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.

糖尿病视网膜病变是美国失明的主要原因。炎症分子和视网膜内皮细胞死亡（毛细血管变性）我们发现局部视网膜缺血对于这种疾病的发生很重要。 CD40是视网膜炎症分子上调和发育的主要驱动因素此外，Müller 细胞中的 CD40 会触发实验性糖尿病视网膜病变中的毛细血管变性。嘌呤能信号（ATP-P2X7）驱动旁观者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上调是毛细血管渗漏和视网膜新生血管形成的核心事件糖尿病视网膜病变中的 VEGF 上调是由未折叠的激活驱动的。 Müller 细胞中的蛋白质反应 (UPR) 然而，我们对 UPR 的机制尚不完全了解。在疾病中被激活。] 此应用程序的目的是加深我们对 [UPR 的归纳、糖尿病视网膜病变中 VEGF] 和炎症分子的上调核心假设是。 CD40下游的特定信号通路控制着[UPR、VEGF上调和 ATP-P2X7 级联，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，并将防止实验性糖尿病视网膜病变 [第一个目标是研究 CD40 如何刺激 UPR。在第二个目标中，我们将确定 CD40 是否通过 UPR 上调 VEGF 以及是否介导 UPR/VEGF 上调的信号通路与引起 UPR/VEGF 上调的信号通路不同直接上调穆勒细胞中的炎症分子将利用遗传来实现这两个目标。阻断特定信号通路的方法。]在第三个目标中，我们将使用动物模型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 体内上调以及 CD40 信号传导上游事件的基因阻断是否会损害糖尿病视网膜中 UPR、VEGF 和各种炎症分子的上调。] 使用类似的方法在第四个目标中，我们将测试 CD40 信号传导特定抑制剂的体内效果 [拟议的工作将进一步加深我们对上述事件的理解。糖尿病视网膜病变中 UPR/VEGF 上调]并可能导致选择性的进一步发展 CD40信号传导抑制剂作为治疗糖尿病视网膜病变的新方法。

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.