This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Diabetic retinopathy is a leading cause of vision impairment and blindness in the working adult. Oxidative stress and subsequent alteration of signaling pathways are the primarily causal factors in the disease progression. The retinal pigment epithelial (RPE) cell layer is responsible for maintaining the health of the retina by providing structural and nutritional support. Hyperglycemia would cause oxidative stress in the retinal pigment epithelium. A natural mixture of phytochemicals has received much recent attention in prevention of oxidative stress-related eye diseases, including diabetic retinopathy. We hypothesize that wolfberry phytochemicals may act as potential modifiers of the pathology associated with diabetic retinopathy through simultaneous regulation of cell survival/apoptosis pathways, rebalance of cellular fuel homeostasis in the retinal pigment epithelial cell layer. We have found that wolfberry phytochemicals, and its purified fractions, including polysacchardies, have enhanced antioxidant activity in vitro and in vivo. Application of water soluble wolfberry phytochemicals prevents RPE cells from hyperglycemia/oxidative stress damage by scavenging cellular free radicals. In the current proposal, we use both crude water extracts and the purified fractions of wolfberry, to treat RPE cells in culture and type 2 diabetic mice. We are determining how wolfberry bioactive compounds protect RPE and/or other retinal cells from hyperglycemia-induced cell apoptosis. We are trying to better understand the molecular mechanism on endoplasmic reticulum stress-related retinal degeneration in the type 2 diabetic mouse. The outcome of the current study will lead to the development of complementary therapeutic regimens for prevention or delay of the onset of the disease.