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）：糖尿病性视网膜病是发达国家视力丧失的主要原因。糖尿病性视网膜病变的视力威胁阶段，包括糖尿病性黄斑水肿（DME），通常与潜在的视网膜血管功能障碍和疾病的恶化有关，包括视网膜出血的数量和严重程度增加。最近的临床进展表明，玻璃体内注射抗VEGF的定向疗法可有效改善DME的视力和解决黄斑水肿，而FDA最近批准了玻璃体内注射Ranibizumab的DME。尽管这种治疗对许多DME患者非常有效，但一些大型临床研究表明，大约40％至50％的研究受试者似乎屈光不清，或者在改善视力和视网膜增厚对抗VEGF的有指示疗法方面没有完全反应。这些临床发现表明，与VEGF无关的机制也可能导致大量DME患者的视网膜水肿。在最近的报告和其他初步数据中，我们表明血浆kallikrein（PKAL），FXII因子和差异因素因DME患者的玻璃体增加而增加。我们还表明，玻璃体中的PKAL水平与VEGF水平不相关，这表明DME患者的分子异质性的成分。使用敲除和药理学方法，我们表明PKAL有助于视网膜血管过敏性和啮齿动物的视网膜增厚，并且我们已经开始表征依赖性基金蛋白依赖性和独立的机制，这些机制有助于这种反应。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等人糖尿病2011； Liu等人自然医学2011）。我们最近还表明，引入玻璃体的自体血会增加视网膜炎症和视网膜血管通透性（Liu等人IOV，2013），而Kallikrein系统与VEGF诱导视网膜增厚一样有效。此外，我们还使用蛋白质组学来表征心动激肽诱导的视网膜水肿，并确定了一组血浆蛋白质，这些等离子体蛋白质在视网膜水肿中稳健地增加，并在视网膜中间丝质蛋白的一部分中降低了醒目的降低。该赠款将确定引起视网膜血管过敏性和视网膜增厚的PK诱导的机制，并检查假设PKAL-BRADYKILIN系统是造成DME的视网膜功能障碍的独立于VEGF的视网膜功能障碍介质。具体目的是1）表征和比较糖尿病小鼠中PKAL对视网膜水肿的黑头阳极受体依赖性和独立的影响，2）比较PKAL和VEGF诱导的视网膜水肿，并研究这些途径的相互作用，并研究这些途径之间的相互作用，以及3）表征一氧化物氧化物合酶和calpain介导的介导的作用。进一步识别视网膜等离子体Kallikrein系统的作用机理和调节机制将有所帮助 评估针对PKAL系统治疗DME的潜在临床机会。