The corneal epithelium modulates fluid transport for normal stromal hydration and corneal transparency, and serves as an anatomical and physiological barrier against ocular infection. This epithelium is in a constant state of renewal, and injury to this epithelium requires prompt resurfacing in order to re-establish visual function. Tools to achieve research and clinical applications to corneal diseases at the molecular level offer exciting avenues for advancement, but are stymied by the need for manipulating gene activity. Progress has been made in gene therapy through the development of a particle-mediated gene transfer delivery system (gene gun), a technique shown to be a rapid, highly efficient, and nontoxic method for transfection of genes both in vivo and in vitro. In this grant we propose to establish the gene gun as a valuable research tool in corneal epithelial biology, obtain preliminary information for the efficacy of the gene gun as a device for clinical treatment, and document the importance of the interaction of a native inhibitory peptide, opioid growth factor (OGF) with its receptor (OGFr) at the molecular level as a system regulating the homeostasis and healing of the ocular surface epithelium in humans and animals.
The specific aims i nclude: 1. Determine the importance of OGF-OGFr interfacing on maintenance of rat corneal epithelium by examining the consequences of molecular perturbation of OGF receptor gene and protein activity. 2. Define the role of an endogenous opioid system related to wound healing of the rat corneal epithelium following genetic alteration of the OGF receptor gene and protein expression in rat. 3. Ascertain the significance of OGF and OGFr function during wound healing of the human corneal epithelium using organ culture of tissues genetically modified to yield an excess or deficit of OGF receptor. Information derived from these studies will contribute to a breakthrough understanding of gene delivery systems to the corneal surface. Moreover, these investigations will simultaneously acquire invaluable knowledge about the molecular basis by which an endogenous opioid system relates to corneal epithelial homeostasis, and the restoration of corneal integrity following injury. Ultimately, such data can be employed to design molecular strategies to remedy visual dysfunction.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Small Research Grants (R03)
Project #
5R03EY013734-02
Application #
6525355
Study Section
Special Emphasis Panel (ZEY1-VSN (04))
Program Officer
Fisher, Richard S
Project Start
2001-08-01
Project End
2004-07-31
Budget Start
2002-08-01
Budget End
2003-07-31
Support Year
2
Fiscal Year
2002
Total Cost
$140,500
Indirect Cost
Name
Pennsylvania State University
Department
Neurosciences
Type
Schools of Medicine
DUNS #
129348186
City
Hershey
State
PA
Country
United States
Zip Code
17033
Sassani, Joseph W; Mc Laughlin, Patricia J; Zagon, Ian S (2016) The Yin and Yang of the Opioid Growth Regulatory System: Focus on Diabetes-The Lorenz E. Zimmerman Tribute Lecture. J Diabetes Res 2016:9703729
McLaughlin, Patricia J; Sassani, Joseph W; Klocek, Matthew S et al. (2010) Diabetic keratopathy and treatment by modulation of the opioid growth factor (OGF)-OGF receptor (OGFr) axis with naltrexone: a review. Brain Res Bull 81:236-47
Zagon, Ian S; Sassani, Joseph W; Malefyt, Kristin J et al. (2006) Regulation of corneal repair by particle-mediated gene transfer of opioid growth factor receptor complementary DNA. Arch Ophthalmol 124:1620-4
Zagon, Ian S; Sassani, Joseph W; Verderame, Michael F et al. (2005) Particle-mediated gene transfer of opioid growth factor receptor cDNA regulates cell proliferation of the corneal epithelium. Cornea 24:614-9
Zagon, Ian S; Ruth, Torre B; Leure-duPree, Alphonse E et al. (2003) Immunoelectron microscopic localization of the opioid growth factor receptor (OGFr) and OGF in the cornea. Brain Res 967:37-47
Zagon, Ian S; Verderame, Michael F; McLaughlin, Patricia J (2002) The biology of the opioid growth factor receptor (OGFr). Brain Res Brain Res Rev 38:351-76