Autophagy and Retinal Ganglion Cell Death in Glaucoma

青光眼中的自噬和视网膜神经节细胞死亡

• 批准号: 10390035
• 负责人: Paloma Liton
• 金额: $ 47.55万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-30 至 2026-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10390035
• 关键词: Acute; Address; Apoptosis; Apoptotic; Applications Grants; Autophagocytosis; Autophagosome; Axon; Axonal Transport; Biological Models; Blindness; Cell Death; Cessation of life; Chronic; Complex; Conflict (Psychology); Consensus; Data; Development; Disease; Early identification; Evaluation; Event; Exhibits; Experimental Models; Functional disorder; Genetic Models; Glaucoma; Homeostasis; Injury; Laboratories; Magnetism; Microspheres; Modeling; Molecular; Mus; Nature; Nerve Degeneration; Neurodegenerative Disorders; Neuronal Injury; Ocular Hypertension; Optic Nerve; Organelles; Pathogenicity; Pathway interactions; Pattern; Pharmacology; Physiologic Intraocular Pressure; Play; Process; Proteins; Regulation; Retinal Ganglion Cells; Role; Scotoma; Signal Pathway; Stress; Testing; Therapeutic; Time; Tissues; Transgenic Mice; Transgenic Organisms; Traumatic injury; Vesicle; acute stress; age related; axon injury; axonal degeneration; human disease; hypertensive; neuron loss; neuroprotection; new therapeutic target; novel; overexpression; relating to nervous system; response; response to injury; retinal ganglion cell degeneration; tool; treatment strategy

ABSTRACT Glaucoma is a group of diseases, second leading cause of permanent blindness worldwide, characterized by the chronic degeneration of RGC axons and progressive loss of retinal ganglion cells (RGCs), which results in visual field defects and vision loss. Elevated intraocular pressure (IOP) is the best-well known factor contributing to the onset and progression of glaucoma. There are not therapeutic treatments to offer neuroprotection in glaucoma. Current glaucoma therapies are directed at lowering IOP, but cannot rescue RGCs. A better understanding of the exact molecular mechanisms triggering RGC death and axonal degeneration in glaucoma is essential for the development of neuroprotective treatments. Autophagy is a lysosomal degradative process, which plays a central role in cellular homeostasis by eliminating damage organelles and proteins. In addition to having a key role on maintaining cellular and tissue homeostasis, autophagy is regarded as a survival pathway, involved in stress-induced adaptation. Dysfunction of the autophagy pathway has been associated to a growing number of human diseases, in particular age-related diseases, as well as to several neurodegenerative disorders. Paradoxically, in the neural tissue, autophagy plays an important role in neuroprotection as well as neuronal injury and death depending on the circumstances. Although not extensively, autophagy within a context of glaucoma, has been investigated by independent laboratories using different experimental models. While all of the studies agree that autophagy is activated in RGC in response to injury or elevated IOP, there is no consensus on whether autophagy promotes survival or triggers cell death. Latest studies seem to suggest that a protective or pro-death role of autophagy depend on the initial injury (i.e traumatic insult vs IOP elevation). Moreover, autophagy seems to have a different role in RGC death and axonal degeneration. The purpose of this grant application is to investigate the independent contribution of autophagy to apoptotic RGC death and axonal degeneration in acute injury and chronic hypertensive experimental models of glaucoma. For this, we will use unique tools generated in our laboratory, including our unique DBA/2J transgenic mouse glaucoma models with upregulated and deficient basal autophagy. We anticipate that completion of this project will contribute to a further understanding of the role of autophagy in neurodegeneration in glaucoma. Most importantly, our studies have the potential of identifying a novel therapeutic target for the treatment of ocular hypertension and glaucoma.

摘要 青光眼是一组疾病，是全球永久性失明的第二大原因，其特征在于 RGC轴突的慢性变性和视网膜神经节细胞（RGC）的进行性丧失，这导致 视野缺损和视力丧失。眼内压升高（IOP）是最广为人知的因素， 青光眼的发病和发展没有治疗性治疗可以提供神经保护， 青光眼目前的青光眼治疗是针对降低IOP，但不能挽救RGC。更好的 了解青光眼中触发RGC死亡和轴突变性的确切分子机制 对神经保护治疗的发展至关重要。 自噬是一种溶酶体降解过程，它通过清除细胞内毒素， 破坏细胞器和蛋白质。除了在维持细胞和组织稳态方面具有关键作用外， 自噬被认为是一种生存途径，参与应激诱导的适应。功能障碍 自噬途径与越来越多的人类疾病有关，特别是与年龄相关的疾病 疾病，以及几种神经退行性疾病。奇怪的是，在神经组织中， 在神经保护以及视情况而定的神经元损伤和死亡中起重要作用。 虽然不是广泛的，自噬在青光眼的背景下，已被独立的研究， 实验室使用不同的实验模型。虽然所有的研究都认为自噬是在 RGC对损伤或IOP升高的反应，对于自噬是否促进存活或 触发细胞死亡最新的研究似乎表明，自噬的保护或促死亡作用取决于 初始损伤（即创伤性损伤vs IOP升高）。此外，自噬似乎有不同的作用， RGC死亡和轴突变性。 这项资助申请的目的是研究自噬对细胞凋亡的独立贡献。 青光眼急性损伤和慢性高血压实验模型中的RGC死亡和轴突变性。 为此，我们将使用我们实验室中产生的独特工具，包括我们独特的DBA/2 J转基因小鼠 具有上调和缺乏的基础自噬的青光眼模型。我们预计这个项目的完成 将有助于进一步了解自噬在青光眼神经变性中的作用。最 重要的是，我们的研究有可能确定一个新的治疗靶点，用于治疗眼部疾病。 高血压和青光眼。