Targeting ARF6, A Convergence Point For Multiple Pathways of Diabetic Retinopathy

靶向 ARF6，糖尿病视网膜病变多种途径的汇聚点

基本信息

批准号：
8863531
负责人：
Weiquan (Wendy) Zhu
金额：
$ 33.53万
依托单位：
UNIVERSITY OF UTAH
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-04-01 至 2020-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8863531
关键词：
Adherens Junction Affect Age Alleles Angiogenic Factor Animals Apoptosis Avastin Biological Models Blindness Blood Vessels Blood-Retinal Barrier Caring Cell Communication Cell surface Cells Clinical Complications of Diabetes Mellitus DR1 gene Data Development Diabetes Mellitus Diabetic Angiopathies Diabetic Retinopathy Diabetic mouse Disease Endocytosis Endothelial Cells Exhibits Experimental Animal Model Extravasation Exudative age-related macular degeneration Eye Eye diseases Failure Future Genetic Models Growth Human Immune Infiltration Inflammation Inflammatory Insulin-Dependent Diabetes Mellitus Intercellular Junctions Knockout Mice Leukostasis Methods Modeling Molecular Molecular Target Monomeric GTP-Binding Proteins Mus Non-Insulin-Dependent Diabetes Mellitus Oxygen PDGF receptor tyrosine kinase Pathologic Pathology Pathway interactions Patients Pattern Permeability Pharmaceutical Preparations Phenocopy Platelet-Derived Growth Factor Play Proteins Publishing Refractory Research Retina Retinal Retinal Diseases Retinal Neovascularization Role Signal Pathway Signal Transduction Streptozocin TLR4 gene TNF gene Testing Thick Tumor Necrosis Factor-alpha Tyrosine Kinase Inhibitor United States Vascular Diseases Vascular Endothelial Growth Factors Vascular Permeabilities Visual Acuity Visual impairment WNT Signaling Pathway Wild Type Mouse Work angiogenesis bevacizumab cadherin 5 cancer cell cell motility cell type diabetic diabetic patient improved inhibitor/antagonist macular edema migration mouse model neovascular neovascularization non-diabetic novel therapeutics patient population public health relevance receptor receptor internalization research study response small molecule trafficking

项目摘要

DESCRIPTION (provided by applicant): Diabetic retinopathy (DR) is a common microvascular complication of diabetes. It occurs in nearly all patients with type 1 diabetes and over 60% of patients with type 2 diabetes during the first two decades of disease. The major pathological factors of DR include local inflammation with hypercytokinemia, retinal infiltration with immune cells, uncontrolled neovascular growth penetrating the retina, and retinal vascular leakage that leads to vision loss. All of these pathologies are related to vascular dysfunction and can be impacted by multiple pro-inflammatory and pro-angiogenic signals such as IL-1ß, TNFa, DAMPs, VEGF and WNTs. However, anti-VEGF biologics, which is the current pharmacological standard-of-care, improves visual acuity in less than half of the patient population. This failure n efficacy is commonly ascribed to functional redundancy between VEGF and other DR- related pathogenic factors and suggests a need for a drug that can block multiple DR-related signaling pathways. We have identified a small GTPase ARF6 is over-expressed in diabetic human and mouse eyes. Inhibition of ARF6 reduces IL-1ß- and VEGF-induced retinal permeability and neovascularization in OIR. Published and our unpublished data have also shown that activated ARF6 plays a critical role in IL-1ß, TNFa and VEGF signaling in endothelial cells and WNT signaling in cancer cells. These results suggest that ARF6 is a convergence point for many DR-related inflammatory, angiogenic, and WNT pathways and is a key player in the pathologic progression of DR. We therefore hypothesize that inhibiting ARF6 activation will reduce vascular permeability and neovascularization and their debilitating sequelae. To test this hypothesis, we will pursue two aims. In Aim 1, we will determine whether endothelial expression of Arf6 is required for the development and/or progression of diabetic retinopathy by assessing pathologic responses in endothelial-specific Arf6 knockout mice using oxygen induced retinopathy (OIR) and streptozotocin (STZ)-induced diabetic mouse models. We will also determine whether the results from this genetic model are phenocopied in wild-type mice treated with the ARF6 small molecule inhibitor, NAV2729. In Aim 2, we will examine how universal the activation of ARF6 may be in controlling DR-related pathologic signaling pathways and will also define the mechanism by which activated ARF6 controls endothelial permeability or migration. If our hypothesis is correct, ARF6 will become an ideal molecular target for the treatment DR due to the fact that and may overcome many of the current problems with we will determine the role of activated ARF6 in the other retinal cell types and expand our study to other vascular eye diseases.

描述（通过应用程序提供）：糖尿病性视网膜病（DR）是糖尿病的常见微血管并发症。它发生在几乎所有1型糖尿病患者和60％以上的2型糖尿病患者中，在疾病的前二十年中。 DR的主要病理因素包括局部炎症患有高环境血症，免疫细胞的视网膜浸润，不受控制的新生血管生长穿透视网膜以及视网膜血管渗漏，从而导致视力丧失。所有这些病理都与血管功能障碍有关，可以受到多种促炎和促血管生成信号的影响，例如IL-1ß，TNFA，潮湿，潮湿，VEGF和WNT。但是，抗VEGF生物制剂是当前的药物标准护理，可改善不到一半的患者人群的视力。这种失败N效率通常归因于VEGF与其他DR相关的病原因子之间的功能冗余，并表明需要阻止多个DR相关信号通路的药物。我们已经确定了一个小的GTPase ARF6在糖尿病的人和小鼠眼中过表达。抑制ARF6可降低OIR中IL-1ß-和VEGF诱导的视网膜渗透性和新血管形成。已发布和我们未发表的数据还表明，激活的ARF6在癌细胞中内皮细胞中的IL-1ß，TNFA和VEGF信号传导中起关键作用。这些结果表明，ARF6是许多与DR相关的炎症，血管生成和WNT途径的收敛点，并且是DR病理发展的关键参与者。因此，我们假设抑制ARF6激活将减少血管渗透性和新血管形成及其衰弱的后遗症。为了检验这一假设，我们将追求两个目标。在AIM 1中，我们将确定使用氧诱导的视网膜病（OIR）和链球菌（STZ）诱导的糖尿病小鼠模型来评估糖尿病性视网膜病变的内皮表达是否需要糖尿病性视网膜病变的发展和/或进展。我们还将确定在用ARF6小分子抑制剂NAV2729处理的野生型小鼠中，该遗传模型的结果是否是表型。在AIM 2中，我们将研究ARF6的激活在控制与DR相关的病理信号通路方面的普遍性，还将定义激活的ARF6控制内皮渗透性或迁移的机制。如果我们的假设是正确的，ARF6将成为治疗DR的理想分子靶标，这是因为并且可以克服当前许多问题的事实，我们将确定活化的ARF6在其他永久细胞类型中的作用，并将我们的研究扩展到其他血管眼疾病。