Department of Biology

University of Kentucky

Lexington, Kentucky

BASIC RESEARCH PROJECT

Retinal damage and regeneration in the African spiny mouse ( Acomys cahirinus ): a novel mammalian model for translational research

Research Interests

It is commonly believed that the ability to regenerate neurons in vertebrates is an exclusive property of non-mammalian species such as fish and amphibians. However, in recent years, spiny mice (Acomys) have become the focus of intense research for their enhanced wound repair and regenerative ability in many tissues. This raises the question of whether these mammals might regenerate retinal neurons in response to damage. Dr. Morris has obtained preliminary data that this may indeed be the case.

The purpose of this project is to test the hypothesis that the spiny mouse possesses the capacity to regenerate retinal neurons in response to damage, and to take the first steps in determining the underlying biological mechanism. This study may identify promising avenues for promoting regeneration in human patients with retinal degenerative diseases.

Plans for 2025

In the next funding period, Dr. Morris’ goal is to determine whether hyperglycemia in spiny mice inhibits their retinal regenerative ability, and whether this can be corrected by exposure to insulin or insulin-like growth factor 1 (IGF-1).

Specific Aims:
In Specific Aim 1, we will track blood glucose levels in a cohort of spiny mice before and after retinal injury to determine whether high blood sugar is negatively correlated with the magnitude of RGC recovery.  In Specific Aim 2, the lab will determine whether exogenously provided insulin can boost RGC recovery in normoglycemic and hyperglycemic spiny mice.

Progress in 2024

During the 2024 funding period, Dr. Morris and her team continued to investigate how the spiny mouse (Acomys) retina responds differently to acute injury compared to the common laboratory mouse (Mus). Following acute retinal damage that causes extensive loss of retinal ganglion cells (RGCs), we observed a significant increase in RGC number in Acomys beginning at 21 days post injury. However, the team also observed extensive variability among animals, with some spiny mice showing a strong RGC recovery, and others displaying weak recovery (and these differences were not due to age, size, or sex). Given the well documented propensity of spiny mice to develop type II diabetes, Dr. Morris’ lab hypothesize that the differential RGC recovery response is due to differences in blood sugar levels.

In the next funding period, the goal will be to determine the precise cellular phenotypes and genetic pathways that contribute to this second wave of proliferation and potentially neurogenesis in the spiny mouse retina. Dr. Morris also plans to complement her lab’s cell and molecular analyses with functional assays for vision loss and recovery.

Specific Aims:
Aim 1, to characterize the cellular and transcriptomic response to acute retinal damage at 6-10 post injury in Acomys and Mus using scRNA-Seq analysis; Aim 2, to establish electrophysiologic (ERG) assays of visual function in Acomys to track retinal damage and regeneration.

Progress in 2023

During the 2023 funding period, Dr Morris’ lab further explored how the spiny mouse (Acomys) retina responds differently to acute injury compared to the common laboratory
mouse (Mus). They found that although there is an increase in inflammation in both species just after injury, in the spiny mouse this does not lead to fibrotic scarring in the retina as it does in Mus. Dr. Morris further hypothesizes that this is due to differences in signaling from the retinal microglia, which promote an environment permissive for regeneration in Acomys but not in Mus. Her team also discovered that there is a second wave of cell proliferation in the spiny mouse retina after damage that is associated with the recovery of the lost retinal neurons.

In 2023, Dr. Morris’ goal was to determine how the immune system shapes the regenerative response to retinal damage in Acomys. She and her colleagues will focus on two critical features of immune system responses that have been documented for fully regenerating species – inflammation and the activation of retinal microglia.

Specific Aims: Aim 1, To characterize and compare the scale and timing of inflammatory signaling in Acomys and Mus in response to acute retinal damage; Aim 2, To determine the role of microglia in the Acomys retinal regenerative response.

Progress in 2022:

Using several complementary methods to detect cell proliferation, we confirmed that NMDA damage to the inner retina elicits a significantly stronger proliferative response in Acomys compared to Mus, and this response persists through 48 hours post injury (hpi). Moreover, we found that some of the cell proliferation in Acomys is coming from the Müller glia, indicating that Acomys might use a similar mechanism to regenerate retinal cells as is observed in fully regenerating species such as zebrafish. Excitingly, we observed a large increase in expression of the critical regeneration factor Ascl1 in the injured Acomys (but not Mus) retina, demonstrating that Acomys does mount a pro-regenerative response to inner retinal damage.