The NOTCH Signaling Pathway in Large Vessel Vasculitis

大血管炎中的 NOTCH 信号通路

• 批准号: 10655562
• 负责人: Cornelia M. Weyand
• 金额: $ 59.88万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-01-06 至 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10655562
• 关键词: Affect; Amplifiers; Aneurysm; Aorta; Aortic Aneurysm; Aortic Arch Syndromes; Aortitis; Arteries; Autoimmune; Autoimmune Diseases; Automobile Driving; Biological Models; Blindness; Blood Vessels; CD4 Positive T Lymphocytes; Cell Differentiation process; Cell physiology; Cells; Chimera organism; Citric Acid Cycle; Clinical; Complication; Cytokinesis; DNA Damage; Data; Defect; Development; Disease; Dissection; Effector Cell; Electron Transport; Endothelial Cells; Engraftment; Enzymes; Event; Experimental Designs; Giant Cells; Granulomatous Arteritis; Human; Hyperplasia; IL17 gene; Immune; Immune response; Immune system; Immunity; In Vitro; Infiltration; Inflammatory; Inflammatory Infiltrate; Interferons; Ketoglutarate Dehydrogenase Complex; Life; Macrophage; Maps; Measures; Medial; Mediating; Messenger RNA; Metabolic; Mitochondria; Modification; Molecular; Mus; NF-kappa B; NOTCH1 gene; Notch Signaling Pathway; Nuclear; Oncogenes; Organ; Paralysed; Pathogenicity; Pathologic; Pathway interactions; Patients; Phenotype; Population; Process; Procollagen-Proline Dioxygenase; Production; Proliferating; Proteins; RNA; RNA-Binding Proteins; Resources; Role; Second Messenger Systems; Signal Transduction; Site; Stroke; Succinate Dehydrogenase; Succinates; T-Lymphocyte; TNF gene; Temporal Arteritis; Testing; Thinness; Tissues; Training; Vascular Endothelial Cell; Vascularization; Vasculitis; Veno-Occlusive Disease; Work; angiogenesis; autoinflammatory diseases; bench to bedside; cell motility; cohort; effector T cell; experimental study; in vivo; in vivo Model; inhibitor; interleukin-21; interleukin-22; loss of function; mRNA Stability; mouse model; new technology; notch protein; novel marker; novel therapeutic intervention; nuclear division; programs; response; therapeutic target; transcription factor; vascular inflammation

Project Summary Giant Cell Arteritis (GCA) is an autoimmune and autoinflammatory disease which targets the aorta and its major branch vessels. GCA causes vaso-occlusive disease, leading to blindness and stroke. About half of the patients develop GCA aortitis, a potentially life-threatening complication due to aortic dissection and aneurysm formation. The underlying disease process is a granulomatous arteritis, with CD4 T cells, macrophages and multinucleated giant cells infiltrating into the vessel wall, eliciting maladaptive wall remodeling with neoangiogenesis and lumen- occlusive intimal hyperplasia. We have identified aberrant expression of the oncogene NOTCH1 in CD4 T cells as a key abnormality in the immune system of GCA patients. Here, we will examine the hypothesis that NOTCH signaling transforms protective immunity into pathogenic immunity by suppressing the mitochondrial enzyme succinate dehydrogenase (SDH) and truncating the tricarboxylic acid (TCA) cycle. Fragmentation of the TCA cycle then leads to the accumulation of the metabolic intermediate succinate, which is released into the tissue site and functions as a second messenger. We propose that succinate secreted by NOTCH1hi SDHlo CD4 T cells targets surrounding cells to redirect T effector cell differentiation, to induce multinucleated macrophages and to promote microvascular neoangiogenesis. We have assembled key enabling resources to mechanistically study how NOTCH-instructed succinate release enhances vascular inflammation; including a large cohort of clinically well phenotyped GCA patients and a chimeric mouse model in which vasculitis is induced in engrafted human arteries to corroborate in vitro data by in vivo studies. Aim 1 will define the molecular mechanisms leading to NOTCH-dependent SDH loss-of-function, building on preliminary studies that implicate RNA-binding proteins in regulating SDH mRNA stability through N6-methyladenosine modifications. Aim 2A examines mechanistically how succinate reprograms T effector cell differentiation. Experiments are designed to investigate how succinate paralyzes the NF-kappaB inhibitor A20/TNFAIP3 to unleash NF-kappaB signaling and induce polyfunctional effector T cells (Thpoly), including T cells that co-produce IFN-, IL-17, TNF-α, IL-21 and IL-22. Aim 2B will determine how NOTCH-instructed succinate alters macrophage function, specifically by driving formation of tissue-destructive multinucleated giant cells. We will delineate how succinate elicits a robust DNA damage response and how it promotes nuclear division and halts cytokinesis by interfering with the spindle assembly checkpoint. Aim 2C is focused on succinate’s role in inducing a pro-angiogenic endothelial cell (EC) phenotype and will explore how succinate-trained EC migrate, proliferate, and lose their barrier function. Aim 3 will bridge from the bench to the bedside and will test whether the suppression of succinate production by blocking the upstream enzyme a-ketoglutarate dehydrogenase can successfully treat vasculitis in vivo.

项目摘要 巨细胞动脉炎（GCA）是一种自身免疫性和自身炎症性疾病，针对主动脉及其主要疾病 分支视频。 GCA会引起血管熟悉的疾病，导致失明和中风。大约一半的患者 患有GCA主动脉炎，由于主动脉夹层和动脉瘤形成而导致的潜在威胁生命的并发症。 潜在的疾病过程是一种肉芽肿性动脉炎，具有CD4 T细胞，巨噬细胞和多核核酸 巨型细胞浸入血管壁，引起不良适应壁的重塑，并通过新血管生成和腔内形成 闭塞性内膜增生。 我们已经确定CD4 T细胞中癌基型notch1的异常表达是关键异常 GCA患者的免疫系统。在这里，我们将研究Notch信号转换的假设 通过抑制线粒体酶琥珀酸酯，保护性免疫（保护性免疫史）成为致病性免疫 脱氢酶（SDH）并截断三核酸（TCA）周期。 TCA周期的分裂 然后导致代谢中间琥珀酸酯的积累，该琥珀酸酯被释放到组织中 站点和用作第二使者。我们提出了Notch1hi Sdhlo CD4分泌的琥珀酸酯 T细胞靶向周围的细胞重定向T效应细胞分化，以诱导多核 巨噬细胞并促进微血管新血管生成。我们已经组装了钥匙启用资源 为了机械研究凹槽的琥珀酸盐释放如何增强血管感染；包括 大量的临床表型GCA患者和嵌合小鼠模型在其中诱导血管炎 在植入的人动脉中，通过体内研究证实了体外数据。 AIM 1将定义分子 导致Notch依赖性SDH功能丧失的机制，在初步研究的基础上建立 RNA结合蛋白通过N6-甲基拉丹代胺修饰调节SDH mRNA稳定性。目标2a 从机械上检查琥珀酸酯如何重新编程T效应细胞分化。实验被设计为 研究琥珀酸酯如何瘫痪NF-kappab抑制剂A20/TNFAIP3以释放NF-kappab信号和 诱导多功能效应T细胞（THPOLY），包括共同生产IFN-，IL-17，TNF-α，IL-21和 IL-22。 AIM 2B将确定缺口的琥珀酸酯如何改变巨噬细胞的功能，特别是 驱动组织破坏性多核细胞的形成。我们将描述琥珀酸酯如何引起强大的 DNA损伤反应及其如何通过干扰主轴来促进核分裂并停止细胞因子 组装检查点。 AIM 2C专注于琥珀酸酯在诱导促血管生成的内皮细胞（EC）中的作用 表型并将探讨如何琥珀酸训练的EC迁移，扩散并失去其障碍功能。目标3 将从长凳上桥接到床边，并将测试是否通过 阻断上游酶A-酮戊二酸脱氢酶可以在体内成功治疗血管炎。

项目成果

Visual manifestations in giant cell arteritis: trend over 5 decades in a population-based cohort.

• DOI: 10.3899/jrheum.140188
• 发表时间: 2015-02
• 期刊: The Journal of rheumatology
• 作者: Singh AG;Kermani TA;Crowson CS;Weyand CM;Matteson EL;Warrington KJ
• 通讯作者: Warrington KJ

Giant cell arteritis: immune and vascular aging as disease risk factors.

• DOI: 10.1186/ar3358
• 发表时间: 2011-08-02
• 期刊: Arthritis research & therapy
• 影响因子: 4.9
• 作者: Mohan SV;Liao YJ;Kim JW;Goronzy JJ;Weyand CM
• 通讯作者: Weyand CM

Dynamic immune cell accumulation during flow-induced atherogenesis in mouse carotid artery: an expanded flow cytometry method.

• DOI: 10.1161/atvbaha.111.242180
• 发表时间: 2012-03
• 期刊: Arteriosclerosis, thrombosis, and vascular biology
• 作者: Alberts-Grill N;Rezvan A;Son DJ;Qiu H;Kim CW;Kemp ML;Weyand CM;Jo H
• 通讯作者: Jo H

Telomere dysfunction, autoimmunity and aging.

• 发表时间: 2011-06
• 期刊: Aging and disease
• 影响因子: 7.4
• 作者: P. Hohensinner;J. Goronzy;C. Weyand