Immune injury as a driver for the development of ascending aortic aneurysms and dissections

免疫损伤是升主动脉瘤和夹层发展的驱动因素

基本信息

批准号：
10646241
负责人：
Zhihua Jiang
金额：
$ 55.65万
依托单位：
UNIVERSITY OF FLORIDA
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：
2020-07-01 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10646241
关键词：
Abdominal Aortic Aneurysm Ablation Acceleration Acute Address Adoptive Cell Transfers Adoptive Transfer Affect Animal Model Aorta Aortic Aneurysm Aortic Rupture Autoantigens B-Lymphocytes Back Biological Blood C3AR1 gene CD19 gene CD4 Positive T Lymphocytes Cells Chronic Clinical Complement Complement 3a Complement 5a Coupled Data Decision Making Deposition Development Disease Dissection Equilibrium Event Feedback Foundations Future Genes Genetic Growth Helper-Inducer T-Lymphocyte Human IL5 gene Immune Immune System Diseases Immune response Immunity Immunology Immunotherapy Inflammatory Response Injury Interferon Type II Interferons Interleukin-12 Intervention Life Measures Medial Mediator Mission Modeling Modification Molecular Mus Natural History Pathway interactions Patients Phenotype Regulation Risk Factors Role Rupture Shapes Signal Transduction Smooth Muscle Myocytes Solid Specimen Surrogate Endpoint T-Lymphocyte Testing Thoracic Aortic Aneurysm Tissues Transforming Growth Factor beta United States Work adaptive immunity arm ascending aorta cell mediated immune response complement system cytokine druggable target eosinophil human subject immunoregulation insight mouse model neutrophil novel peripheral blood pharmacologic polarized cell prevent programs receptor response restoration therapeutic development transcription factor translational potential

项目摘要

Abstract Acute aortic dissection, particularly the type A dissection (AAD), is a life-threatening condition. Currently, there are no effective measures to prevent its onset and progression. A major barrier to satisfy these critical, unmet clinical needs is the poor understanding of the mechanisms that drive AAD development. AADs usually occur in aortas suffering progressive aneurysmal degeneration. However, compelling clinical evidence suggests that AADs and aortic aneurysms precede through distinct biological pathways. Yet, uncoupling these pathways has been a challenging task due to the silent onset of aortic dissections in patients coupled with a lack of animal models capable of mimicking the development of AAD reliably. To address this issue, we created two novel mouse AAD models, termed as “aortic tear model” and “aortic rupture model”, respectively. The “aortic tear model” develops spontaneous aortic tears with few ruptures in mildly dilated ascending aortas, whereas the “aortic rupture model” features acute aortic dissections with a high rate (40%) of aortic rupture in the first week. Using these models, we tested the long-standing, but unproved, hypothesis—disorders of immune response promote AAD formation. We found that 1) development of aortic tears is paralleled with an increased CD4+ T- cells and CD19+ B-cells in the AAD tissue as well as in the peripheral blood; 2) Th2 polarization via adoptive transfer of ex vivo expanded Th2 cells or neutralization of the Th1 signature cytokine interferon gamma (INFγ) exaggerates AAD dilation; 3) complement components are upregulated and deposited in the medial layer of AADs; and 4) genetic shifting of T-cell-mediated immune response to a Th2 prominent immunity dramatically provokes aortic rupture (>90% in four weeks). These novel findings led to an overall hypothesis that skewing of the inflammatory response in the aneurysmal aortic wall to type 2 immunity promotes AAD development. In this project, we will use genetic, adoptive cell transfer, and pharmacological approaches to evaluate the role of T- cells, B-cells, and complement system in regulating AAD development, with profile of immune cell subsets and cytokine milieu characterized to understand the cellular and molecular events engaged in promoting AAD formation. Critical findings will be validated for their implication across different mouse models, and more importantly, their relevance to human AAD development. Completion of this project will lay a solid foundation for future studies to develop immunotherapies to prevent AAD formation.

抽象的急性主动脉夹层，尤其是A型解剖（AAD）是一种威胁生命的疾病。目前，那里没有有效的措施来防止其发作和进展。满足这些关键，未得到满足的主要障碍临床需求是对推动AAD发展的机制的不良理解。 AAD通常发生在主动脉患有进展性动脉瘤变性。但是，令人信服的临床证据表明 AADS和主动脉瘤在不同的生物学途径之前。但是，解开这些途径由于患者的主动脉夹层的沉默发作和缺乏动物，他是一项挑战任务能够可靠地模仿AAD的发展的模型。为了解决这个问题，我们创建了两本小说小鼠AAD模型，分别称为“主动脉撕裂模型”和“主动脉破裂模型”。 “主动脉撕裂模型”会发展出赞助的主动脉眼泪，而在轻度扩张的主动脉中发生了很少的破裂，而却 “主动脉破裂模型”以急性主动脉夹层为特征，在第一周，主动脉破裂率高（40％）。使用这些模型，我们测试了长期但未证实的假设 - 免疫反应的疾病促进AAD形成。我们发现1）与CD4+ t-的增加，主动脉眼泪的发展与 AAD组织以及外周血中的细胞和CD19+ B细胞； 2）通过自适应的TH2极化离体扩展的Th2细胞的转移或Th1签名细胞因子干扰素伽马（INFγ）的谈判夸大AAD词典； 3）补体组件被更新并存放在媒体层中 aads; 4）T细胞介导的免疫响应向TH2显着免疫学的遗传转移显着挑衅主动脉破裂（在四个星期内> 90％）。这些新颖的发现导致了一个总体假设动脉瘤主动脉壁对2型免疫力的炎症反应促进了AAD的发育。在这个项目，我们将使用遗传，适应性细胞转移和药物方法来评估T-的作用细胞，B细胞和调节中的完成系统AAD发育，具有免疫细胞子集和细胞因子环境的特征是了解参与促进AAD的细胞和分子事件形成。关键发现将因其在不同鼠标模型中的影响而验证，更多重要的是，它们与人类AAD发展的相关性。该项目的完成将为未来开发免疫疗法以防止AAD形成的研究。

项目成果

期刊论文数量（3）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Commonly Used Myh11-CreERT2Strain Carries a Y-Linked Functional Wild-Type Tlr7 Allele.

常用的 Myh11-CreERT2 菌株携带 Y 连锁功能野生型 Tlr7 等位基因。

DOI：
10.1161/atvbaha.122.318919
发表时间：
2023
期刊：
Arteriosclerosis, thrombosis, and vascular biology
影响因子：
0
作者：
Li,Jie;Xu,Haiyan;Hung,Alex;Javed,MuhammadJavad;UpchurchJr,GilbertR;Jiang,Zhihua
通讯作者：
Jiang,Zhihua

Nicotine Exacerbates TAAD Formation Induced by Smooth Muscle-Specific Deletion of the TGF-β Receptor 2.

DOI：
10.1155/2021/6880036
发表时间：
2021
期刊：
Journal of immunology research
影响因子：
4.1
作者：
Chun C;Qi X;Wang F;Madrid KB;Saldarriaga LA;Fisch MR;Brantly ML;Upchurch GR Jr;Jiang Z
通讯作者：
Jiang Z

Maresin 1 activates LGR6 signaling to inhibit smooth muscle cell activation and attenuate murine abdominal aortic aneurysm formation.