Sex dependent regulation of retinal degeneration

摘要： 视网膜脱离(RD)，由损伤或视网膜疾病(如老年性黄斑变性)引起 和糖尿病视网膜病变)，是视网膜退化和视力丧失的主要原因。在持续的患者中 由于光感受器细胞死亡导致的进行性视力下降是常见的，并导致显著的下降 在视觉敏锐度。然而，控制光感受器细胞死亡的潜在生物学过程 目前还不清楚情况，目前除了手术重新连接视网膜外，还没有其他治疗方法。 细胞在RD期间的死亡被认为是由于光感受器和它们之间的物理分离引起的 主要的氧气和营养来源，导致严重的缺血和代谢困难。我们的预赛 有证据表明，患有RD的雄性小鼠的光感受器细胞死亡显著增加。 与她们的女性同龄人相比。此外，我们已经确定雌激素是一种关键的调节因子。 感光细胞对RD损伤的敏感性。重要的是，在许多大脑退行性疾病中，雌激素发挥其 通过改善线粒体功能和减少氧化损伤来发挥神经保护作用。 因此，这项研究的目标是检验这样一种假设，即女性受到保护，不受RD诱导的影响 雌激素依赖的光感受器正常化和/或修复导致的视网膜变性 代谢功能障碍。我们将利用一种定义明确的RD小鼠模型，在该模型中，视网膜下注射 透明质酸钠是用来制造脱离的。鼠标研发模型将使我们能够利用 在受控环境中建立良好的小鼠遗传操作平台。为了刻画角色的特征 关于光感受器细胞死亡中的性别和雌激素信号系统，我们将：1)定义雌激素信号 在体内使用遗传模型和性腺切除来精确描述信号通路和 代谢过程参与雌激素依赖的光感受器变性的挽救；2)阐明 雌激素在减轻RD反应中光感受器线粒体应激和氧化损伤中的作用； 3)描述与性行为有关的特定代谢途径、关键代谢物和线粒体功能 RD细胞死亡的依赖性调控。我们相信，这项研究将对 雌激素在视网膜神经保护中的作用和提供新的性别特异性治疗靶点和/或治疗 管理诸如RD等威胁视力的疾病的方式。

Summary: Retinal detachment (RD), caused by injury or retinal disorders (e.g. age-related macular degeneration and diabetic retinopathy), is a leading cause of retinal degeneration and vision loss. In patients with sustained RD, progressive visual decline due to photoreceptor cell death is common and leads to a significant decrease in visual acuity. However, the underlying biological processes controlling photoreceptor cell death in this context are not well understood and currently no treatments exist, aside from surgery to reattach the retina. Cell death during RD is thought to be caused by the physical separation between the photoreceptors and their primary source of oxygen and nutrients resulting in severe ischemia and metabolic distress. Our preliminary evidence has demonstrated that male mice with a RD have a significant increase in photoreceptor cell death compared to their female counterparts. Moreover, we have identified estrogen as a key modulator of photoreceptor susceptibility to RD injury. Importantly, in many brain degenerative diseases, estrogen exerts its neuroprotective actions by improving mitochondrial function and reducing oxidative damage. The goal of this study therefore is to test the hypothesis that females are protected from RD-induced retinal degeneration through the actions of estrogen-dependent normalization and/or rescue of photoreceptor metabolic dysfunction. We will utilize a well-defined mouse model of RD, in which a subretinal injection of sodium hyaluronate is used to create a detachment. The mouse RD model will allow us to take advantage of well-established genetic manipulation platforms in mice in a controlled setting. In order to characterize the role of sex and the estrogen signaling system in photoreceptor cell death we will: 1) Define how estrogen signaling is modulated in vivo using genetic models and gonadectomy to precisely delineate the signaling pathways and metabolic processes involved in estrogen-dependent rescue of photoreceptor degeneration; 2) Elucidate the role of estrogen in alleviating mitochondrial stress and oxidative damage in photoreceptors in response to RD; 3) Delineate the specific metabolic pathways, key metabolites and mitochondrial functions involved in the sex dependent regulation of cell death in RD. It is our belief that this study will yield insights into the role of estrogen in retinal neuroprotection and provide new sex-specific therapeutic targets and or treatment modalities for the management of sight-threatening diseases such as RD.