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; 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.

抽象的 青光眼是一组疾病，是全球永久失明的第二大原因，其特征是 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 视野缺陷和视力丧失。眼内压（IOP）是促成最佳孔的已知因素 达到青光眼的发作和进展。没有治疗治疗可提供神经保护作用 青光眼。当前的青光眼疗法针对降低IOP，但无法营救RGC。更好 了解触发RGC死亡和青光眼轴突变性的精确分子机制 对于开发神经保护疗法至关重要。 自噬是一种溶酶体降解过程，它通过消除在细胞稳态中起着核心作用 损害细胞器和蛋白质。除了在维持细胞和组织稳态方面发挥关键作用， 自噬被视为与压力诱导的适应有关的生存途径。功能障碍 自噬途径与越来越多的人类疾病有关，特别是与年龄有关 疾病以及几种神经退行性疾病。矛盾的是，在神经组织中，自噬作用 根据情况，在神经保护以及神经元损伤和死亡中的重要作用。 尽管并非广泛，但在青光眼的背景下进行了自噬，已经由独立研究 实验室使用不同的实验模型。尽管所有研究都同意在 RGC响应伤害或IOP升高，关于自噬是促进生存还是 触发细胞死亡。最新研究似乎表明自噬的保护性或促成死亡的作用取决于 最初的伤害（即创伤性侮辱与IOP升高）。而且，自噬似乎在 RGC死亡和轴突变性。 该赠款申请的目的是调查自噬对凋亡的独立贡献 急性损伤和青光眼慢性高血压实验模型中的RGC死亡和轴突变性。 为此，我们将使用实验室中生成的独特工具，包括我们独特的DBA/2J转基因鼠标 青光眼模型具有上调和不足的基础自噬。我们预计该项目的完成 将有助于进一步了解自噬在青光眼中神经退行性中的作用。最多 重要的是，我们的研究具有鉴定出治疗眼的新型治疗靶标的潜力 高血压和青光眼。