GRP78 signaling and retinal angiogenesis

GRP78 信号传导和视网膜血管生成

• 批准号: 10728654
• 负责人: GADIPARTHI N RAO
• 金额: $ 51.11万
• 依托单位: UNIVERSITY OF TENNESSEE HEALTH SCI CTR
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-01 至 2027-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10728654
• 关键词: ATF6 gene; Address; Adherens Junction; Adult; Affect; Age related macular degeneration; Animal Model; Binding; Blindness; Blood Vessels; Cell Proliferation; Cell Survival; Choroid; Complex; Cyclin D1; Development; Diabetes Mellitus; Diabetic Retinopathy; Disease; Drug resistance; Endothelial Cells; Event; Eye diseases; GRP78 gene; Hemorrhage; Homologous Gene; Hypoxia; IL8 gene; Infant; Link; Mediating; Modeling; Mus; NF-kappa B; Neural Retina; Outcome Study; Oxygen; Pathologic; Pathologic Neovascularization; Persons; Play; Proliferating; Proteins; Reporting; Retina; Retinal Diseases; Retinal Neovascularization; Retinal Vascular Occlusion; Retinopathy of Prematurity; Role; STAT3 gene; Signal Transduction; Testing; Therapeutic; Time Study; Tube; VEGFA gene; Vascular Diseases; Vascular Endothelial Growth Factors; Vision; Vitreous Hemorrhage; adherent junction; angiogenesis; beta catenin; bevacizumab; blood vessel development; cadherin 5; cell motility; conditional knockout; diabetic patient; endoplasmic reticulum stress; inhibitor; light transmission; neoplastic cell; neovascularization; neutralizing antibody; novel; pharmacologic; proliferative diabetic retinopathy; pup; response; retinal angiogenesis; small hairpin RNA; targeted treatment; therapeutic target; transcription factor; tumor growth

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.

视网膜新生血管（RNV）是视力丧失的主要因素之一，尤其是糖尿病患者。在 事实上，世界卫生组织报告称，到 2040 年，全球 6.42 亿糖尿病患者中，35%（2.24 亿）患有糖尿病 将出现某种形式的糖尿病视网膜病变，其中 11%（7000 万人）将遭受视力威胁 视网膜病变。模拟视网膜血管病变的动物模型确定了 VEGF 的主导作用， 随后导致了针对 RNV 的抗 VEGF 疗法的开发。然而，这些抗 VEGF 单独抑制 RNV 的疗法并不具有选择性，因为它们还会影响发育和修复 血管生成。此外，长期使用抗VEGF药物会导致正常血液变性。 神经视网膜和脉络膜的血管和血管纤维化导致玻璃体出血。因此，它是 有必要找到仅针对 VEGF 病理信号而不是生理信号的治疗方法。对此 最后，我们发现 GRP78 被 OIR 强烈诱导，并具有影响 RNV 的能力。 GRP78 是 ER 应激诱导的未折叠蛋白反应 (UPR) 的主要调节因子。除了在普遍定期审议中的作用外， GRP78 已被证明与肿瘤细胞存活、增殖和耐药性有关。此外，一个 GRP78 水平与 RNV 之间的相关性也有报道。然而，这些之间存在因果关系 两个事件未知。在这方面，我们的初步结果表明，GRP78不仅是由 OIR 及其在 EC 中的条件删除也减少了缺氧诱导的 RNV。此外，我们观察到 GRP78 通过触发 Wnt 依赖性的 β-连环蛋白从粘附连接处释放及其复合物形成 STAT3 导致细胞周期蛋白 D1 表达，从而增强 EC 增殖和迁移。与 β-连环蛋白平行- STAT3-Cyclin D1 信号传导、GRP78 通过非典型 NFkB RelB 激活也介导 IL-8/Cxcl1/2 在调节EC发芽中的表达。基于这些新的观察结果，我们假设 GRP78 在 RNV 中起着至关重要的作用。我们将通过测试以下三个具体目标来解决这一主要假设。 目标 1. ATF6-GRP78 信号传导的 UPR 独立激活对于 VEGF/OIR 诱导的视网膜至关重要 新生血管形成；目标 2. GRP78 介导的不依赖 Wnt 的 β-连环蛋白激活是 VEGFA/OIR诱导的细胞周期蛋白D1表达和视网膜新生血管形成；目标 3.非规范 NFkB， RelB 介导的 IL-8 表达是 VEGFA/OIR 诱导的视网膜新生血管形成所必需的。结果 这些研究可能会确定治疗 RNV 的选择性药物靶点，包括增殖性糖尿病 视网膜病变。