Our objective is to evaluate whether inhibition of fibronectin-dependent leukocyte infiltration into peripheral nerves is a specific therapy for chronic peripheral nerve inflammation seen in immune-mediated disorders and neuropathic pain. Using chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) as an example of persistent peripheral nerve inflammation that results in significant long-term disability, we propose to address a fundamental question: Is competitive antagonism of fibronectin connecting segment-1 (FN CS1) a potential treatment strategy for peripheral neuritis? Based on our exciting new preliminary data using in vitro and in vivo approaches, we propose the following hypothesis: Endothelial FN CS1 actively participates in the recruitment of pathogenic hematogenous mononuclear leukocytes across the blood-nerve barrier in CIDP. As an extension of this, we propose that competitive inhibition with a FN CS1 peptide antagonist would reduce leukocyte trafficking at the blood-nerve barrier. Reduction in leukocyte infiltration would limit the harmful consequences of prolonged peripheral nerve inflammation, demyelination and axonal injury. This strategy provides an opportunity to develop a novel targeted therapy for CIDP and neuropathic pain. In order to address this hypothesis, we will determine that competitive FN CS1 peptide blockade reduces trafficking of untreated CIDP patient peripheral blood mononuclear leukocytes on a novel cytokine- stimulated human in vitro blood-nerve barrier model that incorporates capillary flow rates. Trafficking events would be captured real-time and quantified by video microscopy. We will also evaluate the effect of this peptide antagonist on the behavioral, electrophysiological and histopathological features of progressive chronic peripheral nerve inflammation, demyelination and axonal injury in a severe, reliable CIDP mouse model, using our published methods. Current therapies for CIDP and other peripheral nerve inflammatory disorders, including neuropathic pain are non-specific and partly effective. This proposal is a preclinical evaluation of FN CS1 peptide antagonism as a targeted anti-inflammatory therapy for CIDP. Inhibiting disease-specific inflammatory pathways has the potential to revolutionize the treatment of chronic peripheral nerve inflammation. The proposed work could lead towards the development of novel, small molecular antagonists for phase I clinical trials in CIDP and other chronic inflammatory neuropathies, as well as neuropathic pain.

Public Health Relevance

The purpose of our work is to discover a new treatment for an under-recognized, but severe disabling nerve inflammation disease called chronic inflammatory demyelinating polyradiculoneuropathy (CIDP). CIDP equally affects both sexes, all ages, racial/ ethnic groups and socioeconomic status. By finding new treatments for CIDP, we can hopefully better treat or cure this problem, improve the lives of patients and their families, and reduce the financial burden of this and similar diseases, such as Guillain-Barri syndrome and neuropathic pain, on the health care system nationally and internationally. Disclaimer: Please note that the following critiques were prepared by the reviewers prior to the Study Section meeting and are provided in an essentially unedited form. While there is opportunity for the reviewers to update or revise their written evaluation, based upon the group's discussion, there is no guarantee that individual critiques have been updated subsequent to the discussion at the meeting. Therefore, the critiques may not fully reflect the final opinions of th individual reviewers at the close of group discussion or the final majority opinion of the group. Thus the Resume and Summary of Discussion is the final word on what the reviewers actually considered critical at the meeting.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21NS073702-02
Application #
8338443
Study Section
National Institute of Neurological Disorders and Stroke Initial Review Group (NSD)
Program Officer
Gwinn, Katrina
Project Start
2011-09-30
Project End
2014-08-31
Budget Start
2012-09-01
Budget End
2014-08-31
Support Year
2
Fiscal Year
2012
Total Cost
$195,625
Indirect Cost
$70,625
Name
Baylor College of Medicine
Department
Neurology
Type
Schools of Medicine
DUNS #
051113330
City
Houston
State
TX
Country
United States
Zip Code
77030
Yuan, Furong; Yosef, Nejla; Lakshmana Reddy, Chetan et al. (2014) CCR2 gene deletion and pharmacologic blockade ameliorate a severe murine experimental autoimmune neuritis model of Guillain-Barré syndrome. PLoS One 9:e90463
Chiang, Sharon; Ubogu, Eroboghene E (2013) The role of chemokines in Guillain-Barre syndrome. Muscle Nerve 48:320-30
Ubogu, Eroboghene E (2013) The molecular and biophysical characterization of the human blood-nerve barrier: current concepts. J Vasc Res 50:289-303
Ubogu, Eroboghene E (2013) Chemokine-dependent signaling pathways in the peripheral nervous system. Methods Mol Biol 1013:17-30
Ubogu, Eroboghene E; Yosef, Nejla; Xia, Robin H et al. (2012) Behavioral, electrophysiological, and histopathological characterization of a severe murine chronic demyelinating polyneuritis model. J Peripher Nerv Syst 17:53-61