Autoimmune mechanisms of gastrointestinal dysmotility in multiple sclerosis

多发性硬化症胃肠动力障碍的自身免疫机制

基本信息

批准号：
9757775
负责人：
Gary M Mawe
金额：
$ 46.18万
依托单位：
UNIVERSITY OF VERMONT & ST AGRIC COLLEGE
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-09-20 至 2021-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9757775
关键词：
Achalasia Affect Animals Antibodies Antibody Formation Applications Grants Area Astrocytes Autoantibodies Autoimmune Diseases Autoimmune Process Autoimmunity Autonomic Dysfunction B-Lymphocytes Binding Biological Assay Blood Vessels Blood flow Blood specimen Brain Calcium Central Nervous System Diseases Chagas Disease Clinical Colon Constipation Data Development Diabetes Mellitus Distant Effectiveness Enteral Enteric Nervous System Enzymes Exhibits Experimental Autoimmune Encephalomyelitis Exposure to Frequencies Functional disorder Future Ganglia Gastrointestinal Diseases Gastrointestinal Motility Gastrointestinal tract structure General Population Goals Guanylate Cyclase Human Image Immune system Immunoglobulin G Immunoglobulins Immunosorbents Individual Inflammatory Response Intestinal Motility Intestines Investigation Lead Link Mediating Membrane Modeling Multiple Sclerosis Mus Myelin Basic Proteins Nerve Tissue Nervous System Physiology Nervous system structure Neuraxis Neuroglia Neurons Oligodendroglia Pain Parkinson Disease Patients Physiological Population Preparation Process Production Property Proteins Proteolipids Quality of life Reflex action Research Project Grants Sampling Serum Site Specificity Spinal Cord Study models Symptoms Techniques Testing Therapeutic Therapeutic Intervention Treatment Efficacy calcium indicator cell motility cell type clinically relevant design experience experimental study gastrointestinal gastrointestinal function gastrointestinal symptom improved in vivo motility disorder mouse model multiple sclerosis patient multiple sclerosis treatment nerve supply neurological pathology neuromuscular neuromuscular function neuromuscular transmission patient population relating to nervous system theories tositumomab transcriptome treatment response

项目摘要

Project Summary/Abstract Individuals with multiple sclerosis (MS) frequently suffer from autonomic dysfunction in addition to the neuromuscular ailments that represent their hallmark symptoms, and one of the most common and debilitating of their autonomic problems is constipation. Our theory is that constipation develops as a form of collateral damage from the central nervous system (CNS) inflammatory response that occurs in MS. During this inflammatory response, the patient's immune system generates antibodies that target proteins in the cellular debris of dying neurons and glial cells in affected areas, and these autoantibodies could have actions at distant sites. The enteric nervous system (ENS) is unique in that it contains intrinsic reflex circuitry that regulates motility, secretion and vascular tone in the gut, independently of CNS innervation. The ENS contains glial cells that share transcriptome features of oligodendrocytes and astrocytes, including proteolipid protein and myelin basic protein. These are two known antigenic targets in MS that could be incidentally targeted where they are also expressed in the ENS. This grant proposal is designed to test the hypothesis that autoantibodies generated in MS patients can target proteins on neuronal and glial membranes in the ENS, resulting in altered enteric neural reflex activity leading to constipation. In support of our hypothesis and the feasibility of our proposed studies, we have demonstrated that GI function is altered in mice with experimental autoimmune encephalomyelitis (EAE), the predominant mouse model of MS, in ways that are consistent with the development of constipation. Furthermore, we have found that blood samples from MS patients and EAE mice contain antibodies that bind to neurons and glial cells in the GI tract. In our proposed studies, we will examine the features of GI dysfunction in EAE mice, and confirm that the changes in gut motility involve circulating autoantibodies. We will determine the ENS cell types that MS autoantibodies bind to, and what effects these antibodies have on GI function in naïve mice. We will also directly examine the physiological activities of glial cells and neurons in the GI tract, and we will elucidate how these activities are altered in EAE mice, and in response to treatment with autoantibodies from MS patients. In these studies, we will also use colons from mice in which a calcium indicator protein is expressed by enteric glial cells or select populations of enteric neurons, and we will use intracellular recording to evaluate the strength of excitatory and inhibitory neuromuscular transmission. Finally, we will test potential therapeutic approaches for their effectiveness in alleviating constipation in the MS mouse model. Understanding the mechanisms responsible for constipation in MS is a clinically relevant goal since it is a critical step toward developing an effective therapeutic solution for the GI ailments of affected MS patients and others with autoimmune-mediated dysmotility.

项目摘要/摘要多发性硬化症（MS）的个体经常患有自主神经功能障碍代表其标志性符号的神经肌肉疾病，也是最常见和令人衰弱的疾病之一他们的自主问题是便秘。我们的理论是，便秘是作为抵押的一种形式 MS中发生的中枢神经系统（CNS）炎症反应的损害。在此期间炎症反应，患者的免疫系统会产生靶向细胞中蛋白质的抗体垂死的神经元和神经胶质细胞的碎片在受影响区域，这些自身抗体可能在遥远的站点。肠神经系统（ENS）的独特之处在于它包含调节的固有反射电路肠道中的运动，分泌和血管张力，独立于CNS神经。 ENS包含神经胶质细胞共享少突胶质细胞和星形胶质细胞的转录组特征，包括蛋白质脂质蛋白和髓磷脂碱性蛋白质。这是MS中两个已知的抗原靶标，可以偶然针对它们也在ENS中表达。该赠款提案旨在检验自身抗体的假设在MS患者中产生的可以靶向ENS中神经元和神经胶质膜上的蛋白质，从而改变肠神经反射活性导致便秘。支持我们的假设和我们的可行性拟议的研究，我们已经证明了使用实验自身免疫的小鼠中的胃肠道功能发生了变化脑脊髓炎（EAE）是MS的主要小鼠模型，以与便秘的发展。此外，我们发现MS患者和EAE小鼠的血液样本包含与胃肠道中神经元和神经胶质细胞结合的抗体。在我们提出的研究中，我们将研究 EAE小鼠中GI功能障碍的特征，并确认肠运动的变化涉及循环自动抗体。我们将确定MS自动抗体结合的ENS细胞类型，以及这些影响在幼稚小鼠中具有胃肠道功能的抗体。我们还将直接检查神经胶质的体育活动胃肠道中的细胞和神经元，我们将阐明在EAE小鼠中如何改变这些活动，并在对MS患者自身抗体治疗的反应。在这些研究中，我们还将使用钙指示剂蛋白通过肠神经胶质细胞或肠群的精选群体表达的小鼠神经元，我们将使用细胞内记录来评估兴奋和抑制的强度神经肌肉传播。最后，我们将测试潜在的治疗方法的有效性在MS小鼠模型中减轻便秘。了解负责便秘的机制在MS中是一个临床上相关的目标，因为它是开发有效治疗解决方案的关键一步受影响的MS患者的GI疾病和自身免疫介导的运动障碍的其他患者的疾病。