Date on Master's Thesis/Doctoral Dissertation

8-2025

Document Type

Doctoral Dissertation

Degree Name

Ph. D.

Department

Pharmacology and Toxicology

Degree Program

Pharmacology and Toxicology, PhD

Committee Chair

Ceresa, Brian P.

Committee Member

Siskind, Leah J.

Committee Member

Clark, Geoffrey J.

Committee Member

Petruska, Jeffrey

Committee Member

Scott, Patrick A.

Author's Keywords

cornea; growth factors; E3 ligases; corneal wound healing; corneal epithelium; receptor tyrosine kinases

Abstract

The cornea is the most anterior portion of the eye and permits light passage through to retina, allowing formation of a clear image as long as it remains healthy. If the cornea sustains damage, it creates and entrance for foreign body invasion, infection, and ultimately blindness in the immunocompromised eye. Healing the corneal tissue is critical for vision restoration and pain alleviation, as it is the most densely innervated tissue in the body. Growth factors and their cognate receptors are currently under investigation as tools to restore proper corneal physiology. We hypothesize that manipulating the hepatocyte growth factor (HGF) /c-Met signaling pathway is one route to promote quality corneal healing. This dissertation investigates the regulation of this signaling pathway by the CBL family of E3 ligases in corneal epithelial cells. This dissertation is divided into 6 chapters. Chapter One is a literature review giving insight to the cornea, how it heals, and the effects of c-Met signaling on the ocular surface. Chapter Two contains the materials and methods followed while performing experiments in the laboratory to test our theory. Chapters Three-Five are all data containing, showing our initial in vitro results, our characterization of a CBL knockout mouse model, and finally, the wound healing data. Chapter Three reveals that c-Cbl and Cbl-b both ubiquitylate c-Met, and that this ubiquitylation limits c-Met signaling. The knockout of the CBL genes results in slowed receptor trafficking to the lysosome, allowing for c-Met to signal for a longer duration of time. Chapters Four and Five go together, as the former is the characterization of a mouse model and the latter is the use of these mice for wound healing experiments. In brief, we discovered that receptor ubiquitylation is also limiting in vivo in certain situations, however, the model needs some minor adjustments to ensure full health of the mice before full conclusions should be drawn regarding healing rates in the absence of the CBL genes.

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