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: 8697839
• 负责人: EDWARD P FEENER
• 金额: $ 41.44万
• 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/8697839
• 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; 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; public health relevance; 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。糖尿病视网膜病变（包括糖尿病黄斑水肿（DME））进展到威胁视力的阶段通常与潜在视网膜血管功能障碍和疾病的恶化有关，包括视网膜出血数量和严重程度的增加。最近的临床进展表明，玻璃体内注射抗 VEGF 定向疗法可有效提高 DME 的视力和解决黄斑水肿，FDA 最近批准玻璃体内注射雷珠单抗治疗 DME。虽然这种治疗对于许多 DME 患者非常有效，但几项大型临床研究表明，约 40% 至 50% 的研究对象出现屈光，或者对抗 VEGF 定向疗法在视力改善和视网膜增厚消退方面没有完全反应。这些临床结果表明，VEGF 独立机制也可能导致大量 DME 患者出现视网膜水肿。在最近的报告和其他初步数据中，我们表明 DME 患者玻璃体内血浆激肽释放酶 (Pkal)、因子 FXII 和激肽原增加。我们还表明，玻璃体中的 Pkal 水平与 VEGF 水平不相关，揭示了 DME 患者分子异质性的一个组成部分。通过基因敲除和药理学方法，我们发现 Pkal 会导致啮齿类动物视网膜血管通透性过高和视网膜增厚，并且我们已经开始表征导致这种反应的缓激肽依赖性和非依赖性机制。我们的研究表明，糖尿病会增加 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会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，我们还使用蛋白质组学来表征缓激肽诱导的视网膜水肿，并鉴定了一组血浆蛋白，它们在视网膜水肿中急剧增加，同时视网膜中间丝蛋白的子集显着减少。这笔资助将确定 PK 诱导的导致视网膜血管通透性过高和视网膜增厚的机制，并检验 Pkal-缓激肽系统是导致 DME 的视网膜功能障碍的 VEGF 独立介质的假设。具体目标是 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独立作用，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。