The NOTCH Signaling Pathway in Large Vessel Vasculitis

大血管炎中的 NOTCH 信号通路

基本信息

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
项目类别：
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

项目摘要

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.

项目概要巨细胞动脉炎（GCA）是一种自身免疫性和自身炎症性疾病，以主动脉及其主要部位为靶点。 GCA 会导致血管闭塞性疾病，导致大约一半的患者失明和中风。发展为 GCA 主动脉炎，这是一种由于主动脉夹层和动脉瘤形成而可能危及生命的并发症。潜在的疾病过程是肉芽肿性动脉炎，伴有 CD4 T 细胞、巨噬细胞和多核细胞巨细胞浸润到血管壁，引起适应不良的血管壁重塑，新生血管生成和管腔闭塞性内膜增生。我们已经确定 CD4 T 细胞中癌基因 NOTCH1 的异常表达是 CD4 T 细胞中的一个关键异常。在这里，我们将检验 NOTCH 信号传导转变的假设。通过抑制线粒体琥珀酸酶将保护性免疫转变为致病性免疫脱氢酶 (SDH) 和截断三羧酸 (TCA) 循环 TCA 循环的碎片化。然后导致代谢中间体琥珀酸盐的积累，并释放到组织中我们认为琥珀酸是由 NOTCH1hi SDHlo CD4 分泌的。 T 细胞靶向周围细胞以重定向效应 T 细胞分化，诱导多核巨噬细胞和促进微血管新生血管生成我们已经聚集了关键的支持资源。从机制上研究 NOTCH 指示的琥珀酸释放如何增强血管炎症，包括大量临床良好表达的 GCA 患者和诱导血管炎的嵌合小鼠模型在移植的人类动脉中通过体内研究证实体外数据，目的 1 将定义分子。导致 NOTCH 依赖性 SDH 功能丧失的机制，建立在涉及 RNA 结合蛋白通过 N6-甲基腺苷修饰调节 SDH mRNA 稳定性。从机制上研究琥珀酸如何重新编程 T 效应细胞分化。研究琥珀酸如何麻痹 NF-kappaB 抑制剂 A20/TNFAIP3 以释放 NF-kappaB 信号传导并诱导多功能效应 T 细胞 (Thpoly)，包括共同产生 IFN-α、IL-17、TNF-α、IL-21 和 IL-22。目标 2B 将确定 NOTCH 指导的琥珀酸如何改变巨噬细胞功能，特别是通过驱动组织破坏性多核巨细胞的形成我们将描述琥珀酸如何引发强健的细胞。 DNA 损伤反应及其如何通过干扰纺锤体促进核分裂和停止胞质分裂目标 2C 重点关注琥珀酸在诱导促血管生成内皮细胞 (EC) 中的作用。表型并将探索琥珀酸训练的 EC 如何迁移、增殖和丧失其屏障功能 Aim 3。将从实验室到临床进行桥梁，并测试是否会抑制琥珀酸的产生阻断上游酶α-酮戊二酸脱氢酶可以成功治疗体内血管炎。

项目成果

期刊论文数量（6）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

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

巨细胞动脉炎：免疫和血管老化作为疾病危险因素。

DOI：
发表时间：
2011
期刊：
影响因子：
4.9
作者：
Mohan, Shalini V;Liao, Y Joyce;Kim, Jonathan W;Goronzy, Jorg J;Weyand, Cornelia M
通讯作者：
Weyand, Cornelia M

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

小鼠颈动脉流诱导动脉粥样硬化过程中的动态免疫细胞积累：一种扩展的流式细胞术方法。

DOI：
发表时间：
2012-03
期刊：
影响因子：
0
作者：
Alberts;Rezvan, Amir;Son, Dong Ju;Qiu, Haiwei;Kim, Chan Woo;Kemp, Melissa L;Weyand, Cornelia M;Jo, Hanjoong
通讯作者：
Jo, Hanjoong

Telomere dysfunction, autoimmunity and aging.

端粒功能障碍、自身免疫和衰老。

DOI：
发表时间：
2011-12
期刊：
影响因子：
0
作者：
Hohensinner, Philipp J;Goronzy, Jörg J;Weyand, Cornelia M
通讯作者：
Weyand, Cornelia M

Vasculitis in systemic sclerosis.

系统性硬化症中的血管炎。

DOI：
发表时间：
2010
期刊：
影响因子：
0
作者：
Kao, Lily;Weyand, Cornelia
通讯作者：
Weyand, Cornelia

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

巨细胞动脉炎的视觉表现：基于人群的队列中 5 年来的趋势。

DOI：
发表时间：
2015-02
期刊：
影响因子：
0
作者：
Singh, Abha G;Kermani, Tanaz A;Crowson, Cynthia S;Weyand, Cornelia M;Matteson, Eric L;Warrington, Kenneth J
通讯作者：
Warrington, Kenneth J