Regulation of retinopathies

糖尿病视网膜病变是美国致盲的主要原因。增加了对 炎症分子与视网膜内皮细胞死亡(毛细血管变性) 视网膜局部缺血被认为是该病发生发展的重要因素。我们揭开了 CD40作为视网膜和发育中炎性分子上调的主要驱动力 实验性糖尿病视网膜病变的毛细血管变性。此外，Müler细胞中的CD40可触发 旁观者促炎细胞因子表达的嘌呤能信号转导(ATP-P2X7) 小胶质细胞/巨噬细胞与视网膜内皮细胞程序性死亡。 血管内皮生长因子上调是血管渗漏和视网膜新生血管形成的中心事件 糖尿病视网膜病变。糖尿病视网膜中血管内皮生长因子的上调是由未折叠的激活所驱动的 Müler细胞的蛋白质反应(UPR)。然而，我们对普遍定期审议如何 在疾病中被激活。] 这项申请的目的是加深我们对[普遍定期审议的诱导， 血管内皮生长因子和炎症分子在糖尿病视网膜病变中的上调。中心假设是 CD40下游的一条特定的信号通路控制着[UPR，VEGF的上调和 ATP-P2X7级联反应选择性阻断这一通路将阻止UPR、VEGF 上调，炎性分子上调，毛细血管变性，并将保护 实验性糖尿病视网膜病变。[在第一个目标中，我们将研究CD40如何刺激UPR 米勒细胞。在第二个目标中，我们将确定CD40是否通过UPR上调血管内皮生长因子，以及是否 介导UPR/VEGF上调的信号通路与导致UPR/VEGF上调的信号通路不同 Müler细胞中炎性分子的直接上调。这两个目标都将使用基因 阻止特定信号通路的方法。]在第三个目标中，我们将使用 实验性糖尿病视网膜病变和转基因小鼠以确定[CD40是否驱动UPR和VEGF 体内上调和CD40信号上游事件的基因阻断是否损害 糖尿病视网膜中UPR、VEGF和各种炎症分子的表达上调。]使用类似的 方法，在第四个目标中，我们将测试CD40信号的特定抑制剂的体内效应 在上述事件的诱导中。[拟议的工作将加深我们对 UPR/VEGF在糖尿病视网膜病变中上调]，并可能导致选择性视网膜病变的进一步发展 CD40信号抑制剂作为治疗糖尿病视网膜病变的新方法。

Diabetic retinopathy is a major cause of blindness in the United States. Increased expression of inflammatory molecules and death of retinal endothelial cells (capillary degeneration) with resulting local retinal ischemia are believed to be important for development of this disease. We uncovered CD40 as a major driver of the upregulation of inflammatory molecules in the retina and development of capillary degeneration in experimental diabetic retinopathy. In addition, CD40 in Müller cells triggers purinergic signaling (ATP-P2X7) that drives expression of pro-inflammatory cytokines in by-stander microglia/macrophages and programmed cell death of retinal endothelial cells. [VEGF upregulation is an event central to capillary leakage and retinal neovascularization in diabetic retinopathy. VEGF upregulation in the diabetic retina is driven by activation of the Unfolded Protein Response (UPR) in Müller cells. However, we have an incomplete understanding on how UPR is activated in the disease.] The objective of this application is to further our understanding of the [induction of UPR, the upregulation of VEGF] and inflammatory molecules in diabetic retinopathy. The central hypothesis is that a specific signaling pathway downstream of CD40 controls [UPR, VEGF upregulation and the ATP-P2X7 cascade such that selective blockade of this pathway will prevent UPR, VEGF upregulation,] inflammatory molecule upregulation, capillary degeneration and will protect against experimental diabetic retinopathy. [In the first aim we will examine how CD40 stimulates UPR in Müller cells. In the second aim we will determine if CD40 upregulates VEGF via UPR and whether the signaling pathway that mediates UPR/VEGF upregulation is different from the pathway that causes direct upregulation of inflammatory molecules in Müller cells. Both aims will be pursued using genetic approaches that block specific signaling pathways.] In the third aim we will use an animal model of experimental diabetic retinopathy and transgenic mice to determine if [CD40 drives UPR and VEGF upregulation in vivo and whether genetic blockade of an upstream event in CD40 signaling impairs upregulation of UPR, VEGF and various inflammatory molecules in the diabetic retina.] Using similar methodologies, in the fourth aim we will test the in vivo effects of a specific inhibitor of CD40 signaling in the induction of the events described above. [The proposed work will further our understanding of UPR/VEGF upregulation in diabetic retinopathy] and may lead to further development of selective inhibitors of CD40 signaling as a novel approach for treatment of diabetic retinopathy.