Retinal endothelial cells (RECs) are the major component in inner blood-retinal barrier (BRB). Disruption of inner BRB contributes to the pathogenesis of diabetic retinopathy (DR), a common microvascular complication of diabetes. Ophthalmologists have limited options to delay or treat DR. I propose hydroxycarboxylic acid receptor 2 (HCAR2) as a potential target for DR prevention by protecting against REC damage and loss of barrier function. My central hypothesis is that HCAR2 is involved in regulation of barrier function of RECs and its activation protects against barrier disruption. To test this hypothesis, I developed two specific aims (Aim 1) to demonstrate the relevance of endothelial-cell specific HCAR2 expression, (Aim 2) to demonstrate the efficacy of HCAR2 activation by specific agonists against endothelial cell damage and barrier disruption in retina. For (Aim1), human retinal endothelial cells and primary brain endothelial cells isolated from wild-type and Hcar2 knockout (Hcar2 KO) mice will be used to evaluate the differential expression of genes related to endothelial barrier cell function and inflammatory responses. In Aim 2, I will evaluate directly the impact of HCAR2 expression and activation in endothelial cells in the diabetic retina using streptozotocin-induced diabetes in Hcar2 KO mice and wild type (WT) mice +/- treatment with HCAR2 agonists. End points to be monitored include: fluorescein angiography, albumin extravasation, and the expression of tight junction markers (claudin-5, occludin, zona occludens-1). This study is expected to validate HCAR2 as a therapeutic target for protection against endothelial cell damage in DR.
|Program type||Predoctoral Fellowship|
|Effective start/end date||01/01/2019 → 12/31/2020|