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

• 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
• 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

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.

项目总结/摘要 患有多发性硬化症（MS）的个体除了患有神经功能紊乱外，还经常患有自主神经功能紊乱。 神经肌肉疾病，代表他们的标志性症状，和一个最常见的和衰弱 是便秘我们的理论是，便秘是作为一种附带疾病而发展的 MS中发生的中枢神经系统（CNS）炎症反应造成的损伤。 当炎症反应时，患者的免疫系统产生靶向细胞内蛋白质的抗体。 受影响区域的垂死神经元和神经胶质细胞碎片，这些自身抗体可以在远处发挥作用。 网站.肠神经系统（ENS）是独特的，因为它包含内在的反射回路，调节 运动，分泌和血管张力在肠道中，独立于中枢神经系统的神经支配。ENS含有神经胶质细胞 其具有少突胶质细胞和星形胶质细胞的转录组特征，包括蛋白脂质蛋白和髓鞘 碱性蛋白质。这是MS中的两个已知抗原靶点，它们可能偶然靶向它们所在的位置 也表达在ENS。这项拨款提案旨在测试假设， 在MS患者中产生的蛋白质可以靶向ENS中神经元和神经胶质细胞膜上的蛋白质， 肠神经反射活动导致便秘。为了支持我们的假设和可行性， 我们提出的研究表明，实验性自身免疫性疾病小鼠的GI功能发生了改变， 脑脊髓炎（EAE），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 含有与胃肠道神经元和神经胶质细胞结合的抗体。在我们建议的研究中，我们将研究 EAE小鼠胃肠道功能障碍的特点，并证实肠道运动的变化涉及循环 自身抗体我们将确定MS自身抗体结合的ENS细胞类型，以及这些细胞的影响。 抗体对幼稚小鼠胃肠道功能的影响。我们还将直接研究神经胶质细胞的生理活动， 细胞和神经元在胃肠道，我们将阐明如何改变这些活动在EAE小鼠， 对MS患者自身抗体治疗的反应。在这些研究中，我们还将使用来自 其中钙指示蛋白由肠神经胶质细胞或选择的肠神经胶质细胞群表达的小鼠 神经元，我们将使用细胞内记录来评估兴奋和抑制的强度 神经肌肉传递最后，我们将测试潜在的治疗方法的有效性， 缓解MS小鼠模型中的便秘。了解便秘的机制 是临床相关的目标，因为它是开发有效治疗方案的关键步骤， 受影响的MS患者和其他自身免疫介导的运动障碍患者的胃肠道疾病。