Autoimmune and Diabetic Dysmotility

自身免疫性和糖尿病运动障碍

基本信息

批准号：
7456510
负责人：
STEVEN A VERNINO
金额：
$ 33.95万
依托单位：
MAYO CLINIC ROCHESTER
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-07-01 至 2009-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7456510
关键词：
Accounting Acetylcholine Active Immunization Address Animal Model Animals Antibodies Autoantibodies Autoimmune Diabetes Autoimmune Process Autoimmunity Binding Characteristics Cholinergic Receptors Clinical Complement Complication Diagnosis Disruption Elements Enteral Enteric Nervous System Exhibits Fc Receptor Frequencies Ganglia Gastrointestinal Motility Human Hyperglycemia IgG Receptors Immunoglobulin G Inbred NOD Mice Inflammation Insulin-Dependent Diabetes Mellitus Mediating Mediator of activation protein Morbidity - disease rate Mus Muscle Myxoid cyst Neurologic Neurons Non-Insulin-Dependent Diabetes Mellitus Organ Pathogenesis Patients Physiological Physiology Reporting Risk Serological Serum Synaptic Transmission Testing base diabetic gastrointestinal human study motility disorder mouse model nerve supply neurotransmission non-diabetic novel receptor

项目摘要

Gastrointestinal (GI) dysmotilty is a significant cause of morbidity in diabetic patients, but the patho-physiology of this complication has not been established. Autoimmunity is the basis of juvenile diabetes and may account for 10% of adult-onset diabetes. Patients with autoimmune diabetes are predisposed to other manifestations of organ-specific autoimmunity. We propose to test the hypothesis that diabetic GI dysmotility results from autoimmune disruption of the intrinsic and/or extrinsic enteric nervous system. This hypothesis is based on 1) reports that several neuronal and muscle autoantibodies serve as markers of autoimmune GI dysmotility and 2) our discovery that IgG specific for ganglionic neuronal acetylcholine receptor (AChR, a critical mediator of fast synaptic transmission in autonomic and enteric ganglia) is both a marker and cause of severe GI hypomotility. We have developed animal models of autoimmune GI dysmotility by active immunization with ganglionic AChR protein and by passive transfer of ganglionic AChR-specific IgG. We propose to characterize and compare two mouse models of autoimmune GI dysmotility with spontaneous GI dysmotility in the diabetic NOD mouse, looking for common immuno-histopathological and electrophysiological features. We will investigate the mechanism of lgG-meditated GI dysmotility in detail in conventional mice and determine whether NOD mice exhibit heightened sensitivity to IgG-mediated dysmotility. In parallel serological studies, we will determine the frequency of neuronal and other organ-specific autoantibodies in diabetic patients with dysmotility, searching in particular for novel enteric nervous system-specific antibodies. We will also investigate in mice the effects on GI motility of injecting human IgG containing novel enteric autoantibodies. Our project will combine both animal and human studies to elucidate whether or not autoimmunity is involved in diabetic dysmotility, what mechanism are involved in IgG-mediated dysmotility and whether serum autoantibody profiles might aid the diagnosis of autoimmune GI dysmotility and justify immunomodulatory therapy.

胃肠道（GI）肌动症是糖尿病患者发病率的重要原因，但是尚未确定这种并发症的病理生理学。自身免疫性是青少年糖尿病的基础，可能占成年糖尿病的10％。自身免疫性糖尿病的患者易患器官特异性自身免疫性的其他表现。我们建议检验以下假设：糖尿病性胃肠道失调性障碍是由于内在和/或外在肠神经系统的自身免疫性破坏引起的。该假设基于1）报告说，几种神经元和肌肉自身抗体是自身免疫性胃肠弹不良症的标志物，以及2）我们发现的发现，对于神经神经神经元乙酰胆碱受体的IgG（ACHR）（ACHR）（ACHR（ACHR）（ACHR）（ACHR（ACHR），自主和刺激性的快速突触传播的hypot and Granglia和MarkeraR and Arage and Acrain and Acrain a Markerer and Ass a Markerer and a Markerer。我们已经开发了自身免疫性GI的动物模型通过神经节ACHR蛋白的主动免疫和神经节ACHR特异性IgG的被动转移通过主动免疫发作。我们建议在糖尿病点头小鼠中表征和比较两种自身免疫性胃肠道不良功能障碍的小鼠模型与自发性GI失调性，以寻找常见的免疫 - 助理病理学和电生理特征。我们将在常规小鼠中详细研究LGG-鉴定的GI失调性的机制，并确定点头小鼠是否对IgG介导的功能障碍表现出较高的敏感性。在平行的血清学研究中，我们将确定患有运动障碍性的糖尿病患者中神经元和其他器官特异性自身抗体的频率，特别是寻找新型肠神经系统特异性抗体。我们还将在小鼠中调查对含有新型肠自身抗体的人类IgG的胃肠道运动的影响。我们的项目将结合动物和人类研究，以阐明自身免疫是否涉及糖尿病性运动障碍，IgG介导的功能障碍涉及哪些机制以及血清自身抗体特征是否有助于诊断自身免疫性胃肠道功能障碍并证明免疫调节疗法是合理的。