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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS054962-04
Application #
7844987
Study Section
Clinical Neuroimmunology and Brain Tumors Study Section (CNBT)
Program Officer
Utz, Ursula
Project Start
2007-07-15
Project End
2012-05-31
Budget Start
2010-06-01
Budget End
2011-05-31
Support Year
4
Fiscal Year
2010
Total Cost
$324,844
Indirect Cost
Name
University of Texas Health Science Center Houston
Department
Neurology
Type
Schools of Medicine
DUNS #
800771594
City
Houston
State
TX
Country
United States
Zip Code
77225
Zhang, Gang; Lin, Jianxin; Ghauri, Sameera et al. (2017) Modulation of IgG-FcRn interactions to overcome antibody-mediated inhibition of nerve regeneration. Acta Neuropathol 134:321-324
Asthana, Pallavi; Vong, Joaquim Si Long; Kumar, Gajendra et al. (2016) Dissecting the Role of Anti-ganglioside Antibodies in Guillain-Barré Syndrome: an Animal Model Approach. Mol Neurobiol 53:4981-91
Sheikh, Kazim A; Zhang, Gang (2016) Antibody-based neuronal and axonal delivery vectors for targeted ligand delivery. Neural Regen Res 11:712-4
Zhang, Gang; Massaad, Cynthia A; Gao, Tong et al. (2016) Sialylated intravenous immunoglobulin suppress anti-ganglioside antibody mediated nerve injury. Exp Neurol 282:49-55
Rozés Salvador, Victoria; Heredia, Florencia; Berardo, Andrés et al. (2016) Anti-glycan antibodies halt axon regeneration in a model of Guillain Barrè Syndrome axonal neuropathy by inducing microtubule disorganization via RhoA-ROCK-dependent inactivation of CRMP-2. Exp Neurol 278:42-53
Nguyen, Thy P; Biliciler, Suur; Wiszniewski, Wojciech et al. (2015) Expanding Phenotype of VRK1 Mutations in Motor Neuron Disease. J Clin Neuromuscul Dis 17:69-71
Massaad, Cynthia A; Zhang, Gang; Pillai, Laila et al. (2015) Fluorescently-tagged anti-ganglioside antibody selectively identifies peripheral nerve in living animals. Sci Rep 5:15766
Vegosen, Leora; Breysse, Patrick N; Agnew, Jacqueline et al. (2015) Occupational Exposure to Swine, Poultry, and Cattle and Antibody Biomarkers of Campylobacter jejuni Exposure and Autoimmune Peripheral Neuropathy. PLoS One 10:e0143587
Joshi, Abhijeet R; Bobylev, Ilja; Zhang, Gang et al. (2015) Inhibition of Rho-kinase differentially affects axon regeneration of peripheral motor and sensory nerves. Exp Neurol 263:28-38
He, Lan; Zhang, Gang; Liu, Weiqiang et al. (2015) Anti-Ganglioside Antibodies Induce Nodal and Axonal Injury via Fc? Receptor-Mediated Inflammation. J Neurosci 35:6770-85

Showing the most recent 10 out of 23 publications