Page 70

Contents | 70 of 230

Page 70

Download PDF | | Reference URL | Gallery View | Parent Record

Title	The role of glycosaminoglycan motifs in regulating neuronal growth, guidance and inhibition
Publication Type	dissertation
School or College	College of Engineering
Department	Biomedical Engineering
Author	Swarup, Vimal Paritosh
Date	2014
Description	This work investigates the structure-function relationship of glycosaminoglycans (GAGs) with respect to neuronal outgrowth. Chondroitin sulfate (CS) and Heparan sulfate (HS) are the two most important kinds of GAGs found in the CNS. CS proteoglycans (CSPGs) are overexpressed in the central nervous system (CNS) after injury and form the inhibitory barriers for regenerating neurons, whereas HSPGs mediate essential growth factor-receptor interactions in the CNS. The first of part of my research explored the impact of CS sulfation patterns on growth and pathfinding of the hippocampal neurons. Specific CS variants: CS-A, CS-B, and CS-E attracted neurites, whereas CS-C was avoided by the hippocampal neurons. The differential response of neurons was exploited to create binary patterns of surface-immobilized CS chains to enhance both growth and guidance of neurons. In the second part, the importance of the GAG-sulfation pattern was further demonstrated by analyzing astrocytes HS. The astrocytes synthesized HSPGs containing a very distinct sulfation profile. The trisulfated residues containing NS2S6S sulfation were significantly lower than the disulfated residues containing NS2S sulfation. It was hence hypothesized that the secretion of endosulfatases in astrocytes condition media was responsible for conversion of the NS2S6S residues into NS2S residues. Substrate specificity for human isoform of the enzyme was also performed. It was confirmed that astrocytes secreted endosulfatase enzymes into the condition media. These results suggest the possibility of an additional mechanism through which astrocytes mediate neuronal inhibition. By removing specific HS domains that interact with growth factors, the scar extracellular matrix (ECM) could hinder the regeneration process in neurons. In the final part of the study, an approach to reduce the inhibitory GAGs secreted by astrocytes was explored. Click-xylosides reduced the amount of CS chains attached to core protein by competing with endogenous xylose residues. Upon treatment with condition media, neuronal growth was directly related to the CSPG content of the media. By using bis-xylosides or chemically conjugated xylosides-primed CS chains, it was demonstrated that multivalency is essential to impart inhibitory functions to CS chains. Overall, this part of the study explores a therapeutic strategy of reducing neuronal inhibition by exploiting click-xylosides to modulate CSPG secretion in the scar ECM.
Type	Text
Publisher	University of Utah
Subject	Chondroitin sulfate; Glycosaminoglycan; Heparan sulfate; Hippocampal neurons; Microcontact printing; Proteoglycan
Dissertation Name	Doctor of Philosophy
Language	eng
Rights Management	©Vimal Paritosh Swarup
Format	application/pdf
Format Medium	application/pdf
ARK	ark:/87278/s65q922f
DOI	https://doi.org/doi:10.26053/0H-QMWT-WC00
Setname	ir_etd
ID	1353912
Reference URL	https://collections.lib.utah.edu/ark:/87278/s65q922f

Page Metadata

Title	Page 70
Format	application/pdf
Setname	ir_etd
ID	1353982
OCR Text	Show 55 M/versican on avian neural crest cell migration, The FASEB Journal 10, 293-301. 62. Ishii, M., and Maeda, N. (2008) Oversulfated chondroitin sulfate plays critical roles in the neuronal migration in the cerebral cortex, The Journal of Biological Chemistry 283, 32610-32620. 63. Saunders, S., Paine-Saunders, S., and Lander, A. D. (1997) Expression of the cell surface proteoglycan glypican-5 is developmentally regulated in kidney, limb, and brain, Developmental Biology 190, 78-93. 64. Hsueh, Y. P., and Sheng, M. (1999) Regulated expression and subcellular localization of syndecan heparan sulfate proteoglycans and the syndecanbinding protein CASK/LIN-2 during rat brain development, The Journal of Neuroscience 19, 7415-7425. 65. Ivins, J., Litwack, E., Kumbasar, A., Stipp, C., and Lander, A. (1997) Cerebroglycan, a Developmentally Regulated Cell-Surface Heparan Sulfate Proteoglycan, Is Expressed on Developing Axons and Growth Cones, Developmental Biology 184, 320-332. 66. Wang, L., and Denburg, J. (1992) A role for proteoglycans in the guidance of a subset of pioneer axons in cultured embryos of the cockroach, Neuron 8, 701-714. 67. Walz, A., McFarlane, S., Brickman, Y., Nurcombe, V., Bartlett, P., and Holt, C. (1997) Essential role of heparan sulfates in axon navigation and targeting in the developing visual system, Development 124, 2421. 68. Zhou, Y., and Besner, G. E. (2010) Heparin-Binding Epidermal Growth Factor-Like Growth Factor Is a Potent Neurotrophic Factor for PC12 Cells, NeuroSignals 18, 141-151. 69. Muramatsu, T. (2010) Midkine, a heparin-binding cytokine with multiple roles in development, repair and diseases, Proceedings of the Japan Academy, Series B 86, 410-425. 70. Liang, Y., Annan, R., Carr, S., Popp, S., Mevissen, M., Margolis, R., and Margolis, R. (1999) Mammalian homologues of the Drosophila slit protein are ligands of the heparan sulfate proteoglycan glypican-1 in brain, The Journal of Biological Chemistry 274, 17885-17892. 71. Hu, H. (2001) Cell-surface heparan sulfate is involved in the repulsive guidance activities of Slit2 protein, Nature Neuroscience 4, 695-701.
Reference URL	https://collections.lib.utah.edu/ark:/87278/s65q922f/1353982