Src Family Kinases May Be Therapeutic Target for NK, Preclinical Data Suggest

Src Family Kinases May Be Therapeutic Target for NK, Preclinical Data Suggest

Activating Src family kinases, a family of enzymes involved in cell migration and growth, enhanced corneal wound healing in cellular and animal models, a preclinical study has found.

The findings suggest these enzymes might be a promising therapeutic target for neurotrophic keratitis, a rare eye disorder in which the cornea — the transparent outer layer of the eye — loses the ability to self-repair, and starts to breakdown.

Preclinical findings were presented at the 2020 Society for Investigative Dermatology (SID) Meeting virtual conference earlier this year. The presentation abstract, “Src-family kinases enhance corneal wound healing and compensate for neurotrophic keratopathy,” was published in the Journal of Investigative Dermatology.

Neurotrophic keratitis affects the cornea, which functions as a window to control and focus light entering in the eye. It is caused by the malfunction of nerves that serve (innervate) the cornea, reducing tear production and sensitivity in the cornea’s outer layer, which is composed of epithelial cells.

Src family kinases (SFKs), which are known to play a vital role in the migration and growth of epithelial cells, have been found to be particularly active at the edge of corneal wounds.

Based on these preliminary findings, researchers at the University of Pennsylvania wondered if actively increasing the activity of SFKs might promote corneal wound healing in cellular and animal models.

To test this hypothesis, they first did a series of scratch tests to create wounds on a “sheet” of primary human corneal epithelial cells (HCECs) cultured in a lab dish. They then measured SFK levels after treating cells with increasing doses of sodium orthovanadate, a chemical that normally increases SFK levels. Images of the cells migrating to close the wound were taken every hour for 24 hours. 

These experiments showed wound healing was progressively better with increasing doses of sodium orthovanadate, and increasing SFK levels.

They then performed a series of corneal wound experiments using three groups of mice: normal mice; mice lacking Fyn kinase, one member of the Src family that is needed for proper nerve function; and mice with a mutant form of Fyn, known as FynY528, in which the enzyme is continuously active. 

Additionally, in one set of mice, the nerve that serves the cornea was surgically severed in one of two eyes. Mice corneal epithelial cells were wounded, and the animals’ eyes were then imaged to assess healing. Mice also were treated with sodium orthovanadate. 

Again, sodium orthovanadate was found to enhance wound healing, and activate SFKs as well as an enzyme called Akt, which is involved in cell survival and proliferation.

Furthermore, they found that wound healing was faster in FynY528 mice compared with normal mice, and slower in mice that lacked Fyn kinase compared with normal mice, indicating Fyn kinase played a role in corneal wound healing. 

Would healing rates also were slower in mice with severed corneal nerves, “suggesting a critical role for nerve function in epithelial wound healing,” the researchers wrote. 

Despite the loss of nerves that serve the cornea, preclinical findings showed that increasing SFK activity — either using a pharmacological or genetic approach — may promote wound healing. 

“These data suggest that delayed corneal epithelial wound healing from loss of corneal innervation can be compensated by increasing SFK activity,” the investigators wrote. 

“Further studies to delineate the downstream effectors of SFK in regards to wound healing should be conducted,” they wrote. 

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