Mechanisms of Retinal Vascular Permeability in Diabetes

描述（由申请人提供）：糖尿病视网膜病变仍然是美国失明的主要原因。最近的临床试验表明，靶向血管内皮生长因子（VEGF）可以有效地预防视力丧失的进展，并使一些患者恢复视力。这些研究表明，药物治疗视网膜可以有效地治疗糖尿病视网膜病变。然而，并非所有患者都对抗vegf治疗有反应，这需要反复进行眼内注射，有眼内炎的风险。除了VEGF，

DESCRIPTION (provided by applicant): Diabetic retinopathy remains a leading cause of blindness in the United States. Recent clinical trials have demonstrated that targeting vascular endothelial growth factor (VEGF) can effectively prevent progression of vision loss and for some patients restore visual acuity. These studies demonstrate that medical therapy for the retina can effectively treat diabetic retinopathy. However, not all patients respond to anti-VEGF therapies, which require repeat intra-ocular injections with the risk of endophthalmitis. In addition to VEGF, a number of inflammatory factors are elevated in patients with diabetic retinopathy that are believed to contribute to disease pathology including tumor necrosis factor, the chemokine (C-C motif) ligand 2 (CCL2), interleukin 6 and 8. Therefore, understanding the mechanisms by which growth factors and inflammatory cytokines alter the retinal vascular endothelium leading to vascular permeability and angiogenesis remains of high significance. Research from the previous funding period has identified two important signaling pathways that control permeability in response to VEGF. The first pathway involves conventional protein kinase C (PKC) activation and phosphorylation of the tight junction protein occludin and is required for VEGF induced vascular permeability. Published and preliminary data also reveal that occludin phosphorylation contributes to growth control and angiogenesis. Thus, occludin phosphorylation downstream of VEGF activation contributes to both vascular permeability and angiogenesis suggesting an important role in growth and blood-retinal barrier differentiation. Further, research over the previous funding period has identified a second signaling pathway involving atypical PKC activation as required for permeability response to both VEGF and inflammatory cytokines such as TNF and CCL2. Utilizing mass spectrometry phosphoproteomic analysis we have identified downstream targets linking this pathway to small G-protein regulation and control of permeability. Here we propose to define the role of occludin phosphorylation in permeability and angiogenesis in vivo while also elucidating the aPKC activation pathway to the control of vascular permeability. Collectively, these studies will provide novel insight into the mechanisms of VEGF induced permeability and angiogenesis specifically through the control of the tight junctions' complex and small G-protein regulation of the cytoskeleton. This research is expected to provide new insight into the nature of blood vessel growth and maturation and identify new targets for therapeutic intervention that are effective against both growth factors and inflammatory cytokines.