权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Muscularization of pulmonary arteries induced by an adaptive immune response

适应性免疫反应诱导的肺动脉肌化

基本信息

批准号：
7844971
负责人：
Gabriele Grunig
金额：
$ 23.24万
依托单位：
NEW YORK UNIVERSITY SCHOOL OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-06-01 至 2012-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7844971
关键词：
Ablation Alleles Antigens Appearance Arteries Autoantibodies Autoimmune Process Blood Vessels Breathing CD4 Positive T Lymphocytes Cell Count Cell Culture Techniques Cell Proliferation Cell physiology Cells Chronic Clinical Communicable Diseases Companions Complement Correlation Studies Data Development Endothelial Cells Enhancers Epithelial Etiology Generations Genetic Enhancer Element Goals Helminths Histocompatibility Antigens Class II Histologic Homologous Gene Human Hyperplasia Hypertrophy Hypoxia ITGAM gene Immune Immune System Diseases Immune response In Situ In Vitro Incidence Infection Injury Interleukin-13 Interleukin-4 Interleukins Lesion Leukocytes Life Expectancy Lung Maps Mediator of activation protein Mesenchymal Mitogens Molecular Morphology Mus Myeloid Cells Parasites Pathogenesis Patients Process Proliferating Proliferation Marker Pulmonary artery structure Quality of life Role Route Schistosome Parasite Severities Smooth Muscle Smooth Muscle Myocytes Specificity Testing Time Transgenic Mice Work abstracting antigen challenge arterial remodeling cell type cytokine fighting filaria monocyte mouse model precursor cell promoter public health relevance pulmonary arterial hypertension receptor research study resistin response treatment strategy

项目摘要

DESCRIPTION (provided by applicant): Muscularization of pulmonary arteries induced by an adaptive immune response Abstract Pulmonary arterial hypertension (PAH) is a devastating condition because of its deleterious impact on quality of life, and life expectancy. Clinical correlation studies have suggested an immune pathogenesis because of the increased incidence of PAH in autoimmune and infectious diseases. Helminth infections can also cause PAH, but direct injury by the migrating parasites to the arteries has been thought to be the major cause of arterial remodeling. Pulmonary arterial remodeling associated with smooth muscle cell hyperplasia is frequently seen in PAH. In preliminary experiments, severe pulmonary arterial muscularization was induced by intermittent antigen challenge for a prolonged period of time via the inhaled route in primed mice. Essential roles for CD4+ T cells, the antigen- specific T helper (Th)2 response, and a pathogenic Th2 cytokine [Interleukin (IL) 13] in inducing severe pulmonary arterial musularization were identified. This indicated that the host's immune response developed to fight helminth infections alone is sufficient to induce severe pulmonary arterial muscularization, even without the presence of parasites. The severity of arterial remodeling was highly significantly correlated with the numbers of cells that bordered pulmonary arteries and expressed resistin-like molecule (RELM)1. RELM1 is known as a smooth muscle cell mitogen, induced by Th2 responses and by chronic hypoxia. But the role of RELM1 in pulmonary arterial remodeling has not been experimentally tested. The preliminary data show that the majority of proliferation marker positive cells within the remodeled pulmonary arteries had the appearance of endothelial cells and neo-intima cells. Few cells with smooth muscle morphology were proliferation marker positive. These data indicate that the origin of the cells within the remodeled pulmonary arteries might not be smooth muscle cells. The long range goal of this proposal is to understand how the Th2 immune response induces pulmonary arterial muscularization. To accomplish this goal, specific aims are proposed to identify the origin of the cells that populate the remodeled pulmonary arteries and to define the role of RELM1. The experimental approach will be to study mice that carry fluorescent tags driven by cell-type specific promoters for endothelial cells, leukocytes, and monocytes / myeloid cells, and RELM1 KO mice. Studies with mice that express receptors that can be used for cell ablation, and in vitro cell culture will be used for mechanistic analysis. The working hypothesis is that precursor cell proliferation followed by differentiation into smooth muscle cells and RELM1 are essential contributors to Th2-response-induced pulmonary arterial remodeling. PUBLIC HEALTH RELEVANCE: Muscularization of pulmonary arteries induced by an adaptive immune response Relevance: Pulmonary arterial hypertension (PAH) is a devastating condition that can accompany chronic parasite infections and auto-immune diseases. Thickening of the walls of pulmonary arteries by layers of smooth muscle cells is one of the typical morphological alterations seen in PAH and this process is a target for the development of new treatment strategies. The proposed studies are aimed at delineating the cellular origin and mediators that cause the accumulation of these smooth muscle cells in a mouse model of severe pulmonary arterial remodeling induced by the adaptive immune response.

描述（由申请人提供）：适应性免疫反应诱导的肺动脉肌化摘要肺动脉高压（PAH）是一种毁灭性的疾病，因为它对生活质量和预期寿命产生有害影响。临床相关研究表明，由于自身免疫性疾病和传染病中 PAH 的发病率增加，因此存在免疫发病机制。蠕虫感染也可引起肺动脉高压，但迁移到动脉的寄生虫造成的直接损伤被认为是动脉重塑的主要原因。与平滑肌细胞增生相关的肺动脉重塑常见于 PAH。在初步实验中，通过吸入途径长时间间歇性抗原激发小鼠，诱导了严重的肺动脉肌化。确定了 CD4+ T 细胞、抗原特异性 T 辅助细胞 (Th)2 反应和致病性 Th2 细胞因子 [白细胞介素 (IL) 13] 在诱导严重肺动脉肌肉化中的重要作用。这表明，即使没有寄生虫存在，宿主单独对抗蠕虫感染的免疫反应也足以诱导严重的肺动脉肌化。动脉重塑的严重程度与肺动脉边缘并表达抵抗素样分子 (RELM)1 的细胞数量高度显着相关。 RELM1 被称为平滑肌细胞有丝分裂原，由 Th2 反应和慢性缺氧诱导。但 RELM1 在肺动脉重塑中的作用尚未经过实验测试。初步数据显示，重塑的肺动脉内大多数增殖标志物阳性细胞具有内皮细胞和新内膜细胞的外观。很少有平滑肌形态的细胞呈增殖标记阳性。这些数据表明，重塑的肺动脉内的细胞起源可能不是平滑肌细胞。该提案的长期目标是了解 Th2 免疫反应如何诱导肺动脉肌化。为了实现这一目标，提出了具体目标，以确定重塑肺动脉中细胞的起源并定义 RELM1 的作用。实验方法将是研究携带由内皮细胞、白细胞和单核细胞/骨髓细胞的细胞类型特异性启动子驱动的荧光标签的小鼠，以及 RELM1 KO 小鼠。对表达可用于细胞消融的受体的小鼠进行的研究以及体外细胞培养将用于机制分析。工作假设是前体细胞增殖然后分化为平滑肌细胞和 RELM1 是 Th2 反应诱导的肺动脉重塑的重要贡献者。公共卫生相关性：适应性免疫反应引起的肺动脉肌化相关性：肺动脉高压 (PAH) 是一种破坏性病症，可伴随慢性寄生虫感染和自身免疫性疾病。平滑肌细胞层使肺动脉壁增厚是 PAH 中常见的形态学改变之一，该过程是开发新治疗策略的目标。拟议的研究旨在描绘在由适应性免疫反应诱导的严重肺动脉重塑的小鼠模型中引起这些平滑肌细胞积累的细胞起源和介质。