GRP78 signaling and retinal angiogenesis

点击翻译按钮获取中文摘要

Retinal neovascularization (RNV) is one of the major factors in vision loss, particularly in diabetic patients. In fact, WHO reported that by 2040, out of 642 million people with diabetes globally, 35% (224 million) of them will develop some form of diabetic retinopathy, and 11% (70 million) will suffer with sight-threatening retinopathy. The animal models mimicking retinal vasculopathies identified a dominant role for VEGF, which subsequently led to the development of anti-VEGF therapies targeting RNV. However, these anti-VEGF therapies are not selective in inhibiting RNV alone, as they also affect developmental and reparative angiogenesis. Furthermore, long-term use of anti-VEGF regiments can cause degeneration of normal blood vessels and angiofibrosis of neural retina and choroid resulting in vitreous hemorrhage. Therefore, it is necessary to find therapeutics that target only pathological but not physiological signaling of VEGF. To this end, we found that GRP78 was induced robustly by OIR and possessed the capacity to influence RNV. GRP78 is the main regulator of ER stress-induced unfolded protein response (UPR). In addition to its role in UPR, GRP78 has been shown to be involved in tumor cell survival, proliferation, and drug resistance. Besides, a correlation between GRP78 levels and RNV has also been reported. However, a causal link between these two events is unknown. In this regard, our preliminary results revealed that GRP78 not only was induced by OIR but also its conditional deletion in ECs reduced hypoxia-induced RNV. Furthermore, we observed that GRP78 by triggering Wnt-independent release of b-catenin from adherent junctions and its complex formation with STAT3 leads to cyclin D1 expression in enhancing EC proliferation and migration. Parallel to b-catenin- STAT3-Cyclin D1 signaling, GRP78 via non-canonical NFkB RelB activation also mediates IL-8/Cxcl1/2 expression in the modulation EC sprouting. Based on these novel observations, we hypothesized that GRP78 plays a crucial role in RNV. We will address this major hypothesis by testing the following three specific aims. Aim 1. UPR-independent activation of ATF6-GRP78 signaling is essential for VEGF/OIR-induced retinal neovascularization; Aim 2. GRP78-mediated Wnt-independent activation of b-catenin is required for VEGFA/OIR-induced cyclin D1 expression and retinal neovascularization; and Aim 3. Non-canonical NFkB, RelB-mediated IL-8 expression is required for VEGFA/OIR-induced retinal neovascularization. The outcome of these studies may identify selective drug targets for the treatment of RNV, including proliferative diabetic retinopathy.