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（申请人提供）：糖尿病视网膜病变（DR）是糖尿病常见的微血管并发症，几乎所有1型糖尿病患者和超过60%的2型糖尿病患者在疾病的前20年都会发生。 DR 的原因包括局部炎症伴高细胞因子血症、免疫细胞浸润视网膜、不受控制的新生血管生长穿透视网膜以及导致视力下降的视网膜血管渗漏所有这些病理都与血管功能障碍有关，并且可能受到多种促炎和促血管生成信号的影响，例如 IL-1ß、TNFa、DAMP、VEGF 和 WNT。药理标准护理可改善不到一半患者群体的视力，这种疗效通常归因于 VEGF 和其他 DR 相关致病因素之间的功能冗余。需要一种能够阻断多种 DR 相关信号通路的药物我们未发表的数据还表明，激活的 ARF6 在内皮细胞和 WNT 中的 IL-1ß、TNFa 和 VEGF 信号传导中发挥着关键作用这些结果表明，ARF6 是许多 DR 相关炎症、血管生成和 WNT 通路的汇聚点，并且是 DR 病理进展的关键参与者，因此我们寻求抑制 ARF6 激活将降低血管通透性和为了检验这一假设，我们将追求两个目标：在目标 1 中，我们将确定 Arf6 的内皮表达是否是发育和/或进展所必需的。通过使用氧诱导的视网膜病变（OIR）和链脲佐菌素（STZ）诱导的糖尿病小鼠模型评估内皮特异性Arf6敲除小鼠的病理反应，我们还将确定该遗传模型的结果是否与野生型小鼠相似。在目标 2 中，我们将研究 ARF6 的激活在控制方面的普遍性。 DR 相关的病理信号通路也将定义激活的 ARF6 控制内皮细胞通透性或迁移的机制，如果我们的假设正确，ARF6 将成为治疗 DR 的理想分子靶点，因为它可能克服许多困难。我们将确定激活的 ARF6 在其他视网膜细胞类型中的作用，并将我们的研究扩展到其他血管性眼部疾病。