Vasculitis and Translational Medicine

血管炎和转化医学

基本信息

批准号：
9359810
负责人：
Peter Grayson
金额：
$ 51.02万
依托单位：
NATIONAL INSTITUTE OF ARTHRITIS AND MUSCULOSKELETAL AND SKIN DISEASES
依托单位国家：
美国
项目类别：
财政年份：
资助国家：
美国
起止时间：
至
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/9359810
关键词：
American Angiography Animal Model Antineutrophil Cytoplasmic Antibodies Aortic Aneurysm Area Arteries Arthritis Arts Autoantibodies Autoantigens Autoimmune Diseases Autoimmunity Biological Markers Blood Vessels Cell Separation Cells Chronic Disease Clinical Clinical Research Clinical Trials Database Cocaine Collaborations Complex Data Data Collection Development Discipline of Nuclear Medicine Disease Disease Management Disease remission Dissection Endothelial Cells Ethics Etiology Evaluation Extramural Activities Flow Cytometry Foundations Future Gene Expression Profiling Genetic Goals Gold Helminths Housing Human Hydralazine Image Immune In Vitro Inflammation Intramural Research Laboratories Levamisole Life Manuscripts Metabolism Modeling Muscarinic Acetylcholine Receptor Muscarinic M3 Receptor National Institute of Arthritis and Musculoskeletal and Skin Diseases National Institute of Drug Abuse Natural History Nervous system structure North America Oral Organ Outcome Outcome Measure Pathogenesis Patients Pharmaceutical Preparations Physicians Play Population Positron-Emission Tomography Procainamide Protocols documentation Randomized Clinical Trials Rare Diseases Recording of previous events Recruitment Activity Relapse Research Rheumatism Rheumatology Role Sampling San Francisco Serological Source Steroids Study of serum Surface Systemic Lupus Erythematosus Systemic disease Takayasu&apos s Arteritis Techniques Temporal Arteritis Tissues Translational Research United States United States National Institutes of Health Universities Vascular Endothelial Cell Vasculitis Work abstracting aged biobank biomarker discovery cholinergic clinical predictors cocaine exposure cocaine use cohort college drug mechanism extracellular imaging biomarker immunogenicity meetings neutrophil new therapeutic target novel novel marker novel therapeutics patient advocacy group patient subsets personalized medicine programs research clinical testing research study symposium transcriptome sequencing translational medicine treatment response vascular abnormality vascular inflammation whole genome

项目摘要

Recruitment to date remains strong within the Vasculitis Natural History Study. All patients seen at the NIH Clinical Center receive comprehensive clinical evaluation and contribute samples to a growing biobank. Over the last year, we have focused upon two rarer forms of vasculitis: drug-induced vasculitis and large vessel vasculitis (LVV). In terms of drug-induced vasculitis, we have focused on levamsiole, an anti-helminth drug that has recently been implicated in cases of drug-induced autoimmunity in humans exposed to cocaine adulterated with levamisole for profit. The United States Drug Enforcement Agency estimates that >75% of cocaine within the US has been contaminated with levamisole. We discovered that levamisole induces neutrophil extracellular trap (NET) formation through engagement of muscarinic receptors on the surface of neutrophils. Through animal models we defined that the M3 muscarinic receptor specifically is triggered by levamisole. In collaboration with colleagues from the National Institute of Drug Abuse and colleagues from the University of San Francisco, we studied sera from cohorts of patients actively using cocaine contaminated with levamisole was used to identify novel autoantibodies against NET components. We also studied the effect that levamisole and NETs on vascular endothelial cells and found that levamisole-induced NETs were toxic to endothelial cells in vitro and in aortic myogram models. These data suggest that NETs are a source of autoantigens in levamisole-induced autoimmunity, contribute to vascular damage, and that heretofore uncharacterized interactions between the cholinergic nervous system and neutrophils may play a causal role in autoantibody formation and autoimmune disease. Abstracts related to this work have presented at the 2015 American College of Rheumatology Annual Meeting and the 2016 EULAR League Against Rheumatism Annual meeting as oral presentations. A manuscript of this work is currently under revision. In terms of LVV, we continue to recruit patients with these rare diseases. To date, we have performed whole body PET scans and angiography on 60 patients with LVV. We have discovered vascular abnormalities on PET scans suggestive of ongoing subclinical vascular inflammation in a subset of patients with LVV (approximately 50%) whom clinically were thought to be in disease remission. These findings are intriguing because a subset of patients with LVV are known to develop life-threatening vascular complications including aortic aneurysms and dissections late into the course of disease. We are investigating potential serologic and clinical predictors of abnormal PET scans in our cohort and to study PET scan findings in association with corresponding angiography. Preliminary findings from the clinical analyses have been presented at the 2016 DC Rheumatism Research Conference and were accepted for presentation at the 2016 American College of Rheumatology Annual Meeting. An image from our cohort and accompanying article was accepted as the cover art for Arthritis & Rheumatology May 2015. Preliminary findings from in vitro studies indicate that metabolism is altered in specific immune cell populations in association with PET scan findings in patients with LVV> Additionally, in a subset of patients with LVV in our cohort, we continue to purify immune cell populations using cell sorting techniques. We plan to perform RNA sequencing experiments on the different cell populations and analyze subsequent findings in association with radiographic and clinical outcomes as a means to discover novel markers of disease activity and potentially novel therapeutic targets.

迄今为止，在血管炎自然史研究中招募仍然很强。在NIH临床中心看到的所有患者均接受全面的临床评估，并为不断增长的生物库贡献样本。在过去的一年中，我们专注于两种稀有形式的血管炎：药物诱发的血管炎和大血管血管炎（LVV）。在药物诱导的血管炎方面，我们专注于Levamsiole，Levamsiole是一种抗螺旋药物，最近与药物诱导的人类自身免疫性相关的人与可卡因相关的左旋甲硅烷诱导的人类自身免疫性。美国毒品执法机构估计，美国境内可卡因占75％，已被levamisole污染。我们发现，左毫可异异，通过在嗜中性粒细胞表面的毒蕈碱受体接合诱导中性粒细胞外陷阱（净）形成。通过动物模型，我们定义了M3毒蕈碱受体特别由levamiso触发。与来自旧金山大学的美国国家药物滥用和同事研究所的同事合作，我们研究了利用列瓦米唑污染的可卡因积极的患者的血清来识别针对净组件的新型自身抗体。我们还研究了左旋硅唑和网对血管内皮细胞的影响，并发现左旋硅唑诱导的网络在体外和主动脉肌电图模型中对内皮细胞有毒。这些数据表明，网络是levamisole引起的自身免疫性中的自身抗原的来源，造成了血管损伤，迄今为止，胆碱能神经系统和中性粒细胞之间的未表征的相互作用可能在自身抗体形成和自身免除自身免除免除的自身抗体中起因果作用。与这项工作相关的摘要已在2015年美国风湿病学院年度会议和2016年EULAR联盟反对风湿病年度会议上作为口头演讲。目前正在修订此工作的手稿。就LVV而言，我们继续招募患有这些罕见疾病的患者。迄今为止，我们已经对60名LVV患者进行了全身PET扫描和血管造影。我们发现在PET扫描方面发现了血管异常，这表明在一部分LVV患者（约50％）的一部分中持续的亚临床血管炎症，这些患者被认为临床上被认为处于疾病缓解。这些发现很有趣，因为已知LVV患者的一部分会发展出威胁生命的血管并发症，包括主动脉瘤和疾病后期的解剖。我们正在研究我们队列中PET扫描异常的潜在血清学和临床预测因子，并研究与相应血管造影相关的PET扫描发现。临床分析的初步发现已在2016年DC风湿病研究会议上提出，并在2016年美国风湿病学院年度会议上接受了介绍。我们同类和随附文章的图像被接受为2015年5月关节炎和风湿病学的封面艺术。从体外研究中的初步发现表明，在我们的LVV患者中，在我们的LVV患者中，在我们的COLLIFIEN中，我们的LVV患者中的PET扫描发现中的代谢发生了变化，我们在PET扫描发现中与LVV>患者相关。我们计划在不同的细胞群体上进行RNA测序实验，并分析与射线照相和临床结局有关的随后发现，以此作为发现疾病活动的新颖标志和潜在的新型治疗靶标。