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.

项目概要 姿势性心动过速综合征 (POTS) 是一种由心血管自主神经功能紊乱引起的衰弱性疾病 导致功能障碍的原因较多，且很难有效治疗。该更新提案建立在 支持功能性肾上腺素能自身抗体在 POTS 中的病理生理学作用的工作。这 这些抗体对天然配体的不同变构效应为增加 POTS 的交感神经活动和夸张的直立性心动过速特征。然而， POTS 患者副交感神经活性降低的机制尚未阐明。这 该提案检验了毒蕈碱自身抗体介导的副交感功能障碍的假设 有助于 POTS 的发病机制，并且副交感神经（迷走神经）刺激可改善 POTS 症状、自身免疫和炎症。长期目标是评估 POTS 病理生理学中自身免疫介导的交感迷走失衡并建立 经皮迷走神经刺激 (tVNS) 是一种安全有效的 POTS 治疗选择。这 具体目标是： 1) 确定毒蕈碱的患病率、负担和临床意义 表型良好的 POTS 患者队列和匹配的健康对照队列中的自身抗体 科目； 2) 检查毒蕈碱自身抗体对兔子心血管活动的体内影响 在当前资助期间开发的自身免疫模型； 3）调查潜力 tVNS 在 POTS 患者和动物模型中的治疗机制。 tVNS 是一种重要的治疗方法 需要跨越基础科学和临床研究之间转化桥梁的模式。 这些研究的结果将为有关病因学的新知识提供现实的期望 这种致残性疾病并为 POTS 治疗范式转变奠定了基础。