. The applicant is a physician-scientist who has completed his post-doctoral fellowship in the laboratory of Dr. George L. King, who will continue to function as a mentor while the applicant expands his training in new fields, including retinal endothelial cell biology and animal models of retinal complications of diabetes. This training will be co-mentored by Dr. Lloyd Paul Aiello at the Beetham Eye Institute at Joslin Diabetes Center. The Career Development Award would allow the applicant to become an independent researcher in the field of retinal disease and help achieve the long-term objective of understanding growth factor actions in diabetic eye complications. In diabetic macular edema and proliferative diabetic retinopathy, upregulation of vascular endothelial growth factor (VEGF) plays a central role. Protein kinase C (PKC) isoforms a, (3, and e are activated in the diabetic retina, but so far there has been a lack of data from animal models with isoform-specific manipulation of PKC function. In preliminary results, downregulation of PKCe with small interfering RNA (siRNA) in endothelial cell culture had a dramatic effect on several pathways of VEGF-stimulated signaling and cell function, including nitric oxide production and cell proliferation, with minor or opposite effects seen after downregulation of PKCa, (3, or 8. Further, intravitreal injection of PKCe siRNA inhibited VEGF-stimulated retinal vascular permeability in rats. Therefore, the central hypothesis of this application is that PKCe isoform has a quantitatively major role in mediating VEGF-stimulated Akt, eNOS, and AMP-activated protein kinase (AMPK) signaling, and is critical for development of macular edema and proliferative retinopathy in diabetes.
The specific aims are: i. To characterize mechanisms of activation of PKCe in retinal endothelial cells and cell function regulated by PKCe;2. To determine the effect of PKCe knockout or overexpression on vascular permeability during VEGF stimulation and in diabetes;3. the effect of knockout or overexpression of PKCe function on ischemic neovascularization in the retina. Relevance. The proposed research is expected to have a positive impact on the prevention of macular edema and proliferative retinopathy in patients with diabetes because it will establish the usefulness of the signaling molecule PKCe as a key mediator of these processes and a potential drug target for these conditions.
|Rask-Madsen, Christian; King, George L (2013) Vascular complications of diabetes: mechanisms of injury and protective factors. Cell Metab 17:20-33|
|Rask-Madsen, Christian; Kahn, C Ronald (2012) Tissue-specific insulin signaling, metabolic syndrome, and cardiovascular disease. Arterioscler Thromb Vasc Biol 32:2052-9|
|Mima, Akira; Qi, Weier; Hiraoka-Yamomoto, Junko et al. (2012) Retinal not systemic oxidative and inflammatory stress correlated with VEGF expression in rodent models of insulin resistance and diabetes. Invest Ophthalmol Vis Sci 53:8424-32|
|Rask-Madsen, Christian; Buonomo, Erica; Li, Qian et al. (2012) Hyperinsulinemia does not change atherosclerosis development in apolipoprotein E null mice. Arterioscler Thromb Vasc Biol 32:1124-31|
|Mima, Akira; Ohshiro, Yuzuru; Kitada, Munehiro et al. (2011) Glomerular-specific protein kinase C-?-induced insulin receptor substrate-1 dysfunction and insulin resistance in rat models of diabetes and obesity. Kidney Int 79:883-96|
|Rask-Madsen, Christian; King, George L (2011) Endothelium-dependent delivery of insulin to muscle interstitium. Cell Metab 13:236-8|
|Cao, Lan; Arany, Praveen R; Kim, Jaeyun et al. (2010) Modulating Notch signaling to enhance neovascularization and reperfusion in diabetic mice. Biomaterials 31:9048-56|
|Rask-Madsen, Christian; Li, Qian; Freund, Bryn et al. (2010) Loss of insulin signaling in vascular endothelial cells accelerates atherosclerosis in apolipoprotein E null mice. Cell Metab 11:379-89|
|Rask-Madsen, Christian; King, George L (2008) More sugar, less blood vessels: another piece in the puzzle of increased cardiovascular risk in diabetes. Arterioscler Thromb Vasc Biol 28:608-10|