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.

摘要 早产儿视网膜病变（ROP）和糖尿病视网膜病变（DR）是导致失明的两大主要原因 在儿童和工作年龄的成年人，分别。这两种毁灭性的情况都有其特点， 病理性视网膜血管生成，这是由缺氧刺激引起的。脂肪酸结合蛋白4 （FABP 4）是可逆结合疏水配体的细胞内脂质伴侣。FABP 4扮演着 在维持葡萄糖和脂质稳态中起关键作用。FABP 4的生物学相关性是 FABP 4基因敲除（FABP 4-/-）小鼠表现出明显的保护作用， 胰岛素抵抗、动脉粥样硬化和脂肪肝。虽然FABP 4最初被认为是 FABP 4主要在脂肪细胞和巨噬细胞中表达，我们最近进行了一项新的观察， 也在正常组织中的某些内皮细胞（EC）中表达。FABP 4在EC中的作用不是 已知的，但我们最近的研究强烈表明促血管生成的作用。开始调查 FABP 4在病理性视网膜血管生成中的潜在作用，我们首先描述了其表达模式 FABP 4 mRNA在氧诱导视网膜病变（OIR）小鼠模型中的表达，发现FABP 4 mRNA 在出生后第15天（P），OIR组中的水平与对照组相比显著增加。 为了进一步检验这一假设，我们将FABP 4-/-小鼠暴露于OIR模型，发现FABP 4-/-小鼠在OIR模型中的表达增加。 小鼠被显著保护免于病理性视网膜血管生成。此外，FABP 4 表达定位于新生血管丛中的EC，但不表达于邻近的非病理性 P17-OIR样品的平板制备物上的容器。基于这些新的数据，我们假设， FABP 4通过促进OIR中的病理性视网膜新生血管形成而在增强OIR中的病理性视网膜新生血管形成中起关键作用。 EC活化和血管生成。该提案的具体目标是：（1）确定 FABP 4缺陷保护OIR中病理性新血管形成的机制 （2）评估FABP 4的小分子抑制剂预防和治疗病理性炎症的能力 这些研究有可能将FABP 4鉴定为一种新的血管生成抑制剂。 增殖性视网膜病变的治疗靶点。