Neural crest-derived, mesenchymal, fibroblastic cell populations differentiate into distinct cell-types in the eye, including corneal nerves, corneal endothelium, stromal keratocytes, non-myelinating and myelinating Schwann cells, connective tissues of limbus, conjunctiva, choroid, sclera, eyelids, iris, lacrimal and other glands, and in birds, scleral ossicles. Each tissue forms a unique extracellular matrix (ECM) that changes with developmental age. Immunocytochemistry, in situ hybridization, mass spectrometry, surface plasmon resonance spectrometry, knock-down and mis-expression analysis, ability to construct chick-quail chimeric embryos, and laser- assisted microdissection (LMD) now allow examination and manipulation of differentiation in small groups of cells in different parts of the eye to better assess signals regulating cell and nerve growth cone migrations and differentiation. Hypothesis: highly charged ECMs unique to each site, bind and release growth-, differentiation-, neurotropic-, and neurotrophic-factors that determine corneal transparency and innervation, and normal functions of other tissues.
Aim 1 : Determine carbohydrate structures and bound factors in key locations of embryonic eyes. Mass spectrometry will identify and quantitate specific glycosaminoglycans present in ECMs and details of their structures, including structural positions of sulfate groups and identification of sialic acid types.
Aim 2 : Determine the mechanism of each step in corneal sensory innervation by neural crest-derived growth cones of trigeminal ganglion neurons.
Aim 3 : Determine the normal lineage sources of non-myelinating Schwann cells of corneal stroma during development; identify marker proteins expressed by these cells and effects on their differentiation from perturbing ECM synthesis. Significance: Extent to which human corneas heal and become re-innervated after LASEK, LASIK, PRK or transplantation is determined by signals residing in participating ECMs, particularly in their posttranslational modifications. Although transplanted corneas generally remain transparent, re-innervation of the graft is very slow (years) and often incomplete, depriving patients of corneal touch sensitivity and blink reflex. Research proposed here will elucidate relationships between proteoglycan forms and distributions, and paths chosen by corneal nerves and non-myelinating Schwann cells during innervation of embryonic corneas. These data will facilitate designing strategies to better reinnervate transplanted or modified adult corneas.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
5R01EY000952-35
Application #
7213280
Study Section
Special Emphasis Panel (ZRG1-VISA (01))
Program Officer
Shen, Grace L
Project Start
1988-08-01
Project End
2009-03-31
Budget Start
2007-04-01
Budget End
2008-03-31
Support Year
35
Fiscal Year
2007
Total Cost
$354,427
Indirect Cost
Name
Kansas State University
Department
Biology
Type
Schools of Arts and Sciences
DUNS #
929773554
City
Manhattan
State
KS
Country
United States
Zip Code
66506
Mao, Xiuli; Zhang, Yuntao; Schwend, Tyler et al. (2015) Effects of polysialic acid on sensory innervation of the cornea. Dev Biol 398:193-205
Zhang, Yuntao; Mao, Xiuli; Schwend, Tyler et al. (2013) Resistance of corneal RFUVA–cross-linked collagens and small leucine-rich proteoglycans to degradation by matrix metalloproteinases. Invest Ophthalmol Vis Sci 54:1014-25
Schwend, Tyler; Lwigale, Peter Y; Conrad, Gary W (2012) Nerve repulsion by the lens and cornea during cornea innervation is dependent on Robo-Slit signaling and diminishes with neuron age. Dev Biol 363:115-27
Schwend, Tyler; Deaton, Ryan J; Zhang, Yuntao et al. (2012) Corneal sulfated glycosaminoglycans and their effects on trigeminal nerve growth cone behavior in vitro: roles for ECM in cornea innervation. Invest Ophthalmol Vis Sci 53:8118-37
Littlechild, Stacy L; Zhang, Yuntao; Tomich, John M et al. (2012) Fibrinogen, riboflavin, and UVA to immobilize a corneal flap--molecular mechanisms. Invest Ophthalmol Vis Sci 53:5991-6003
Zhang, Guodong; Boyle, Daniel L; Zhang, Yuntao et al. (2012) Development and mineralization of embryonic avian scleral ossicles. Mol Vis 18:348-61
Littlechild, Stacy L; Brummer, Gage; Zhang, Yuntao et al. (2012) Fibrinogen, riboflavin, and UVA to immobilize a corneal flap--conditions for tissue adhesion. Invest Ophthalmol Vis Sci 53:4011-20
Zhang, Yuntao; Sukthankar, Pinakin; Tomich, John M et al. (2012) Effect of the synthetic NC-1059 peptide on diffusion of riboflavin across an intact corneal epithelium. Invest Ophthalmol Vis Sci 53:2620-9
Brummer, Gage; Littlechild, Stacy; McCall, Scott et al. (2011) The role of nonenzymatic glycation and carbonyls in collagen cross-linking for the treatment of keratoconus. Invest Ophthalmol Vis Sci 52:6363-9
Zhang, Yuntao; Conrad, Abigail H; Conrad, Gary W (2011) Effects of ultraviolet-A and riboflavin on the interaction of collagen and proteoglycans during corneal cross-linking. J Biol Chem 286:13011-22

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