The overall goal of this proposal is to provide the Candidate with the education, skills, and experiences to become an independent researcher studying corneal wound healing and ocular optics. The clinical-research focus is on endothelial keratoplasty (EK), a corneal transplant procedure in which the patient's diseased endothelium and Descemet's membrane are removed and replaced with the posterior third of a donor cornea with healthy endothelium. The scientific focus of this proposal is to gain a better understanding of the cell biology and tissue interactions involved in the wound healing response following EK and their subsequent effects on ocular optics. Keratocyte activation and myofibroblast differentiation create haze and cause decreased vision and refractive regression following photorefractive keratectomy and incisional wounds. Endothelial failure accounts for almost one half of the corneal transplants that are performed. EK procedures have now gained widespread acceptance because of the faster recovery, less astigmatism, and greater wound stability. Despite these advantages over traditional corneal transplants, vision remains limited post-operatively. Better visual outcomes may come through improved understanding of wound healing at the stromal graft interface.The hypothesis to be tested is that the interface haze following EK is mediated by keratocyte activation and myofibroblast differentiation, reducing vision by increasing light scatter and higherorder optical aberrations. Better characterization of these changes and cellular pathways involved may suggest rational therapies for their modulation and allow for improved visual outcomes. To address this hypothesis, two specific aims are proposed:
Aim 1 assesses in vivo corneal wound repair at the EK interface and its growth factor control over time. These changes will be correlated with changes in ocular optics and with ex vivo histopathology in humans and in a cat model.
Aim 2 modulates the wound healing response with pharmacological agents with the goal of improving transparency and optics. In addition to the proposed research focusing on cell biology and tissue interactions, the PI will receive invaluable didatic training in optics at the Optics Institute, in vision optimization research at the University of Rochester Center for Visual Science, and will form meaningful collaborations with other investigators in the Clinical and Translational Science Institute while completing a Master of Science in Translational Research.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Mentored Patient-Oriented Research Career Development Award (K23)
Project #
5K23EY019353-05
Application #
8410579
Study Section
Special Emphasis Panel (ZEY1-VSN (01))
Program Officer
Agarwal, Neeraj
Project Start
2009-02-01
Project End
2014-07-31
Budget Start
2013-02-01
Budget End
2014-07-31
Support Year
5
Fiscal Year
2013
Total Cost
$202,344
Indirect Cost
$14,988
Name
University of Rochester
Department
Ophthalmology
Type
Schools of Dentistry
DUNS #
041294109
City
Rochester
State
NY
Country
United States
Zip Code
14627
Venkateswaran, Nandini; Kalsow, Carolyn M; Hindman, Holly B (2014) Phlyctenular keratoconjunctivitis associated with Dolosigranulum pigrum. Ocul Immunol Inflamm 22:242-5
Jeon, Kye-Im; Kulkarni, Ajit; Woeller, Collynn F et al. (2014) Inhibitory effects of PPAR? ligands on TGF-?1-induced corneal myofibroblast transformation. Am J Pathol 184:1429-45
Huxlin, Krystel R; Hindman, Holly B; Jeon, Kye-Im et al. (2013) Topical rosiglitazone is an effective anti-scarring agent in the cornea. PLoS One 8:e70785
Hindman, Holly B; Huxlin, Krystel R; Pantanelli, Seth M et al. (2013) Post-DSAEK optical changes: a comprehensive prospective analysis on the role of ocular wavefront aberrations, haze, and corneal thickness. Cornea 32:1567-77
Weis, Adam J; Huxlin, Krystel R; Callan, Christine L et al. (2013) Keratocyte apoptosis and not myofibroblast differentiation mark the graft/host interface at early time-points post-DSAEK in a cat model. PLoS One 8:e75623
Kuriyan, A E; Lehmann, G M; Kulkarni, A A et al. (2012) Electrophilic PPARýý ligands inhibit corneal fibroblast to myofibroblast differentiation in vitro: a potentially novel therapy for corneal scarring. Exp Eye Res 94:136-45
Hindman, Holly B; Swanton, Jennifer N; Phipps, Richard P et al. (2010) Differences in the TGF-{beta}1-induced profibrotic response of anterior and posterior corneal keratocytes in vitro. Invest Ophthalmol Vis Sci 51:1935-42