Sex dependent regulation of retinal degeneration

视网膜变性的性别依赖性调节

• 批准号: 10132334
• 负责人: Gopalan Gnanaguru
• 金额: $ 44.5万
• 依托单位: MASSACHUSETTS EYE AND EAR INFIRMARY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-04-01 至 2023-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10132334
• 关键词: Acute; Address; Affect; Age related macular degeneration; Anaerobic Bacteria; Animals; Belief; Biogenesis; Biological Process; Biology; Blindness; Brain; Brain Diseases; Cell Death; Clinical; Clinical Management; Complication; Data; Degenerative Disorder; Development; Diabetic Retinopathy; Disease; Disease Progression; Distress; Energy Metabolism; Estrogen Receptors; Estrogens; Eye Neoplasms; Female; Foundations; Genetic Models; Goals; Gonadal Steroid Hormones; Health; Hour; Injury; Ischemia; Knockout Mice; Light; Link; Mediating; Metabolic; Metabolic Pathway; Metabolic dysfunction; Metabolism; Mitochondria; Modality; Modeling; Molecular; Mus; Nerve Degeneration; Neuraxis; Neurodegenerative Disorders; Nutrient; Operative Surgical Procedures; Oxygen; Pathologic; Pathway interactions; Patients; Photoreceptors; Predisposition; Production; Proteomics; Reactive Oxygen Species; Regulation; Research; Retina; Retinal Degeneration; Retinal Detachment; Retinal Diseases; Retinopathy of Prematurity; Risk; Role; Sampling; Sex Differences; Signal Pathway; Signal Transduction; Sodium Hyaluronate; Source; Stress; Structure of retinal pigment epithelium; System; Testing; Therapeutic; Vision; Visual; Visual Acuity; Visual impairment; Wild Type Mouse; Work; anaerobic glycolysis; base; epidemiology study; experimental study; extracellular; genetic manipulation; human disease; improved; in vivo; insight; male; metabolomics; mitochondrial dysfunction; mouse model; neuroprotection; oxidative damage; photoreceptor degeneration; physical separation; primary outcome; respiratory; response; screening; sex; sexual dimorphism; subretinal injection; therapeutic target

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.

概括： 视网膜脱离 (RD)，由损伤或视网膜疾病（例如年龄相关性黄斑变性）引起 和糖尿病视网膜病变），是视网膜变性和视力丧失的主要原因。对于持续的患者 RD，由于感光细胞死亡导致的进行性视力下降很常见，并导致视力显着下降 在视力方面。然而，控制感光细胞死亡的潜在生物过程 背景尚不清楚，除了重新连接视网膜的手术外，目前尚无治疗方法。 RD 期间的细胞死亡被认为是由光感受器与其周围的物理分离引起的。 氧气和营养物质的主要来源，导致严重缺血和代谢窘迫。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着增加 与女性同行相比。此外，我们已经确定雌激素是关键的调节剂 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，雌激素发挥其作用 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，本研究的目的是检验以下假设：女性可以免受 RD 诱导的影响。 通过雌激素依赖性正常化和/或光感受器拯救作用引起的视网膜变性 代谢功能障碍。我们将利用一个明确的 RD 小鼠模型，其中视网膜下注射 透明质酸钠用于产生脱离。鼠标 RD 模型将使我们能够利用 在受控环境下对小鼠建立完善的基因操作平台。为了刻画角色的特点 为了了解性和雌激素信号系统在感光细胞死亡中的作用，我们将： 1) 定义雌激素信号如何传导 使用遗传模型和性腺切除术在体内进行调节，以精确描绘信号传导途径和 参与雌激素依赖性光感受器退化救援的代谢过程； 2) 阐明 雌激素在缓解 RD 反应中线粒体应激和光感受器氧化损伤方面的作用； 3）描绘与性别有关的具体代谢途径、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，这项研究将深入了解 雌激素在视网膜神经保护中的作用并提供新的性别特异性治疗靶点和/或治疗 治疗 RD 等威胁视力的疾病的方法。