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：
8789332
负责人：
Cornelia M. Weyand
金额：
$ 39.61万
依托单位：
STANFORD UNIVERSITY
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 2018-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8789332
关键词：
1-Phosphatidylinositol 3-Kinase 3-Dimensional Acute T Cell Leukemia Adhesiveness Adrenal Cortex Hormones Adult Affect Antibodies Antigens Aorta Aortic Aneurysm Aortic Arch Syndromes Aortic Diseases Arteries Arteritis Automobile Driving Behavior Biological Models Biomedical Engineering Blindness Blood Vessels CCL2 gene CD4 Positive T Lymphocytes Calcineurin Cell Communication Cell Differentiation process Cell Survival Cell physiology Cells Cellulose Chimera organism Chimeric Proteins Chronic Clinic Clinical Clonal Expansion Communication Custom Dendritic Cells Development Disease Dose Endothelial Cells Fiber Growth Health Human Hyperplasia Hypertension Immune Immune response Immune system Immunity Indium Inflammation Inflammatory Interferons Interleukin-17 Knowledge Lesion Life Ligands Mediating Modeling Molecular Myocardial NOTCH1 gene Oncogenic Pathway interactions Patients Pattern Phenotype Point Mutation Population Process Production RNA Interference Resources Role SCID Mice Series Shapes Signal Pathway Signal Transduction Smooth Muscle Myocytes Stroke System T cell response T-Cell Proliferation T-Lymphocyte TCF3 gene Takayasu&apos s Arteritis Technology Temporal Arteritis Testing Therapeutic Tissues Transplantation Tumor Suppressor Proteins Vascular Endothelial Cell Vasculitis aging population base body system c-myc Genes cell behavior cell growth cohort cytokine design human FRAP1 protein in vivo inhibitor/antagonist interleukin-22 migration mouse model notch protein novel novel therapeutic intervention novel therapeutics overexpression receptor receptor expression response restoration scaffold small molecule

项目摘要

DESCRIPTION (provided by applicant): Large vessel vasculitides (LVV), such as giant cell arteritis (GCA) cause blindness, stroke, aortic arch syndrome, aortic aneurysm, hypertension and myocardial insufficiency. In an aging population the number of patients requiring chronic management for LVV has been steadily rising, while the therapeutic armamentarium has remained strictly limited to high-dose corticosteroids. The last decade has seen exciting progress in implicating the innate and adaptive immune system in the immunopathogenesis of LVV. However, there is a critical gap in our knowledge why the disease targets the aorta and its major branches and how immuno- stromal communications in the arterial wall initiate and promote vasculitis. The pathogenic immune response has a signature of antigen-induced clonal expansion, but we have recently seen that costimulatory signals deriving from resident cells in the tissue niche are equally important in driving tissue-damaging immunity. GCA arteries express abundant levels of NOTCH receptors and ligands, providing a molecular platform for superb cell-to-cell communication. Blocking of NOTCH signaling effectively inhibits vasculitis. CD4 T cells from GCA patients constitutively express NOTCH1 receptor, enabling them to interact with NOTCH ligand expressing vascular smooth muscle cells (VSMC) and endothelial cells (EC). This application is designed to uncover how the Notch pathway participates in immuno-endothelial and immuno-stromal communications and how NOTCH- dependent signaling shapes vasculitogenic T cell responses and maladaptive VSMC and EC behavior. The project builds on a series of enabling resources; including a clinically phenotyped cohort of GCA patients; a novel 3-D model system of human arterial walls which permits assembly of custom-made vessels from stackable units populated with defined cell populations; and a humanized mouse model carrying inflamed human arteries. Access to Notch receptor and ligands can be blocked through ligand-competing antibodies/fusion proteins and cells can be rendered Notch signaling deficient by RNAi technology. Specific Aim 1 examines on a mechanistic level how NOTCH ligands on VSMC and EC regulate effector functions of vasculitogenic CD4 T cells; modulate their growth, tissue invasion capacity and cytokine production. Specific Aim 2 seeks to identify signaling networks that can be utilized to either suppress NOTCH1 expression or target NOTCH-dependent survival signals in pathogenic T cells. Small molecule inhibitors disrupting Notch-derived signals will be tested in the chimera model for their anti-vasculitic potential. Specific Aim 3 is focused on the role of VSMC as signal-sending and signal-receiving cells and determines how NOTCH-NOTCH ligand interactions affect VSMC survival, migration, matrix production, contractility and ROS release. Specific Aim 4 unravels the molecular mechanisms through which patient-derived CD4+NOTCH1+ T cells regulate the functional behavior of ECs and investigates how such T cells modulate EC proinflammatory functions, angiogenic capacity, adhesiveness and leakiness of the EC barrier.

描述（由申请人提供）：大血管血管炎（LVV），例如巨细胞动脉炎（GCA）会导致失明、中风、主动脉弓综合征、主动脉瘤、高血压和心肌功能不全。在老龄化人口中，需要长期治疗 LVV 的患者数量一直在稳步上升，而治疗药物仍然严格限于高剂量皮质类固醇。过去十年，先天性和适应性免疫系统在 LVV 免疫发病机制中的作用取得了令人兴奋的进展。然而，我们对为什么该疾病针对主动脉及其主要分支以及动脉壁中的免疫基质通讯如何引发和促进血管炎的认识存在重大差距。致病性免疫反应具有抗原诱导的克隆扩张的特征，但我们最近发现，来自组织生态位中常驻细胞的共刺激信号在驱动组织损伤性免疫方面同样重要。 GCA 动脉表达丰富水平的 NOTCH 受体和配体，为出色的细胞间通讯提供了分子平台。阻断 NOTCH 信号传导可有效抑制血管炎。 GCA 患者的 CD4 T 细胞组成型表达 NOTCH1 受体，使其能够与表达 NOTCH 配体的血管平滑肌细胞 (VSMC) 和内皮细胞 (EC) 相互作用。该应用旨在揭示Notch通路如何参与免疫内皮和免疫基质通讯，以及NOTCH依赖性信号传导如何塑造血管生成性T细胞反应和适应不良的VSMC和EC行为。该项目建立在一系列支持资源的基础上；包括具有临床表型的 GCA 患者队列；一种新颖的人体动脉壁 3D 模型系统，允许使用填充有特定细胞群的可堆叠单元组装定制血管；以及携带发炎人类动脉的人源化小鼠模型。可以通过配体竞争抗体/融合蛋白阻断对Notch受体和配体的访问，并且可以通过RNAi技术使细胞呈现Notch信号传导缺陷。具体目标 1 在机制水平上研究 VSMC 和 EC 上的 NOTCH 配体如何调节血管炎性 CD4 T 细胞的效应功能；调节它们的生长、组织侵袭能力和细胞因子的产生。具体目标 2 旨在鉴定可用于抑制 NOTCH1 表达或靶向致病性 T 细胞中 NOTCH 依赖性生存信号的信号网络。破坏Notch衍生信号的小分子抑制剂将在嵌合体模型中测试其抗血管炎潜力。具体目标 3 重点关注 VSMC 作为信号发送和信号接收细胞的作用，并确定 NOTCH-NOTCH 配体相互作用如何影响 VSMC 存活、迁移、基质产生、收缩性和 ROS 释放。具体目标 4 揭示了患者来源的 CD4+NOTCH1+ T 细胞调节 EC 功能行为的分子机制，并研究这些 T 细胞如何调节 EC 促炎功能、血管生成能力、EC 屏障的粘附性和渗漏性。