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：
7695001
负责人：
KAZIM A SHEIKH
金额：
$ 32.81万
依托单位：
UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
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 2012-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7695001
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 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）：在近乎根除脊髓灰质炎之后，Guillain-Barre综合征（GBS）是急性脆性瘫痪的最常见原因。 GBS包括一组临床和病理生理学相关的，急性单相神经性疾病的自身免疫性起源。尽管有两种免疫调节疗法可用，但很大一部分患者仍有永久性神经系统后遗症，包括无法独立行走。神经系统后遗症的患者几乎总是会导致轴突再生和靶向连接失败。抗缠结的抗体（ABS）是与GBS相关的最常见的自身免疫标记。这些ABS的病理生物学效应的光谱尚未完全定义。我们假设通过某些特异性与某些特异性的抗绞中ABS通过对再生轴突的生长锥进行交联的神经节苷脂，作为抑制性指导提示。我们的目标是检查抗缠结的抑制作用（AIM 1）的特异性，并表征脂质筏和神经节苷脂交联的作用（AIM 2）和次要信使（TNF受体家族成员P75和Troy和Troy和Troy和Troy和Troy and Troy and and Troy和Rho GTPases）参与了AB介导的轴突再生在生长锥水平上的抑制（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，以及在神经移植动物模型中，研究实验产生的单克隆抗抗细胞固醇ABS的病理生物学效应，并将其与来自GBS患者衍生的抗蛋白酶ABS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的作用以及RhoA GTPase的下游效应子。拟议的研究将提供原则证明，抗绞痛ABS及其目标神经苷可以在再生轴突中诱导抑制信号，并有可能识别出特定疗法开发的靶标。我们的发现应洞悉轴突再生失败的生物学，这不仅与周围神经病有关，而且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永久神经系统后遗症的潜在机制和Guillain-Barre综合征和其他神经系统疾病后不完整的恢复，并确定靶标以制定合理的治疗策略以防止这种并发症。