Intestinal Dysmotility in Multiple Sclerosis

 描述（由申请人提供）：多发性硬化症（MS）是一种炎性疾病，可导致中枢神经系统（CNS）轴突脱髓鞘和轴突变性。除了疲劳外，特征性症状还包括视觉、运动和感觉障碍。便秘等肠道功能障碍在许多多发性硬化症患者中很常见，但这种症状的病因尚不清楚。骨盆底肌肉功能障碍可能发生在MS中，但不能解释便秘的所有方面。相反，有证据表明，肠神经系统（ENS）参与的情况下，在近端结肠传输延迟和延迟结肠迁移肌电复合体的MS患者的存在。此外，一些MS患者的血液含有针对CNS和ENS中发现的抗原的循环抗体，包括肠神经元中发现的神经丝和肠神经胶质中发现的S100 B。这使我们假设MS中的便秘是由靶向ENS本身的血清抗体引起的。我们将从MS患者和实验性自身免疫性脑脊髓炎（EAE）小鼠（MS的小鼠模型）中收集血清样本。我们将通过间接和直接免疫染色方法检测血清中是否含有针对ENS（Aim 1）的抗体。然后，我们将这些抗体给予小鼠和分离的小鼠结肠，以确定抗体是否引起肠道生理学的变化。接下来，我们将描述EAE小鼠中发生的胃肠道（GI）功能障碍（目的2）。我们将测试在具有某些免疫缺陷的小鼠（包括B淋巴细胞缺陷小鼠）中诱导EAE时是否可以改善GI功能障碍。这些目标将在加里马维博士赞助的培训计划的背景下完成，一位肠道神经生物学家，由科里·托伊舍尔博士共同赞助，具有丰富MS小鼠模型经验的免疫学家，和Angela Applebee，M.D.，培训计划将包括研究，课程和专业发展经验，以培训Estelle（Stellie）Spear作为独立的翻译神经科学家。科学的培训计划将侧重于健康和MS和EAE疾病状态下炎症反应中GI运动的神经控制。课程将补充Stellie从她的共同赞助商那里获得的教育;课程将包括UVM医学和研究生院在解剖学，生理学，免疫学和相关技术方面提供的课程。职业发展培训将包括口头/海报会议介绍和技能讲习班。Stellie和她的赞助商之间的每月讨论和个性化发展计划（IDP）的形成将确保她接受必要的培训，以追求她作为一个独立的学术研究者的目标。

 DESCRIPTION (provided by applicant): Multiple sclerosis (MS) is an inflammatory disease that causes demyelination and axonal degeneration of central nervous system (CNS) axons. Characteristic symptoms include visual, motor and sensory disturbances in addition to fatigue. Bowel dysfunction, such as constipation, is common in many MS patients but the etiology of this symptom is poorly understood. Dysfunction of the pelvic floor muscles can occur in MS, but cannot account for all aspects of the constipation. Instead, there is evidence of enteric nervous system (ENS) involvement as demonstrated by instances of delayed transit in the proximal colon and the presence of delayed colonic migrating myoelectric complexes in MS patients. Further, the blood of some MS patients contains circulating antibodies directed against antigens that are found in both the CNS and the ENS, including neurofilaments, found in enteric neurons, and S100B, found in enteric glia. This leads us to the hypothesis that constipation in MS is caused by serum antibodies that target the ENS itself. We will collect serum samples from patients with MS, and from mice with experimental autoimmune encephalomyelitis (EAE), the mouse model of MS. We will test whether the sera contain antibodies against the ENS (Aim 1) by indirect and direct immunostaining methods. We will then administer these antibodies to mice and isolated mouse colons to determine if the antibodies elicit a change in gut physiology. Next, we will characterize the gastrointestinal (GI) dysfunction that occurs in EAE mice (Aim 2). We will test whether the GI dysfunction can be ameliorated when EAE is induced in mice with certain immunological deficiencies, including B-lymphocyte deficient mice. These aims will be completed in the context of a training plan sponsored by Gary Mawe, Ph.D., an enteric neurobiologist, and co-sponsored by Cory Teuscher, Ph.D., an immunologist with extensive MS mouse model experience, and Angela Applebee, M.D., a neurologist who specializes in MS. The training plan will include research, coursework, and professional development experiences to train Estelle (Stellie) Spear as an independent translational neuroscientist. The scientific training plan will focus on the neurological control of GI motility in health and in response to inflammation under MS and EAE disease states. Coursework will supplement the education that Stellie gains from her co-sponsors; classes will include those offered by the UVM medical and graduate schools in anatomy, physiology, immunology, and relevant techniques. Career development training will include oral/poster conference presentations and skills workshops. Monthly discussions between Stellie and her sponsors and formation of an individualized development plan (IDP) will ensure that she receives the training necessary to pursue her objective as an independent academic researcher.