Human Stem Cell Modeling of the APBB2 Risk Variant for Glaucoma

This project focuses on human stem cell models and gene editing technologies to study the APBB2 gene variant and identify how it contributes to RGC neurodegeneration in those of African ancestry.

In Specific Aim 1, we will obtain induced pluripotent stem (iPS) cell lines from donors of African ancestry and apply CRISPR/Cas9 gene editing approaches to generate paired cell lines either with the APBB2 gene variant (disease model) or without this variant (paired isogenic control). In Specific Aim 2, we will differentiate these iPS cells into retinal ganglion cells (RGCs), the cell type directly affected in glaucoma. Upon the generation of RGCs, they will be analyzed for phenotypic and functional changes, as well as the exploration of transcriptional changes due to the APBB2 gene variant by RNA-seq analyses.

This application represents a unique and innovative approach to explore this novel gene variant associated with glaucoma. As individuals of African ancestry have a higher risk for developing glaucoma, the focus of this study upon the APBB2 risk variant represents a new avenue of exploration. Additionally, the use of human stem cell models is a unique approach to explore the functional consequences of this gene variant that disproportionately affects those of African ancestry.

Upon completion of this study, we will have a more comprehensive understanding about how this APBB2 risk variant acts to increase risk for glaucoma. By directly analyzing the effects of this risk variant within stem cell-derived retinal ganglion cells, the research field will have a greater understanding of how this gene variant leads to the degeneration of these cells. For the general public, the results of this study will represent a significant advance toward understanding why individuals of African ancestry are at a significantly greater risk for developing glaucoma.