| dc.description.abstract | Diabetic retinopathy (DR) is a chronic complication associated with diabetes and the number one cause of blindness in working adults in the US. More than 90% of diabetic patients have obesity-associated type 2 diabetes (T2D), and 60% of T2D patients will develop DR. Degeneration of retinal neurons and vasculature manifests in the diabetic retina and early stage of DR. Photoreceptors undergo apoptosis shortly after the onset of diabetes, which contributes to the retinal dysfunction and microvascular complications leading to vision impairment. Chronic inflammation is a hallmark of obesity and T2D and a contributor to apoptosis; and retinal photoreceptors are a major source of intraocular inflammation which contributes to vascular abnormalities in diabetes. However, how diabetic insults cause inflammation and apoptosis in photoreceptors remains unclear. MicroRNA-150 (miR-150) is downregulated in diabetic patients and is a regulator that suppresses inflammation, apoptosis, and pathological angiogenesis. Several confirmed target genes of miR-150, including the ETS-domain transcription factor (Elk1), regulate both inflammation and apoptosis. In this study, I used a high-fat diet (HFD)-induced T2D mouse model and cultured photoreceptors treated with palmitic acid (PA) to decipher the functions of miR-150 and its target genes in mediating the high-fat-induced retinal degeneration, apoptosis, and inflammation. I found that deletion of miR-150 exacerbated HFD-induced dysfunction and inflammation in the neural retina. The miR-150 knockout (miR-150-/-) mice also had increased numbers of degenerated retinal capillaries and apoptotic photoreceptors compared to WT mice. Knocking down miR-150 also exacerbates the PA-elicited apoptosis and inflammation in cultured photoreceptors. The functional screen showed that Elk1 is the target gene of miR-150 that responses to the PA treatment in photoreceptors. The phosphorylated ELK1 at threonine 417 (pELK1T417) and phosphorylated ELK1 at serine 383 (pELK1S383) are the active forms of ELK1 that can regulate apoptosis and inflammation, respectively. I found that miR-150 knockout/ knockdown upregulates the expressions of ELK1, pELK1T417, and pELK1S383 in photoreceptors. Knocking down Elk1 alleviated the PA-induced inflammation and decreased the nuclear-to-cytoplasmic (N/C) ratio of pELK1S383 in cultured photoreceptors. However, Elk1 knockdown did not rescue the apoptosis or decrease the N/C ratio of pELK1T417 in PA-treated photoreceptors. | |
