The NOTCH Signaling Pathway in Large Vessel Vasculitis

大血管炎中的 NOTCH 信号通路

• 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
• 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' 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

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Vasculitides（LVV），例如巨细胞炎（GCA）导致失明，中风，主动脉弓综合征，主动脉动脉瘤，高血压和心肌不足。在老龄化的人群中，需要长期管理LVV的患者数量一直在稳步上升，而治疗性武术仍然严格限于高剂量皮质类固醇。在过去的十年中，在LVV的免疫发病发生中，将先天和适应性免疫系统牵涉到了令人兴奋的进步。然而，我们的知识存在一个危险的差距，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传播如何启动并促进血管炎。致病性免疫反应具有抗原引起的克隆膨胀的特征，但是我们最近看到，从组织壁she中衍生的居民细胞衍生出的共刺激信号对于驱动组织损害组织的免疫力同样重要。 GCA动脉表达了大量的Notch受体和配体，为超级细胞与细胞通信提供了一个分子平台。凹槽信号的阻塞有效地抑制了血管炎。来自GCA患者的CD4 T细胞组成型表达Notch1受体，使其与表达血管平滑肌细胞（VSMC）和内皮细胞（EC）的Notch配体相互作用。该应用旨在揭示Notch途径如何参与免疫 - 内皮和免疫 - 层的通信以及一个依赖性信号传导如何塑造血管生成T细胞反应以及不良适应性VSMC和EC行为。该项目建立在一系列启用资源的基础上；包括临床表型GCA患者的队列；人类动脉壁的新型3-D模型系统，允许从人口组成的具有定义的细胞群体的可堆叠单元组装定制的容器；以及带有发炎人类动脉的人源化小鼠模型。可以通过RNAi技术缺乏缺陷的Notch信号传导，可以通过配体的抗体/融合蛋白来阻断Notch受体和配体的访问。具体目标1在机械水平上检查了VSMC和EC上的Notch配体如何调节血管生成CD4 T细胞的效应子功能；调节其生长，组织侵袭能力和细胞因子产生。特定目标2试图识别可用于抑制Notch1表达或靶向Notch依赖性生存信号的信号网络。在嵌合体模型中将测试破坏Notch衍生信号的小分子抑制剂的抗血脉脉冲潜力。特定的目标3集中在VSMC作为信号端端和信号接收单元的作用上，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。特定目标4揭开了患者衍生的CD4+ NOTCH1+ T细胞调节EC的功能行为的分子机制，并研究了此类T细胞如何调节EC促性功能，血管生成能力，EC屏障的粘附性和渗漏性。