Mechanisms of retinal neuronal injury

描述（由申请人提供）：视网膜神经元死亡是许多视力威胁疾病的常见病理特征，如糖尿病视网膜病变、视网膜血管闭塞、青光眼、外伤性视神经病变等。这些疾病会导致失明，损害患者的生活质量，并给我们的医疗保健系统带来压力。视网膜神经元损伤是这些疾病的共同病理特征。本研究旨在描述视网膜病变期间神经元损伤的常见机制，并确定限制损伤和保护视力的新策略。我们将使用不同的视网膜神经元损伤模型来验证我们的新假设，即内质网（ER）应激诱导的CXCL10表达在视网膜病变期间由cxcr3介导的炎症反应和诱导氧化应激引起的视网膜神经元损伤中起关键作用。我们将使用遗传学和药理学方法来解决以下具体目标：1)确定内质网应激在视网膜病变期间增加CXCL10表达和视网膜神经元损伤中的作用。2)探讨CXCL10/CXCR3在视网膜病变视网膜神经元损伤中的作用。3)评价通过内质网应激或CXCR3阻断神经保护的治疗效果。本研究结果将为视网膜神经元损伤提供新的共同机制，并可用于视网膜病变的临床实践。

DESCRIPTION (provided by applicant): Retinal neuronal death is a common pathological feature of many vision threatening diseases, such as diabetic retinopathy, retinal vascular occlusion, glaucoma, traumatic optic neuropathy, and others. These diseases can cause blindness, impair patients' quality of life, and stress our health care system. Retinal neuronal injury is a common pathological feature of these diseases. This study is to delineate the common mechanisms of neuronal injury during retinopathy and identify novel strategies to limit injury and preserve vision. We will use different models of retinal neuronal injury to test our novel hypothesis that endoplasmic reticulum (ER) stress- induced expression of CXCL10 has a key role in retinal neuronal damage due to CXCR3-mediated inflammatory reactions and induction of oxidative stress during retinopathy. We will use genetic and pharmacological approaches to address the following specific aims: 1) Determine the role of ER stress in increasing CXCL10 expression and retinal neuronal injury during retinopathy. 2) Investigate the role of CXCL10/CXCR3 in retinal neuronal injury during retinopathy. 3) Evaluate therapeutic benefits of neuroprotection by pharmacological blockade of ER stress or CXCR3. Outcomes from this study will provide novel common mechanisms of retinal neuronal injury and may be readily put into clinical practice for retinopathy. PUBLIC HEALTH RELEVANCE: ER stress is involved in tissue injury and CXCR3 is a chemokine receptor which has an essential role in inflammation, cell death, and anti-angiogenesis. This project is designed to understand whether and how ER- stress-induced activation of CXCR3 is involved in retinal neuronal injury in retinopathy and to investigate the therapeutic benefit by blocking ER stress and CXCR3.