Regulation of retinopathies

视网膜病变的调节

基本信息

批准号：
10391449
负责人：
CARLOS S SUBAUSTE
金额：
$ 39.04万
依托单位：
CASE WESTERN RESERVE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-04-01 至 2025-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10391449
关键词：
ATF6 gene Amino Acid Sequence Apoptosis Automobile Driving Binding Binding Sites Blindness Blood capillaries CCL2 gene Cells Cessation of life Development Diabetes Mellitus Diabetic Retinopathy Diabetic mouse Disease Endothelial Cells Enzymes Event Experimental Animal Model Extravasation Future Genetic Impairment Inflammation Inflammatory Inflammatory Response Inositol Intercellular adhesion molecule 1 Interleukin-1 beta Ischemia Lead Ligation Mediating Mediator of activation protein Methodology Microglia Muller&apos s cell Mus PLC gamma1 Pathogenesis Pathway interactions Peptide Hydrolases Peptides Permeability Pharmacology Phosphotransferases Process Production Protein Kinase Proteins Regimen Regulation Reperfusion Therapy Resistance Retina Retinal Diseases Retinal Neovascularization Retro-Inverso Peptide Role Signal Pathway Signal Transduction Surface TNF gene TNFRSF5 gene TRAF2 gene TRAF6 gene Testing Therapeutic Transgenic Mice United States Up-Regulation Vascular Endothelial Growth Factors Work chemokine cytokine diabetic genetic approach in vivo in vivo evaluation inhibitor macrophage neovascularization novel novel strategies prevent receptor response retinal damage retinal ischemia sensor

项目摘要

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.

糖尿病性视网膜病是美国失明的主要原因。增加表达炎症分子和残留内皮细胞的死亡（毛细血管变性）导致据信局部视网膜缺血对于这种疾病的发展很重要。我们发现了 CD40是视网膜和发育中炎症分子上调的主要驱动力实验性糖尿病性视网膜病中的毛细管变性。此外，Müller细胞中的CD40触发嘌呤能信号传导（ATP-P2X7）驱动副炎性细胞因子在副标中的表达永久内皮细胞的小胶质细胞/巨噬细胞和程序性细胞死亡。 [VEGF上调是毛细血管泄漏和视网膜新生血管的核心糖尿病性视网膜病。糖尿病性视网膜中的VEGF上调是由展开的激活驱动的 Müller细胞中的蛋白质反应（UPR）。但是，我们对UPR的了解不完全在疾病中被激活。] 该应用的目的是进一步了解[诱导UPR，糖尿病性视网膜病中VEGF]和炎症分子的上调。中心假设是 CD40控制下游的特定信号通路[UPR，VEGF上调和 ATP-P2X7级联上调，]炎症分子上调，毛细管变性，将防止实验性糖尿病性视网膜病。 [在第一个目标中，我们将研究CD40如何刺激UPR müller细胞。在第二个目标中，我们将确定CD40是否通过UPR上调VEGF，以及是否是否介导UPR/VEGF上调的信号通路与引起的途径不同在müller细胞中直接上调炎症分子。两种目标都将使用通用在第三个目标中，我们将使用一个动物模型实验性糖尿病性视网膜病和转基因小鼠以确定[CD40驱动UPR和VEGF是否驱动体内上调以及CD40信号中上游事件的遗传阻塞是否会损害 UPR，VEGF和糖尿病性视网膜各种炎症分子的上调。]使用相似方法，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。 [拟议的工作将进一步我们对糖尿病性视网膜病中的UPR/VEGF上调]，可能导致选择性的进一步发展 CD40信号传导的抑制剂是治疗糖尿病性视网膜病的新方法。

项目成果

期刊论文数量（7）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Animal Models for Toxoplasma gondii Infection.

弓形虫感染的动物模型。

DOI：
10.1002/cpz1.871
发表时间：
2023
期刊：
Current protocols
影响因子：
0
作者：
SSubauste,Carlos;Hubal,Alyssa
通讯作者：
Hubal,Alyssa

CD40 and tumour necrosis factor-α co-operate to up-regulate inducuble nitric oxide synthase expression in macrophages.

CD40 和肿瘤坏死因子-α 协同上调巨噬细胞中诱导型一氧化氮合酶的表达。

DOI：
10.1111/j.1365-2567.2011.03519.x
发表时间：
2012
期刊：
Immunology
影响因子：
6.4
作者：
Portillo,Jose-AndresC;Feliciano,LuisMuniz;Okenka,Genevieve;Heinzel,Frederick;Subauste,MCecilia;Subauste,CarlosS
通讯作者：
Subauste,CarlosS

Loss of CD40 attenuates experimental diabetes-induced retinal inflammation but does not protect mice from electroretinogram defects.