Corneal epithelial proliferation and neovascularization

University Of Wisconsin-Madison, Madison WI

Investigators

Linked publications & trials

Abstract

? DESCRIPTION (provided by applicant): Diseases affecting the cornea comprise a major cause of blindness worldwide. To understand the pathological consequences and develop appropriate treatment protocols for corneal diseases, it is important to elucidate the pathways underlying the normal maintenance of corneal integrity and function, and the molecular mechanisms causing abnormalities. Animal models for corneal diseases provide useful experimental systems for these purposes. Corneal disease 1 (corn1) mice are homozygous for a spontaneous null allele of the destrin (Dstn) gene, which is also known as actin depolymerizing factor. These mice exhibit abnormalities in the cornea including epithelial cell hyperproliferation, inflammation, and neovascularization as well as actin dynamics defects. In the previous funding period, we demonstrated that a transcription factor, serum response factor (SRF), is primarily responsible for the development of these corneal abnormalities in Dstncorn1 mice, and determined gene networks and cellular changes downstream of SRF in the Dstncorn1 cornea. Based on these findings, we have built new hypotheses on the molecular mechanisms underlying corneal abnormalities, which will be tested in the proposed study. Specifically, we aim to determine the cause and consequences of perturbed SRF-dependent gene expression in the Dstncorn1 cornea by investigating the mechanisms through which the Dstncorn1 mutation leads to abnormal SRF-dependent gene expression (Aim 1), examining the cellular changes that arise in the Dstncorn1 corneal epithelium following perturbation of the SRF pathway (Aim 2), and elucidating the mechanisms through which SRF negatively regulates gene expression in the Dstncorn1 corneal epithelium (Aim 3). Findings from this study should further enhance our understanding of how corneal integrity and functions are maintained, and how diseased conditions are caused.