ER stress and diabetic retinopathy

摘要： 糖尿病视网膜病变是以进行性神经血管损伤为特征的糖尿病的常见并发症。 以及由此导致的视网膜功能恶化。目前还没有一种治疗方法可以有效地保护 从而减轻或逆转糖尿病患者的视觉功能障碍。开发这样的产品 治疗是该领域一项迫切而未得到满足的需求。在上一个资助期，我们确定了X-box 结合蛋白1(XBP1)是一种应激诱导的转录因子，在视网膜细胞适应 衰老和糖尿病的慢性应激源。视网膜中XBP1的条件性敲除(CKO)导致加速 视网膜功能下降，视网膜神经元丢失，突触破裂，小胶质细胞异常激活 视网膜随着年龄的增长。重要的是，我们发现XBP1在老化的视网膜中的表达逐渐减少，并且 XBP1对内质网(ER)应激的激活减少。我们的理由是，失去 XBP1削弱视网膜细胞在衰老过程中适应慢性应激的能力，最终导致神经细胞 损坏。我们测试了XBP1是否参与了糖尿病患者对慢性应激的神经元适应。我们发现 XBP1的缺失会导致早发性视网膜功能衰退、神经元丢失和Müler神经胶质细胞激活增强 在糖尿病小鼠身上。基于这些发现，我们假设XBP1介导的应激反应信号是 在自然发生或致病状态下维持视网膜神经元功能和结构完整性的关键 因此，慢性应激状态可以防止糖尿病和衰老中的神经退化。在当前 应用，我们将描述XBP1如何调节糖尿病患者视网膜神经元对代谢应激的适应。在……里面 特别是，我们将探索XBP1通过调节有氧代谢来保护视网膜神经元的机制 光感受器细胞的糖酵解。利用VIS-OCT的创新技术进行视网膜成像， 我们将在任何可检测到的视网膜神经节细胞之前确定视网膜神经纤维层(RNFL)最早的变化 糖尿病视网膜丢失。我们还将测量视网膜氧代谢率的精确变化 糖尿病患者视网膜神经元代谢特征的综合表征。深入的信息 由拟议的研究产生的数据将填补了解有氧糖酵解作用的知识空白 以及XBP1对糖尿病视网膜神经病变的调节作用。此外，我们的研究旨在识别新的分子 调节视网膜神经元代谢将为保护糖尿病患者视网膜神经元的新疗法铺平道路 视网膜病变。

Abstract: Diabetic retinopathy is a common complication of diabetes characterized by progressive neurovascular injury and the consequent retinal function deterioration. Currently there are no therapies that can effectively protect retinal neurons, and thereby mitigate, or reverse, the visual dysfunction in diabetic patients. Developing such therapies is an urgent and unmet need for the field. In the previous funding period, we identified that X-box binding protein 1 (XBP1), a stress-inducible transcription factor, plays a central role in retinal cell adaptation to chronic stressors in aging and diabetes. Conditional knockout (cKO) of XBP1 in the retina results in accelerated retinal function decline, loss of retinal neurons, disruption of synapses, and aberrant microglia activation in the retina with aging. Importantly, we found that XBP1 expression in the aging retina is gradually decreased and activation of XBP1 in response to endoplasmic reticulum (ER) stress is reduced. We reasoned that the loss of XBP1 impairs the ability of retinal cells to adapt to chronic stresses in aging, ultimately leading to neuronal damage. We tested whether XBP1 is involved in neuronal adaptation to chronic stresses in diabetes. We found that loss of XBP1 leads to early onset retinal function decline, neuronal loss, and enhanced Müller glia activation in diabetic mice. Based on these findings, we hypothesize that XBP1-mediated stress response signaling is crucial to maintaining functional and structural integrity of retinal neurons under naturally occurring or pathogenic chronic stress conditions, thus, protecting against neurodegeneration in diabetes and aging. In current application, we will delineate how XBP1 regulates retinal neuronal adaptation to metabolic stress in diabetes. In particular, we will explore the mechanisms by which XBP1 protects retinal neurons through regulation of aerobic glycolysis in photoreceptor cells. Taking advantage of the innovative technology of vis-OCT for retinal imaging, we will identify the earliest change in retinal nerve fiber layer (RNFL) before any detectable retinal ganglion cell loss in diabetic retinas. We will also measure the precise change of retinal metabolic rate of oxygen for a comprehensive characterization of metabolic profiling of retinal neurons in diabetes. The in-depth information generated from the proposed studies will fill the knowledge gap in understanding the role of aerobic glycolysis and its regulation by XBP1 in retinal neuropathy in diabetes. In addition, our study to identify novel molecules that regulate retinal neuronal metabolism will pave the way for new treatment to protect retinal neurons in diabetic retinopathy.