Vasculitis and Translational Medicine

血管炎和转化医学

基本信息

批准号：
9563908
负责人：
Peter Grayson
金额：
$ 47.07万
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/9563908
关键词：
American Angiography Animal Model Antineutrophil Cytoplasmic Antibodies Aortic Aneurysm Area Arteries Arteritis Autoantibodies Autoantigens Autoimmune Diseases Autoimmunity Biological Markers Blood Vessels California Cell Separation Cells Chronic Disease Classification Clinical Clinical Research Clinical Trials Database Cocaine Collaborations Complex Data Data Analyses Data Collection Development Diagnostic radiologic examination Discipline of Nuclear Medicine Disease Disease Management Disease Marker Disease remission Dissection Endothelial Cells Ethics Etiology Evaluation Extramural Activities Flow Cytometry Foundations Future Gene Expression Profiling Genetic Goals Gold Helminths Human Hydralazine Image Immune Immunologics Immunology In Vitro Inflammation International Intramural Research Laboratories Levamisole Life 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 Organ Outcome Outcome Measure Pathogenesis Patient Recruitments Patients Pharmaceutical Preparations Physicians Play Polychondritis Population Positron-Emission Tomography Procainamide Protocols documentation Publications Publishing Randomized Clinical Trials Rare Diseases Recording of previous events Recruitment Activity Relapse Research Rheumatology Role Sampling San Francisco Source Standardization Steroids Suggestion Surface Systemic Lupus Erythematosus Systemic disease Techniques Temporal Arteritis Tissues Translational Research United States United States National Institutes of Health Universities Vascular Endothelial Cell Vasculitis Work activity marker aged biobank biomarker discovery cholinergic cocaine exposure cocaine use cohort college experimental study extracellular imaging biomarker immunogenicity insight meetings neutrophil new therapeutic target novel novel marker novel therapeutics patient advocacy group patient subsets personalized medicine predictive of treatment response programs research clinical testing transcriptome sequencing translational medicine translational research program vascular abnormality vascular inflammation whole genome working group

American Angiography Animal Model Antineutrophil Cytoplasmic Antibodies Aortic Aneurysm Area Arteries Arteritis Autoantibodies Autoantigens Autoimmune Diseases Autoimmunity Biological Markers Blood Vessels California Cell Separation Cells Chronic Disease Classification Clinical Clinical Research Clinical Trials Database Cocaine Collaborations Complex Data Data Analyses Data Collection Development Diagnostic radiologic examination Discipline of Nuclear Medicine Disease Disease Management Disease Marker Disease remission Dissection Endothelial Cells Ethics Etiology Evaluation Extramural Activities Flow Cytometry Foundations Future Gene Expression Profiling Genetic Goals Gold Helminths Human Hydralazine Image Immune Immunologics Immunology In Vitro Inflammation International Intramural Research Laboratories Levamisole Life 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 Organ Outcome Outcome Measure Pathogenesis Patient Recruitments Patients Pharmaceutical Preparations Physicians Play Polychondritis Population Positron-Emission Tomography Procainamide Protocols documentation Publications Publishing Randomized Clinical Trials Rare Diseases Recording of previous events Recruitment Activity Relapse Research Rheumatology Role Sampling San Francisco Source Standardization Steroids Suggestion Surface Systemic Lupus Erythematosus Systemic disease Techniques Temporal Arteritis Tissues Translational Research United States United States National Institutes of Health Universities Vascular Endothelial Cell Vasculitis Work activity marker aged biobank biomarker discovery cholinergic cocaine exposure cocaine use cohort college experimental study extracellular imaging biomarker immunogenicity insight meetings neutrophil new therapeutic target novel novel marker novel therapeutics patient advocacy group patient subsets personalized medicine predictive of treatment response programs research clinical testing transcriptome sequencing translational medicine translational research program vascular abnormality vascular inflammation whole genome working group

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项目摘要

Summary: 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 three forms of vasculitis: drug-induced vasculitis, large vessel vasculitis (LVV), and relapsing polychondritis (RP). 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 approximately 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 California, San Francisco, we studied sera from cohorts of patients actively using cocaine contaminated with levamisole to identify novel autoantibodies against NET components. We also studied the effects of 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. This work was published in JCI Insight in February 2017. 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 approximately 80 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%) who 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. The first publication from this work is currently under revision. Four imaging abstracts from this cohort were submitted to the 2017 American College of Rheumatology Annual Meeting. In the lab, we are studying the immunology of subclinical vascular inflammation in LVV. 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. In a subset of patients with LVV in our cohort, we continue to purify immune cell populations using cell sorting techniques. We are analyzing data from RNA sequencing experiments on the different cell populations in association with radiographic and clinical outcomes as a means to discover novel markers of disease activity and potentially novel therapeutic targets. In terms of relapsing polychondritis, we have recruited 35 patients with this rare disease. We are currently developing classification criteria for this disease and defining an optimal clinical approach to assessment and treatment of this condition. As part of these efforts, we have formed the first International Working Group in Relapsing Polychondritis, dedicated to collaborative clinical and translational research in this disease.

概括：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，我们专注于三种形式的血管炎：药物诱导的血管炎，大血管血管炎（LVV）和复发性多发性炎（RP）。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，美国境内约有75％的可卡因被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。与来自加利福尼亚大学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，我们研究了积极使用与levamisole污染可卡因的患者同类的血清，以识别针对净组件的新型自身抗体。我们还研究了左旋唑和网络对血管内皮细胞的影响，发现左旋硅异异硅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。这项工作于2017年2月在JCI Insight发表。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，我们已经对大约80名LVV患者进行了全身PET扫描和血管造影。我们已经发现，在PET扫描中，有血管异常，暗示着持续的亚临床血管炎症，其中一部分LVV患者（约50％）在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。目前，这项工作的第一个出版物正在修订中。该队列中的四个成像摘要已提交给2017年美国风湿病学院年度会议。在实验室中，我们正在研究LVV中亚临床血管炎症的免疫学。体外研究的初步发现表明，与LVV患者的PET扫描发现有关特异性免疫细胞群体的代谢发生了改变。在我们队列中LVV患者的一部分中，我们继续使用细胞分选技术纯化免疫细胞群体。我们正在分析来自RNA测序实验的数据，这些数据与放射线和临床结局有关，作为发现疾病活动的新颖标志和潜在的新型治疗靶标。在复发性多发性炎方面，我们招募了35例这种罕见疾病。我们目前正在制定该疾病的分类标准，并定义一种评估和治疗此疾病的最佳临床方法。作为这些努力的一部分，我们成立了第一个用于复发多发性炎的国际工作组，致力于该疾病的合作临床和转化研究。