Friday, April 26, 2024
4/26/2024
The transparent cornea is a highly innervated tissue and sustains significant nerve damage during common procedures such as corneal transplantation and vision correction. Unfortunately, the restoration of corneal sensory function after damage is usually inadequate due to aberrant and poor regeneration of axons. In vascularized tissues, such as the sciatic nerve and spinal cord Schwann cells (SCs) are known to support axonal regeneration after injury. However, little is known how corneal SCs respond to injury or surgical procedures as this cell types has not previously been investigated. Studies performed in sciatic injury models reveal that both the genetic encoded factors of SCs, as well as the extracellular matrix components govern the axonal repair process. The dedifferentiation of SCs into a repair SCs – a transient cell type – that re-differentiates into a terminal SC is a hallmark of SC-driven mechanisms in axonal regeneration. In the cornea, the bulk of sensory axons are unmyelinated axons, except at the limbus where they are myelinated. It is presumed that lesions of nonmyelinating corneal axons also enlist the support of their respective SCs for axonal regeneration, mirroring similar activities of SCs of injured vascularized tissues. This idea has not been formally tested before, as experimental evidence to support or refute this paradigm is lacking. To learn what genes are expressed specifically in corneal SCs, we performed a single cell RNA sequence analysis of the rabbit cornea and identified the corneal SC transcriptome. With cross-species validation of several SC-specific target proteins in mouse corneas and validation of a transgenic mouse line expressing proteolipid protein 1-enhanced green fluorescent protein (Plp1-eGFP), we demonstrated SC-specific reporter gene expression in vivo. In this exploratory R21 grant, we propose two aims. In specific aim 1, we will exploit the Plp1- eGFP reporter transgenic line in a corneal stromal injury model causing nerve severance and investigate corneal SC to myofibroblast differentiation over the course of axonal degeneration and repair. These studies will help define whether corneal SCs differentiate into myofibroblasts and nature of injury that promotes this aberrant phenotype. In specific aim 2, we will investigate the wingless (Wnt) signaling pathway in corneal SCs, as molecular components of this pathway showed differential high expression in SCs compared to other corneal cells. We plan to investigate how modulation of the Wnt inhibitor Dickkopf-1 (Dkk1) governs corneal axonal regeneration after injury and effects on corneal mechanical sensation. Together, these objectives will help to lay down the foundation to identify novel targets for SC-therapeutics towards improvement of corneal axonal growth and sensory impairment.
HHS’ Tracking Accountability in Government Grants System (TAGGS) website provides access to detailed descriptions of grants, loans, aggregated direct payments and other types of financial assistance awarded by the HHS Operating Divisions (OPDIVs) and the Office of the Secretary Staff Divisions (STAFFDIVs).
