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Optimizing c-Met signaling to enhance corneal epithelial homeostasis

Award Number: F31EY034730
ORGANIZATION: NATIONAL EYE INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 04/04/2024
PERIOD OF PERFORMANCE END DATE: 08/08/2025
AWARD TERMINATION DATE: 03/04/2026

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Optimizing c-Met signaling to enhance corneal epithelial homeostasis - Project Summary The proposed research is relevant to public health because corneal blindness is the 4th leading cause of blindness globally and is often preventable with proper healthcare. Blindness arises due to damaged integrity of the corneal epithelium as the result of physical, chemical, or thermal trauma and/or as a consequence of diseases, surgery, or anti-cancer drugs. Regardless of the cause, disruption of the epithelial layer is extremely painful due to the dense sensory nerve innervation, makes the eye vulnerable to infection, and can result in blindness. Despite the widespread incidence and the array of medical problems associated with epithelial damage, there are no FDA-approved drugs that promote corneal wound healing or epithelial homeostasis. It is well-established that proteins of the receptor tyrosine kinase (RTK) family can induce cell proliferation, migration, survival, and differentiation of epithelial cells. We are investigating the signaling axis of one of these proteins, c- Met, and its cognate ligand hepatocyte growth factor (HGF). c-Met activity can not only promote the wound healing/re-epithelialization phenotypes stated previously but can also prevent transformation of keratocytes to fibroblasts and promote neuronal growth. However, c-Met is limited for therapeutic reasons in that RTKs have transient activation and are desensitized following ligand stimulation. We hypothesize that extending c-Met receptor activity by disrupting its downregulation will help restore corneal homeostasis following wounding. This hypothesis will be tested through the following aims: Aim 1: Determine if ubiquitylation of the c- Met receptor limits its signaling in corneal epithelial cells in vitro. We hypothesize that inhibiting negative regulation of c-Met signaling will prolong receptor activity and accelerate healing. We will test this by blocking c- Met ubiquitylation in vitro by genetic knockout of CBL genes from immortalized human corneal epithelial cells and measuring receptor phosphorylation, trafficking, in vitro wound healing, and cell migration and proliferation. Aim 2: Determine effect of CBL knockout and c-Met activation in corneal wound healing murine models in vivo. We hypothesize that HGF-induced c-Met signaling will not only aid in re-epithelialization, but also will decrease fibrotic markers in the stromal layer and promote axonal outgrowth of corneal nerves. We will test this by using corneal epithelial-specific, inducible CBL knockout murine models. We will wound the corneas and monitor gross corneal morphology and homeostasis, re-epithelialization, fibrosis and inflammatory markers, and nerve restoration. These studies are innovative because we will manipulate c-Met signaling regulation to extend signaling and promote healing of all layers of the cornea. The proposed research is relevant to the National Eye Institute’s mission of eliminating vision loss and improving quality of life through research.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2026 ( Subtotal = -$18,592 )
2026	2025	UNIVERSITY OF LOUISVILLE	2301 S 3RD ST	LOUISVILLE	KY	40208	JEFFERSON	USA	Vision Research	000	2	3/4/2026	TERMINATION	-$18,592
														Subtotal = -$18,592

Issue Date FY: 2025 ( Subtotal = $36,386 )
2025	2025	UNIVERSITY OF LOUISVILLE	2301 S 3RD ST	LOUISVILLE	KY	40208	JEFFERSON	USA	Vision Research	001	2	7/31/2025	NON-COMPETING CONTINUATION	$564
2025	2025	UNIVERSITY OF LOUISVILLE	2301 S 3RD ST	LOUISVILLE	KY	40208	JEFFERSON	USA	Vision Research	000	2	3/20/2025	NON-COMPETING CONTINUATION	$35,822
														Subtotal = $36,386

Issue Date FY: 2024 ( Subtotal = $35,822 )
2024	2024	UNIVERSITY OF LOUISVILLE	2301 S 3RD ST	LOUISVILLE	KY	40208	JEFFERSON	USA	Vision Research	002	1	6/26/2024	NEW	$1,280
2024	2024	UNIVERSITY OF LOUISVILLE	2301 S 3RD ST	LOUISVILLE	KY	40208	JEFFERSON	USA	Vision Research	000	1	4/4/2024	NEW	$34,542
2024	2024	UNIVERSITY OF LOUISVILLE	2301 S 3RD ST	LOUISVILLE	KY	40208	JEFFERSON	USA	Vision Research	001	1	5/2/2024	NEW	$0
														Subtotal = $35,822

Grand Total All Awards = $53,616

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Optimizing c-Met signaling to enhance corneal epithelial homeostasis

Award Number: F31EY034730

ORGANIZATION: NATIONAL EYE INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 04/04/2024

PERIOD OF PERFORMANCE END DATE: 08/08/2025

AWARD TERMINATION DATE: 03/04/2026

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