用作为与损伤相关的分子模式，以通过自分泌激活病原体识别受体（PRR）和/或旁分泌信号，目前在严格的实验和临床评估的情况下进行其他方案慢性条件。因此，我们探索了AAD模型中先天免疫的激活并获得结果如下。 1）AAD的形成与RNA氧化，Toll样受体（TLR） - 的上调有关 7和SMC坏死性。 2）AAD-但不是正常主动脉衍生的RNA引发了炎症反应免疫细胞。 3）更重要的是，用抑制内体TLR的试剂对小鼠的治疗减弱了AAD 形成。这些新颖的发现导致了我们的整体假设，即自发自动企业触发TLR7介导的危险促进TAAD发展的信号。该假设将通过两个相互关联的特定目的进行检验。具体目标1将确定自动新闻对激活先天免疫伤害和AAD的贡献形成。此目标下的研究将解决三个关键问题。 1）是什么使自我RNA的致病性？ 2）如何 Self-RNA调节RIPK3/PMLKL途径诱导SMC的坏死病？ 3）坏死性的作用是什么 AAD组中的SMC？特定的目标2将确定prr感知自我启动以促进AAD形成的核心。在特定目标2下提出的实验将回答两个关键问题。 1）被自我感知跨物种（即小鼠与人）中不同类型的细胞中相同的内体TLR成员？ 2）是遗传或对负责RNA感应TLR的药理抑制足以改变AAD的过程编队？我们的新颖AAD鼠标模型使我们处于独特的位置，以解决这些问题鼠标AADS的性别。该项目的完成将更好地理解机制在AAD形成期间，这种滋养慢性炎症，并可能导致开发的新方向针对AAD的倡议和进展的药理预防。