Regulation of retinopathies

糖尿病性视网膜病变是导致失明的主要原因。的表达增加 炎症分子和视网膜内皮细胞死亡（毛细血管变性）， 局部视网膜缺血被认为对于这种疾病的发展是重要的。我们发现 CD 40作为视网膜和发育中炎症分子上调的主要驱动因素 实验性糖尿病视网膜病变的毛细血管变性。此外，Müller细胞中的CD 40触发了 嘌呤能信号传导（ATP-P2 X7），驱动旁观者中促炎细胞因子的表达 小胶质细胞/巨噬细胞和视网膜内皮细胞的程序性细胞死亡。 [VEGF上调是在视网膜病变中毛细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VEGF的上调是由未折叠的 Müller细胞中的蛋白质反应（UPR）。然而，我们对普遍定期审议如何 在疾病中被激活]。 本申请书的目的是加深我们对[普遍定期审议的启动， 糖尿病视网膜病变中VEGF和炎性分子的上调。核心假设是 CD 40下游的特异性信号传导途径控制UPR、VEGF上调和细胞凋亡。 ATP-P2 X7级联，这样选择性阻断该途径将阻止UPR、VEGF 上调，]炎症分子上调，毛细血管变性，并将保护免受 实验性糖尿病视网膜病变[In第一个目标，我们将研究CD 40如何刺激UPR， 米勒细胞。在第二个目标中，我们将确定CD 40是否通过UPR上调VEGF， 介导UPR/VEGF上调的信号通路不同于引起UPR/VEGF上调的信号通路。 直接上调Müller细胞中的炎症分子。这两个目标都将通过基因工程来实现。 阻断特定信号通路的方法。在第三个目标中，我们将使用一种动物模型， 实验糖尿病视网膜病变和转基因小鼠，以确定是否[CD 40驱动UPR和VEGF 体内上调以及CD 40信号传导上游事件的遗传阻断是否损害 糖尿病视网膜中UPR、VEGF和各种炎性分子的上调。使用类似 方法，在第四个目标中，我们将测试CD 40信号传导的特异性抑制剂的体内作用 在上述事件的诱导。[The建议的工作将进一步了解 UPR/VEGF在糖尿病视网膜病变中的上调]，并可能导致选择性视网膜病变的进一步发展。 CD 40信号传导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.