Disorders of the central nervous system are often associated with little or no recovery due to in part to poor neural regenerative capacity, damaging mechanisms that persist after initial neuronal injury, and inhibitory properties intrinsic to myelin. Regenerative medicine strategies that utilize synthetic or natural materials as permissive environments for maximizing axonal extension may not be sufficient for restoration of sight because axons that extend from each retina cross at the optic chiasm and selectively project to both hemispheres of the brain. Protein ligands, such as ephrin-B2, activate receptors on retinal ganglion cells to induce directional axon growth in order to form the divergent neural projections during embryogenesis. Development ligands such as these may be able to guide regenerating axons when engineered into biomaterials for tissue engineering. However, there is a critical need for physiologically- and translationally-relevant culture models that support the systematic investigation of structural and molecular parameters that may influence tissue growth. The overall goal of this project is to develop a 3D tissue culture model to study the guidance of retinal neurites in response to engineered cues that mimic the spatial distribution of ligands found at the optic chiasm during development. Specifically, we hypothesize that ephrin-B2, immobilized in a spatially-specific manner within a synthetic three-dimensional matrix, will selectively direct neurite outgrowth from embryonic retinal explants in a structural configuration that mimics the optic chiasm. In order to evaluate this hypothesis, we propose the following specific aims:
Aim 1 : Synthesize a photo-labile peptide hydrogel for localized immobilization of protein ligands.
Aim 2 : Develop a dual hydrogel platform for 3D retinal neurite outgrowth and incorporation of immobilized protein ligands.
Aim 3 : Evaluate the efficacy of ephrin-B2, locally immobilized in a 3D peptide hydrogel, to selectively direct neurite outgrowth from embryonic retinal explants. The techniques developed from this work will allow for the systematic manipulation of the spatial arrangement of structural and molecular cues for directing neuronal growth. Thus, it is anticipated that this work will establish a new experimental platform to study neural growth and guidance and also suggest potential treatment strategies to be explored in future studies. Disorders of the central nervous system, including optic neuropathies, are difficult to treat due to a poor capacity for nerves there to regenerate. In the optic nerve, even maximizing nerve axon regeneration may not lead to restoration of sight because nerves from each eye cross at the optic chiasm and project to specific regions at either side of the brain. The use of functional biomaterials that are able to selectively guide growing axons may suggest new treatment strategies for optic nerve and other central nervous system disorders.

Public Health Relevance

Disorders of the central nervous system, including optic neuropathies, are difficult to treat due to a poor capacity for nerves there to regenerate. In the optic nerve, even maximizing nerve axon regeneration may not lead to restoration of sight because nerves from each eye cross at the optic chiasm and project to specific regions at either side of the brain. The use of functional biomaterials that are able to selectively guide growing axons may suggest new treatment strategies for optic nerve and other central nervous system disorders.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21NS065374-02
Application #
7849020
Study Section
Biomaterials and Biointerfaces Study Section (BMBI)
Program Officer
Riddle, Robert D
Project Start
2009-06-01
Project End
2012-05-31
Budget Start
2010-06-01
Budget End
2012-05-31
Support Year
2
Fiscal Year
2010
Total Cost
$186,250
Indirect Cost
Name
Tulane University
Department
Biomedical Engineering
Type
Schools of Arts and Sciences
DUNS #
053785812
City
New Orleans
State
LA
Country
United States
Zip Code
70118
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Curley, J Lowry; Catig, Gary C; Horn-Ranney, Elaine L et al. (2014) Sensory axon guidance with semaphorin 6A and nerve growth factor in a biomimetic choice point model. Biofabrication 6:035026
Wang, Chih-Chieh; Held, Richard G; Hall, Benjamin J (2013) SynGAP regulates protein synthesis and homeostatic synaptic plasticity in developing cortical networks. PLoS One 8:e83941
Horn-Ranney, Elaine L; Curley, J Lowry; Catig, Gary C et al. (2013) Structural and molecular micropatterning of dual hydrogel constructs for neural growth models using photochemical strategies. Biomed Microdevices 15:49-61
Curley, J Lowry; Moore, Michael J (2011) Facile micropatterning of dual hydrogel systems for 3D models of neurite outgrowth. J Biomed Mater Res A 99:532-43