ER stress and diabetic retinopathy

摘要： 糖尿病视网膜病变是糖尿病常见的并发症，以进行性神经血管损伤为特征 以及随之而来的视网膜功能恶化。目前还没有治疗方法可以有效地保护 视网膜神经元，从而减轻或逆转糖尿病患者的视觉功能障碍。开发这样 治疗是该领域的迫切和未满足的需求。在上一个融资期，我们确定X-box 结合蛋白1（XBP 1）是一种应激诱导的转录因子，在视网膜细胞对应激的适应中起着重要作用。 衰老和糖尿病的慢性压力源。视网膜中XBP 1的条件性敲除（cKO）导致视网膜中的加速生长。 视网膜功能下降，视网膜神经元丢失，突触破坏和异常的小胶质细胞激活， 视网膜老化。重要的是，我们发现，在老化的视网膜中，XBP 1的表达逐渐减少， 降低了响应内质网（ER）应激的XBP 1活化。我们推断， XBP 1损害视网膜细胞适应衰老中慢性应激的能力，最终导致神经元损伤。 损害我们测试了XBP 1是否参与糖尿病慢性应激的神经适应。我们发现 XBP 1的缺失导致早发性视网膜功能下降、神经元缺失和增强的Müller胶质细胞活化 在糖尿病小鼠中。基于这些发现，我们假设，XBP 1介导的应激反应信号是 对于在自然发生或致病的条件下维持视网膜神经元的功能和结构完整性至关重要 慢性压力条件下，从而防止糖尿病和衰老中的神经变性。当前 应用中，我们将描述如何XBP 1调节视网膜神经元适应糖尿病代谢应激。在 特别是，我们将探讨XBP 1通过调节有氧代谢来保护视网膜神经元的机制。 光感受器细胞中的糖酵解。利用vis-OCT视网膜成像的创新技术， 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）的最早变化 糖尿病视网膜的丧失。我们还将测量视网膜氧代谢率的精确变化， 糖尿病视网膜神经元代谢谱的综合表征。深入的信息 从拟议的研究中产生的将填补知识空白，了解有氧糖酵解的作用， 及其在糖尿病视网膜神经病变中的调节作用。此外，我们的研究，以确定新的分子， 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治疗铺平道路 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.