Fatty Acid Binding Protein and Pathological Retinal Vascularization

脂肪酸结合蛋白与病理性视网膜血管化

• 批准号: 8318581
• 负责人: SULE CATALTEPE
• 金额: $ 22.46万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-01 至 2014-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8318581
• 关键词: Adenoviruses; Adipocytes; Adult; Age; Anti-Inflammatory Agents; Anti-inflammatory; Area; Atherosclerosis; Attenuated; Binding; Biological; Blindness; Child; Complex; Control Groups; Data; Development; Diabetic Retinopathy; Diabetic mouse; Disease; Endothelial Cells; Exhibits; Family; Fatty Liver; Gene Expression; Genetic; Glucose; Goals; Homeostasis; Human; Hypoxia; Inflammatory; Insulin Resistance; Intervention Studies; Knockout Mice; Ligands; Lipids; Liver diseases; Maintenance; Mediating; Messenger RNA; Metabolic syndrome; Modeling; Molecular Chaperones; Mus; Normal tissue morphology; Nuclear; Obesity; Oxygen; Pathologic Neovascularization; Pathway interactions; Pattern; Play; Preparation; Preventive; Process; Property; Regulation; Retinal; Retinal Diseases; Retinal Neovascularization; Retinopathy of Prematurity; Role; Sampling; Sirolimus; Stimulus; Therapeutic; Umbilical vein; United States; Vascular Endothelial Growth Factor Receptor-2; Vascular Endothelial Growth Factors; Vascularization; Work; abstracting; angiogenesis; base; fatty acid-binding proteins; human FABP4 protein; human FRAP1 protein; improved; inhibitor/antagonist; insight; mTOR protein; macrophage; member; migration; mouse model; neovascular; neovascularization; new therapeutic target; novel; novel therapeutics; postnatal; prevent; protective effect; retinal angiogenesis; small molecule; transcription factor

Abstract Retinopathy of prematurity (ROP) and diabetic retinopathy (DR) are the two leading causes of blindness in children and working-age adults, respectively. Both of these devastating conditions are characterized by pathological retinal angiogenesis that is preceded by a hypoxic stimulus. Fatty Acid Binding Protein 4 (FABP4) is an intracellular lipid chaperone that reversibly binds hydrophobic ligands. FABP4 plays a critical role in maintenance of glucose and lipid homeostasis. The biologic relevance of FABP4 is underscored by the findings that FABP4 knock-out (FABP4-/-) mice exhibit marked protection against insulin resistance, atherosclerosis and fatty liver disease. Although FABP4 was initially thought to be primarily expressed in adipocytes and macrophages, we recently made a novel observation that FABP4 is also expressed in certain endothelial cells (ECs) in normal tissues. The role of FABP4 in ECs is not known, but our recent studies strongly suggest a pro-angiogenic role. To begin to investigate the potential role of FABP4 in pathological retinal angiogenesis, we first characterized the expression pattern of FABP4 mRNA in a mouse model of oxygen-induced-retinopathy (OIR) and found that FABP4 mRNA levels are significantly increased in the OIR group compared to the control group at postnatal day (P) 15. To examine this hypothesis further, we exposed FABP4-/- mice to the OIR model and found that FABP4-/- mice are significantly protected against pathological retinal angiogenesis. Furthermore, FABP4 expression was localized to ECs in neovascular tufts, but not to those in adjacent non-pathological vessels on flat-mount preparations of P17-OIR samples. Based on these novel data, we hypothesize that FABP4 plays a critical role in enhancing the pathological retinal neovascularization in OIR by promoting EC activation and angiogenesis. The specific aims (SA) of this proposal are to: (1) determine the mechanisms by which FABP4 deficiency protects against pathological neo-vascularization in the OIR model; and (2) assess the ability of a small-molecule inhibitor of FABP4 to prevent and treat pathological angiogenesis in the mouse model of OIR. These studies have the potential to identify FABP4 as a novel therapeutic target in proliferative retinopathies.

抽象的 早产儿视网膜病变（ROP）和糖尿病视网膜病变（DR）是导致失明的两个主要原因 分别针对儿童和工作年龄的成年人。这两种破坏性条件的特点是 由缺氧刺激之前的病理性视网膜血管生成引起。脂肪酸结合蛋白4 (FABP4) 是一种细胞内脂质伴侣，可可逆地结合疏水性配体。 FABP4 扮演 在维持葡萄糖和脂质稳态中发挥关键作用。 FABP4 的生物学相关性是 研究结果强调了 FABP4 敲除 (FABP4-/-) 小鼠表现出显着的保护作用 胰岛素抵抗、动脉粥样硬化和脂肪肝疾病。尽管 FABP4 最初被认为是 主要在脂肪细胞和巨噬细胞中表达，我们最近做了一个新的观察，FABP4 也在正常组织的某些内皮细胞 (EC) 中表达。 FABP4 在 EC 中的作用并不 已知，但我们最近的研究强烈表明其具有促血管生成作用。开始调查 为了了解 FABP4 在病理性视网膜血管生成中的潜在作用，我们首先表征了表达模式 在氧诱导视网膜病变 (OIR) 小鼠模型中检测 FABP4 mRNA，发现 FABP4 mRNA 与对照组相比，OIR 组在出生后第 15 天 (P) 的水平显着升高。 为了进一步检验这一假设，我们将 FABP4-/- 小鼠暴露于 OIR 模型，发现 FABP4-/- 小鼠显着免受病理性视网膜血管生成的影响。此外，FABP4 表达定位于新生血管簇中的 EC，但不定位于邻近非病理性簇中的 EC。 P17-OIR 样品的平装制备容器。根据这些新数据，我们假设 FABP4 通过促进 OIR 中的病理性视网膜新生血管形成，在增强病理性视网膜新生血管形成中发挥关键作用。 EC 激活和血管生成。该提案的具体目标（SA）是：（1）确定 FABP4 缺陷防止 OIR 病理性新生血管形成的机制 模型; (2)评估FABP4小分子抑制剂预防和治疗病理性病变的能力 OIR 小鼠模型中的血管生成。这些研究有可能将 FABP4 确定为一种新型的 增殖性视网膜病的治疗靶点。