Role of the kallikrein-kinin system in diabetic retinopathy

激肽释放酶-激肽系统在糖尿病视网膜病变中的作用

• 批准号: 8827344
• 负责人: EDWARD P FEENER
• 金额: $ 40.55万
• 依托单位: JOSLIN DIABETES CENTER
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-01 至 2018-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8827344
• 关键词: Animal Model; Area; Autologous; BDKRB2 gene; Blindness; Blood; Blood Vessels; Bradykinin; Bradykinin Receptor; Calpain; Clinical; Clinical Research; Coupled; Data; Developed Countries; Diabetes Mellitus; Diabetic Retinopathy; Diabetic mouse; Disease; Edema; Electroretinography; Employee Strikes; Enzymes; Etiology; Experimental Models; Extravasation; Functional disorder; Grant; Health; Hemorrhage; Heterogeneity; Human; Hypoxia; Impairment; Inflammation; Injury; Intermediate Filament Proteins; Intermediate Filaments; Kallikrein-Kinin System; Kininogenase; Kininogens; Knock-out; Knockout Mice; Lead; Liquid substance; Mass Spectrum Analysis; Mediating; Mediator of activation protein; Medicine; Molecular; Mus; Names; Nature; Nitric Oxide Synthase; Optical Coherence Tomography; Pathway interactions; Patients; Perfusion; Physiological Processes; Plasma; Plasma Kallikrein; Plasma Proteins; Prostate-Specific Antigen; Proteins; Proteome; Proteomics; Regulation; Relative (related person); Reporting; Resolution; Retina; Retinal; Retinal Edemas; Retinal Hemorrhage; Rodent; Rodent Model; Role; Sampling; Severities; Site; Staging; Study Subject; System; Translations; Vascular Diseases; Vascular Endothelial Growth Factors; Vascular Permeabilities; Vision; Visual Acuity; Visual impairment; Vitreous Hemorrhage; base; bevacizumab; cohort; diabetic; effective therapy; improved; intravitreal injection; knockout animal; macular edema; neovascularization; ranibizumab; research study; response; screening; standard of care

DESCRIPTION (provided by applicant): Diabetic retinopathy is a leading cause of vision loss in developed countries. Progression to sight threatening stages of diabetic retinopathy, including diabetic macular edema (DME), is usually associated with worsening of underlying retinal vascular dysfunction and disease, including an increase in the number and severity of retinal hemorrhages. Recent clinical advances have demonstrated that intravitreal injection of anti-VEGF directed therapies are effective in improving visual acuity and resolving macular edema in DME, and the FDA has recently approved intravitreal injection of ranibizumab for DME. While this treatment is highly effective for many patients with DME, several large clinical studies have revealed that about 40 to 50% of study subjects appear refractive or do not fully respond in the improvement of visual acuity and the resolution of retinal thickening to anti-VEGF directed therapies. These clinical findings suggest that VEGF-independent mechanisms might also contribute to retinal edema in a large number of DME patients. In recent reports and additional preliminary data, we show that plasma kallikrein (Pkal), factor FXII, and kininogen are increased in the vitreous of patients with DME. We also show that Pkal levels in the vitreous do not correlate with VEGF levels, revealing a component of molecular heterogeneity among DME patients. Using both knockout and pharmacological approaches, we show that Pkal contributes to retinal vascular hyperpermeability and retinal thickening in rodents and we have begun to characterize both bradykinin-dependent and -independent mechanisms that contribute to this response. Our studies have revealed that diabetes increases the effects of Pkal on vascular dysfunction and retinal edema (Clermont et al Diabetes 2011, Liu et al Nature Medicine 2011). We have also recently shown that autologous blood introduced into the vitreous increases retinal inflammation and retinal vascular permeability (Liu et al IOVS 2013) and the kallikrein system is as potent as VEGF in inducing retinal thickening. In addition we have used proteomics to characterize bradykinin-induced retinal edema and have identified a set of plasma proteins that are robustly increased in retinal edema coupled with striking decreases in a subset of retinal intermediate filament proteins. This grant will identify the PK- induced mechanisms that cause retinal vascular hyperpermeability and retinal thickening, and examine the hypothesis that the Pkal-bradykinin system is a VEGF-independent mediator of retinal dysfunction that contributes to DME. The specific aims are 1) to characterize and compare the bradykinin receptor-dependent and independent effects of Pkal on retinal edema in diabetic mice, 2) to compare Pkal and VEGF-induced retinal edema and investigate interactions between these pathways, and 3) characterize the roles of nitric oxide synthase and calpain-mediated intermediate filament degradation/remodeling in retina edema. Further identification of the mechanism of action and regulation of the plasma kallikrein system in the retina will be helpful in evaluating potential clinical opportunities for targeting the Pkal system for the treatment of DME.

描述（由申请人提供）：糖尿病视网膜病变是发达国家视力丧失的主要原因。进展至糖尿病视网膜病变的视力威胁阶段，包括糖尿病黄斑水肿（DME），通常与潜在的视网膜血管功能障碍和疾病的恶化相关，包括视网膜病变的数量和严重程度增加。最近的临床进展已经证明，玻璃体内注射抗VEGF定向疗法在改善DME中的视力和解决黄斑水肿方面是有效的，并且FDA最近已经批准玻璃体内注射雷珠单抗用于DME。虽然这种治疗对许多DME患者非常有效，但几项大型临床研究表明，约40 - 50%的研究受试者出现屈光或在视力改善和视网膜增厚消退方面对抗VEGF定向治疗没有完全反应。这些临床研究结果表明，VEGF非依赖性机制也可能有助于视网膜水肿在大量的DME患者。在最近的报告和额外的初步数据，我们表明，血浆激肽释放酶（Pkal），因子FXII，激肽原增加的DME患者的玻璃体。我们还发现玻璃体中的Pkal水平与VEGF水平无关，揭示了DME患者分子异质性的一个组成部分。使用基因敲除和药理学方法，我们表明，Pkal有助于视网膜血管通透性过高和视网膜增厚的啮齿动物，我们已经开始表征缓激肽依赖和独立的机制，有助于这种反应。我们的研究表明，糖尿病增加了Pkal对血管功能障碍和视网膜水肿的影响（Clermont et al Diabetes 2011，Liu et al Nature Medicine 2011）。我们最近还表明，引入玻璃体的自体血液增加视网膜炎症和视网膜血管通透性（Liu et al IOVS 2013），并且激肽释放酶系统在诱导视网膜增厚方面与VEGF一样有效。此外，我们已经使用蛋白质组学来表征缓激肽诱导的视网膜水肿，并确定了一组血浆蛋白，这些蛋白在视网膜水肿中强烈增加，同时视网膜中间丝蛋白的子集显著减少。这项资助将确定导致视网膜血管通透性过高和视网膜增厚的PK诱导机制，并检查Pkal-缓激肽系统是导致DME的视网膜功能障碍的VEGF非依赖性介导物的假设。具体目的是：1）表征和比较Pkal对糖尿病小鼠视网膜水肿的缓激肽受体依赖性和非依赖性作用，2）比较Pkal和VEGF诱导的视网膜水肿并研究这些途径之间的相互作用，3）表征一氧化氮合酶和钙蛋白酶介导的中间丝降解/重塑在视网膜水肿中的作用。进一步鉴定视网膜中血浆激肽释放酶系统的作用和调节机制将有助于 评估针对Pkal系统治疗DME的潜在临床机会。