Racial Disparities in glaucoma: Implications of SDPR/Cavin2 in human trabecular meshwork

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Project Abstract: Understanding the pathogenesis of glaucoma, a leading cause of blindness, is an important goal of vision research. As indicated in numerous population-based studies, individuals of African descent develop glaucoma at an earlier age with increased severity and risk of blindness compared to Caucasians (CC). The fundamental mechanisms for these disparities are unknown, but genetic influences likely contribute to these phenotypic differences. The TM is important in the regulation of intraocular pressure, the most important and only current modifiable risk factor for glaucoma development. Differential gene expression analysis by RNA sequencing (RNAseq) and quantitative polymerase chain reaction (qPCR) compared trabecular meshwork (TM) specimens from African American (AA) and CC glaucoma patients obtained during surgery indicated SDPR (also known as Cavin2) had significantly lower expression in AA patients compared to CC. This finding led to explorations of how it may be related to physiology and pathology of the TM. SDPR, together with other cavins and caveolin proteins, is associated with regulation of caveolae, sub-microscopic, plasma membrane pits, which have been noted to be abundant in TM. Caveolae are linked to a wide range of cellular functions and disease, but the role of these structures in the eye has not been elucidated. These organelles are composed of caveolin (CAV) and cavin proteins. Gene variants near the CAV1/CAV2 encoding gene in genome wide association studies have been identified in glaucoma patients in select populations. The first specific aim will evaluate expression of SDPR gene/protein as it relates to the ultrastructural changes of caveolae in TM from both AA and CC glaucoma patients and healthy cadaver donors, utilizing both standard and immunogold labeling transmission electron microscopy for SDPR and CAV1. The second specific aim is to investigate SDPR-specific short hairpin RNA (shRNA)-mediated gene silencing in cultured human TM cells to evaluate phenotypic correlations in caveolae as identified in our preliminary observations in POAG TM. In contrast to self-reported racial background, all glaucoma specimens and healthy donor tissues will be confirmed by DNA genotyping, representing more accurate racial ancestry for data analysis. This innovative study represents the first exploration of SDPR/Cavin2 gene expression, protein distribution and ultrastructural effects in human TM and should provide valuable insights into a novel mechanism underlying racial disparities in POAG. The knowledge gained in these studies may lead to new therapies for and strategies to prevent/treat this blinding disease.