Biologic effects of anti-ganglisiode antibodies

描述（由申请人提供）：在几乎根除脊髓灰质炎后，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性疾病。尽管有两种免疫调节疗法可用，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。有神经系统后遗症的患者几乎总是轴突再生和靶神经再支配失败。抗神经节苷脂抗体（Abs）是与GBS相关的单一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。我们推测，具有一定特异性的抗神经节苷脂抗体通过交联再生轴突生长锥上的神经节苷脂作为抑制性引导线索。我们的目标是检查抗神经节苷脂Ab介导的抑制的特异性（目的1），并表征脂筏和神经节苷脂交联（目的2）以及在生长锥水平参与这种Ab介导的轴突再生抑制的第二信使（TNF受体家族成员p75和TROY和Rho GTP酶）的作用（目的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作用，并将其与来自GBS患者的抗神经节苷脂抗体进行比较。这些动物模型也将用于检查神经节苷脂交联，p75，和TROY和RhoA GT3的下游效应的作用。拟议的研究将提供抗神经节苷脂抗体及其靶向神经节苷脂可以诱导再生轴突中的抑制信号的原理证明，并可能确定开发特定疗法的靶点。我们的研究结果应该提供深入了解轴突再生失败的生物学，这不仅与周围神经病变有关，而且与脊髓损伤和多发性硬化等CMS疾病有关。新闻声明：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。

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.