Metabolic vulnerability as a disease target for glaucoma

代谢脆弱性作为青光眼的疾病目标

• 批准号: 9902456
• 负责人: DENISE M INMAN
• 金额: $ 36.5万
• 依托单位: UNIVERSITY OF NORTH TEXAS HLTH SCI CTR
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-04-01 至 2021-09-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9902456
• 关键词: Action Potentials; Animals; Area; Axon; Bioenergetics; Blindness; Cell Count; Cells; Chronic; Data; Diagnosis; Disease; Disease model; Enzymes; Failure; Fatigue; Functional disorder; Glaucoma; Glycogen; Goals; Intervention; Knowledge; Laboratories; Lactate Transporter; Lead; Measurable; Metabolic; Metabolic dysfunction; Microspheres; Mission; Mitochondria; Modeling; Mus; Nerve; Neuroglia; Optic Nerve; Oxidative Stress; Pathogenesis; Pathologic; Pathology; Physiologic Intraocular Pressure; Physiological; Positioning Attribute; Production; Public Health; Quality Control; Reactive Oxygen Species; Recycling; Research; Respiration; Retinal Ganglion Cells; Role; Source; Structure; Testing; United States National Institutes of Health; Work; aging population; anterograde transport; axonal degeneration; base; enzyme activity; experimental study; functional restoration; high intraocular pressure; human disease; improved; innovation; insight; loss of function; mitochondrial dysfunction; mouse model; new therapeutic target; novel; novel therapeutic intervention; optic nerve disorder; preservation; public health relevance; therapeutic development

 DESCRIPTION (provided by applicant): Retinal ganglion cell axons undergo degeneration prior to cell body loss in the pathogenesis of glaucoma. Prior to degeneration, retinal ganglion cell axons demonstrate metabolic dysfunction, including ATP decreases that correlate with high intraocular pressure. This metabolic dysfunction could be a result of changes in axonal mitochondria or alterations in the provision of energy substrates from glia to axons. A critical question for therapeutic development is whether the metabolic dysfunction is intrinsic to the retinal ganglion cell axon. The long-term goal of this work is to determine the onset, progression and mechanisms of retinal ganglion axon dysfunction so that crucial intervention points for developing glaucoma therapies can be defined and prioritized. The overall objective of this proposal is to examine the causes of energy availability failure in early glaucoma and place those causes in context with structural pathology. The central hypothesis of this work is that the mechanism of metabolic dysfunction is shared by the RGC axon mitochondria and optic nerve glia. This hypothesis has been formulated from preliminary data gathered in the applicant's laboratory that suggests deficits in mitochondrial recycling, low glycogen stores and lactate transporters in glaucomatous optic nerve. The rationale for this proposed work is that investigating the source of metabolic dysfunction in glaucomatous optic nerve will identify new therapeutic targets in a disease that has no mechanism-based interventions. Guided by strong preliminary data, this hypothesis will be tested by the following specific aims: 1) determine whether mitochondria underlie the metabolic vulnerability of glaucoma by investigating ROS production and mitochondria quality control; 2) by establishing the relationship between mitochondrial respiration and degeneration; and 3) by determining how glia drive metabolic vulnerability through energy store levels and mobilization, lactate transporter expression and distribution, and metabolic enzyme activity. Overall, this work will determine the contribution of energy availability to glaucoma pathogenesis by analyzing how mitochondrial and glial-related energy substrates and delivery mechanisms are altered in optic neuropathy. Confirmation will occur through manipulation of mitochondrial quality control, reactive oxygen species levels, and energy stores to the nerve, and quantifying the resultant decrease in axon degeneration. The approach is innovative because it departs from the general perspective that energy availability and utilization are tangential to optic neuropathy. Critical intervention points to halt optic neuropathy will emerge from this analysis. For this reason, the proposed research is significant, but also because it will provide insight into the role of energy in axon degeneration generally.

 描述（由申请人提供）：在青光眼发病机制中，视网膜神经节细胞轴突在细胞体损失之前发生退化，在退化之前，视网膜神经节细胞轴突表现出代谢功能障碍，包括与高眼压相关的ATP减少。是由于轴突线粒体的变化或从神经胶质细胞到轴突的能量底物供应的改变造成的。治疗开发的一个关键问题是代谢功能障碍是否是由轴突线粒体的变化引起的。这项工作的长期目标是确定视网膜神经节轴突功能障碍的发病、进展和机制，以便确定和优先考虑青光眼治疗的关键干预点。这项工作的核心假设是，RGC 轴突线粒体和视神经共享代谢功能障碍的机制。该假设回收是根据申请人实验室收集的初步数据制定的，该数据表明青光眼视神经中线粒体储存、低糖原储存和乳酸转运蛋白的缺陷。这项拟议工作的基本原理是调查青光眼代谢功能障碍的根源。视神经将在没有基于机制的干预措施的疾病中确定新的治疗靶点，在强有力的初步数据的指导下，这一假设将通过以下具体目标进行检验：1）确定线粒体是否是代谢脆弱性的基础。通过研究 ROS 产生和线粒体质量控制来研究青光眼；2）建立线粒体呼吸和变性之间的关系；3）确定神经胶质细胞如何通过能量储存水平和动员、乳酸转运蛋白表达和分布以及代谢酶活性来驱动代谢脆弱性。总体而言，这项工作将通过分析线粒体和神经胶质相关的能量底物和传递机制在视神经病变中的作用来确定能量可用性对青光眼发病机制的贡献，并将通过操纵线粒体来进行确认。该方法具有创新性，因为它偏离了能量可用性和利用与视神经病变无关的一般观点。因此，这项研究具有重要意义，而且还因为它将提供对能量在轴突变性中的总体作用的深入了解。