Autoimmune Basis for Postural Tachycardia Syndrome

体位性心动过速综合征的自身免疫基础

• 批准号: 10207892
• 负责人: Xichun Yu
• 金额: $ 49.04万
• 依托单位: UNIVERSITY OF OKLAHOMA HLTH SCIENCES CTR
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-04 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10207892
• 关键词: Acetylcholine; Adrenergic Agents; Adrenergic Receptor; Affect; Age; Animal Model; Animals; Antibodies; Antibody Suppression; Autoantibodies; Autoimmune; Autoimmune Process; Autoimmunity; Autonomic Dysfunction; Autonomic nervous system disorders; Basic Science; Biological; Biological Assay; Blood Vessels; Cardiac; Cardiac Myocytes; Cardiovascular system; Cells; Characteristics; Clinical Research; Data; Disease; Etiology; Foundations; Functional disorder; Funding; Gastroparesis; Goals; Heart Rate; Immunization; Immunize; In Vitro; Inflammation; Inflammatory Response; Knowledge; Ligands; Mediating; Modality; Modeling; Molecular; Muscarinic Acetylcholine Receptor; Muscarinics; Muscle; Neurotransmitters; Orthostatic tachycardia; Oryctolagus cuniculus; Parasympathetic Nervous System; Pathogenesis; Pathogenicity; Patients; Phenotype; Play; Postural Orthostatic Tachycardia Syndrome; Posture; Prevalence; Process; Production; Publishing; Quality of life; Reaction; Regulation; Role; Serum; Severities; Signal Transduction; Stomach; Subgroup; Symptoms; Tachycardia; Testing; Therapeutic; Therapeutic Intervention; Tragus; Vagus nerve structure; Withdrawal; Work; base; cholinergic; clinically significant; cohort; effective therapy; expectation; gastrointestinal; gastrointestinal symptom; human disease; immunoregulation; improved; in vivo; inhibiting antibody; motility disorder; novel therapeutics; positive allosteric modulator; receptor; reduce symptoms; response; sex; transcutaneous stimulation; vagus nerve stimulation

Project Summary Postural tachycardia syndrome (POTS) is a debilitating disorder resulting from cardiovascular autonomic dysfunction, has many causes and is very difficult to treat effectively. This renewal proposal builds on the work that supports a pathophysiological role for functional adrenergic autoantibodies in POTS. The differing allosteric effects of these antibodies on the natural ligands provide an explanation for increased sympathetic activity and exaggerated orthostatic tachycardia characteristic of POTS. However, the mechanism for decreased parasympathetic activity in POTS patients is yet to be elucidated. This proposal tests the hypothesis that muscarinic autoantibody-mediated parasympathetic dysfunction contributes to the pathogenesis of POTS, and that parasympathetic (vagal) stimulation improves POTS symptoms, autoimmunity and inflammation. The long-term goal is to evaluate the significance of autoimmune-mediated sympathovagal imbalance in the pathophysiology of POTS and to establish transcutaneous vagus nerve stimulation (tVNS) as a safe and effective treatment option for POTS. The specific aims are to: 1) determine the prevalence, burden, and clinical significance of muscarinic autoantibodies in a well-phenotyped cohort of POTS patients and a matched cohort of healthy control subjects; 2) examine the in vivo impact of muscarinic autoantibodies on cardiovagal activity in a rabbit autoimmune model developed during the current funding period; and 3) investigate the potential therapeutic mechanisms of tVNS in POTS patients and in animal model. tVNS is an important treatment modality that needs to cross the translational bridge between basic science and clinical research. Findings from these studies will provide realistic expectation of new knowledge regarding the etiology of this disabling disorder and lay the foundation for a paradigm shift for the treatment of POTS.

项目摘要 姿势心动过速综合征（POTS）是由心血管自主神经自主引起的一种使人衰弱的疾病 功能障碍，有很多原因，并且很难有效治疗。该更新提案建立在 支持盆中功能性肾上腺素能自身抗体的病理生理作用的工作。这 这些抗体对天然配体的变构作用的不同，为增加的解释提供了解释 盆栽的交感神经和夸张的矫形心脏特征。但是， POTS患者副交感神经活动降低的机制尚未阐明。这 建议检验毒蕈碱自身抗体介导的副交感神经功能障碍的假设 有助于花盆的发病机理，副交感神经（迷走神经）刺激改善了盆栽 症状，自身免疫性和炎症。长期目标是评估 自身免疫性介导的盆栽病理生理学的交感神经失衡并建立 经皮神经刺激（TVN）作为锅的安全有效的治疗选择。这 具体目的是：1）确定毒蕈碱的患病率，负担和临床意义 在良好的盆栽患者和匹配的健康对照组中，自身抗体 受试者； 2）检查毒蕈碱自身抗体对兔子心脏活动的体内影响 在当前资助期间开发的自身免疫模型； 3）调查潜力 POTS患者和动物模型中TVNS的治疗机制。 TVNS是一个重要的待遇 需要跨越基础科学与临床研究之间的转化桥的方式。 这些研究的发现将对有关新知识的现实期望 这种残疾障碍并为盆栽治疗范式转移奠定了基础。