Sex dependent regulation of retinal degeneration

总结： 视网膜脱离（RD），由损伤或视网膜疾病（如年龄相关性黄斑变性）引起 和糖尿病性视网膜病）是视网膜变性和视力丧失的主要原因。在持续性 RD，由于感光细胞死亡导致的进行性视力下降是常见的，并导致显著降低 视觉敏锐度。然而，在这种情况下，控制感光细胞死亡的潜在生物学过程 背景还没有得到很好的理解，目前除了手术重新连接视网膜外，没有治疗方法。 RD过程中的细胞死亡被认为是由光感受器及其受体之间的物理分离引起的。 氧气和营养的主要来源，导致严重的局部缺血和代谢窘迫。我们的初步 有证据表明患有RD的雄性小鼠的感光细胞死亡显著增加 与女性同行相比，此外，我们已经确定雌激素是一种关键的调节剂， 光感受器对RD损伤的敏感性。重要的是，在许多脑退行性疾病中，雌激素发挥其 神经保护作用通过改善线粒体功能和减少氧化损伤。 因此，本研究的目的是检验雌性动物免受RD诱导的 通过雌激素依赖性正常化和/或光感受器拯救作用的视网膜变性 代谢功能障碍我们将利用一种定义明确的RD小鼠模型，其中视网膜下注射 透明质酸钠用于产生脱离。小鼠RD模型将使我们能够利用 在受控环境中，在小鼠中建立良好的遗传操作平台。为了描述这个角色 性和雌激素信号系统在感光细胞死亡，我们将：1）定义如何雌激素信号 使用遗传模型和性腺切除术在体内进行调节，以精确描绘信号通路， 参与雌激素依赖性光感受器变性的拯救的代谢过程; 2）阐明 雌激素在缓解RD引起的光感受器线粒体应激和氧化损伤中的作用; 3)勾画出性生活中涉及的具体代谢途径、关键代谢物和线粒体功能 RD中细胞死亡的依赖性调节。我们相信，这项研究将有助于深入了解 雌激素在视网膜神经保护中作用并提供新的性别特异性治疗靶点和/或治疗方法 管理威胁视力的疾病（如RD）的模式。

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.