Biologic effects of anti-ganglisiode antibodies

抗神经节苷脂抗体的生物学效应

基本信息

批准号：
7320622
负责人：
KAZIM A SHEIKH
金额：
$ 35.88万
依托单位：
JOHNS HOPKINS UNIVERSITY
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：
2007-07-15 至 2008-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7320622
关键词：
Acute Affect Animal Model Antibodies Autoimmune Diseases Autoimmune Process Axon Behavior Biology Cell membrane Clinical Complement Complex Complication Cues Development Disease Failure Family Family member GD1a ganglioside Gangliosides Goals Growth Growth Cones Guanosine Triphosphate Phosphohydrolases Guillain-Barré Syndrome Immune Injury Left Mediating Membrane Microdomains Modeling Monomeric GTP-Binding Proteins Morphology Motor Neurons Multiple Sclerosis Multiple Trauma Mus Mutant Strains Mice Natural regeneration Nerve Nerve Fibers Neurites Neurologic Neurons Neuropathy Paralysed Patients Peripheral Peripheral Nerves Peripheral Nervous System Diseases Phosphotransferases Poliomyelitis Recovery Research Project Grants Role Signal Transduction Specificity Spinal Ganglia Spinal cord injury Therapeutic Translational Research Tumor Necrosis Factor Receptor Variant Walking axon regeneration crosslink in vitro Model insight nervous system disorder prevent reinnervation response rho rho GTP-Binding Proteins transcriptional coactivator p75 translational study

项目摘要

DESCRIPTION (provided by applicant): After the near eradication of polio, Guillain-Barre syndrome (GBS) is the commonest cause of acute flaccid paralysis. GBS comprises a group of clinically and pathophysiologically related, acute monophasic neuropathic disorders of autoimmune origin. Despite the availability of two immunomodulatory therapies, a significant proportion of patients are left with permanent neurologic sequelae, including inability to walk unaided. Patients with neurologic sequelae almost always have failure of axon regeneration and target reinnervation. Anti-ganglioside antibodies (Abs) are the single most common autoimmune marker associated with GBS. The spectrum of pathobiologic effects of these Abs is not completely defined. We hypothesize that anti-ganglioside Abs with certain specificities act as inhibitory guidance cues by cross-linking gangliosides on growth cones of regenerating axons. Our goals are to examine the specificity of anti-ganglioside Ab- mediated inhibition (Aim 1), and to characterize the role of lipid rafts and ganglioside cross-linking (Aim 2), and secondary messengers (TNF receptor family members p75 and TROY and Rho GTPases) involved in this Ab-mediated inhibition of axon regeneration at the level of growth cones (Aims 3 and 4). We propose to use in vitro models of axon regeneration and growth cone behavior, and in a nerve graft animal model to study the pathobiologic effects of experimentally generated monoclonal anti-ganglioside Abs and compare them to anti-ganglioside Abs derived from GBS patients. These animal models will also be used to examine the role of ganglioside cross-linking, p75, and TROY and a downstream effector of RhoA GTPase. The proposed studies will provide proof of principle that anti-ganglioside Abs and their target gangliosides can induce inhibitory signals in regenerating axons and potentially identify targets for development of specific therapies. Our findings should provide insight into biology of failure of axon regeneration, which is relevant not only to peripheral neuropathies but also to CMS disorders like spinal cord injury and multiple sclerosis. Public information statement: This translational research project seeks to examine the potential mechanisms underlying permanent neurologic sequelae and incomplete recovery after Guillain-Barre syndrome and other neurologic disorders and to identify targets to develop rational therapeutic strategies to prevent this complication.

描述（由申请人提供）：在几乎消灭脊髓灰质炎之后，格林-巴利综合征（GBS）是急性弛缓性麻痹的最常见原因。 GBS 包括一组临床和病理生理学相关的、自身免疫性起源的急性单相神经病。尽管有两种免疫调节疗法可供使用，但仍有相当一部分患者留下永久性神经系统后遗症，包括无法独立行走。患有神经系统后遗症的患者几乎总是轴突再生和目标神经支配失败。抗神经节苷脂抗体 (Abs) 是与 GBS 相关的最常见的自身免疫标志物。这些抗体的病理生物学效应谱尚未完全确定。我们假设具有某些特异性的抗神经节苷脂抗体通过在再生轴突的生长锥上交联神经节苷脂来充当抑制指导线索。我们的目标是检查抗神经节苷脂抗体介导的抑制的特异性（目标 1），并表征脂筏和神经节苷脂交联的作用（目标 2）以及第二信使（TNF 受体家族成员 p75 和 TROY 和Rho GTPases）参与了生长锥水平上 Ab 介导的轴突再生抑制（目标 3 和 4）。我们建议使用轴突再生和生长锥行为的体外模型，并在神经移植动物模型中研究实验产生的单克隆抗神经节苷脂抗体的病理生物学效应，并将其与来自 GBS 患者的抗神经节苷脂抗体进行比较。这些动物模型还将用于检查神经节苷脂交联、p75 和 TROY 以及 RhoA GTPase 下游效应子的作用。拟议的研究将提供原理证明，证明抗神经节苷脂抗体及其靶标神经节苷脂可以在轴突再生中诱导抑制信号，并有可能确定开发特定疗法的靶标。我们的研究结果应该有助于深入了解轴突再生失败的生物学，这不仅与周围神经病有关，还与脊髓损伤和多发性硬化症等 CMS 疾病有关。公共信息声明：该转化研究项目旨在研究格林-巴利综合征和其他神经系统疾病后永久性神经系统后遗症和不完全恢复的潜在机制，并确定目标以制定合理的治疗策略来预防这种并发症。