Astrocyte Networks as Therapeutic Targets in Glaucomatous Neurodegeneration

星形胶质细胞网络作为青光眼神经变性的治疗靶点

• 批准号: 10532932
• 负责人: Andrew M Boal
• 金额: $ 3.19万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-01 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10532932
• 关键词: Action Potentials; Affect; Astrocytes; Axon; Biochemical Pathway; Blindness; Brain; Buffers; Cell physiology; Cells; Cellular Morphology; Characteristics; Clinical; Connexin 43; Coupled; Coupling; Data; Development; Disease; Electrophysiology (science); Elements; Enhancers; Environment; Event; Extracellular Space; Future; Gap Junctions; Generations; Glaucoma; Glutamates; Homeostasis; Hypotensives; Imaging Techniques; Investigation; Knockout Mice; Light; Measures; Mentorship; Metabolic; Microspheres; Modeling; Muller' s cell; Mus; Nerve Degeneration; Neurodegenerative Disorders; Neuroglia; Neurons; Ocular Hypertension; Optic Disk; Optics; Patients; Persons; Pharmacology; Pharmacology Study; Physicians; Physiologic Intraocular Pressure; Physiological; Physiological Processes; Play; Potassium; Potassium Glutamate; Predisposition; Process; Property; Proteins; Regulation; Resources; Retina; Retinal Ganglion Cells; Risk Factors; Role; Scientist; Signal Transduction; Stress; Synapses; Testing; Training; Vision; Work; base; cell type; cellular imaging; cellular targeting; deprivation; experimental study; extracellular; functional decline; genetic predictors; imaging study; insight; modifiable risk; mouse model; neuronal excitability; patch clamp; pressure; response; retinal ganglion cell degeneration; targeted treatment; therapeutic target; tool

Project Summary/Abstract Glaucoma, the leading cause of irreversible vision loss characterized by the degeneration of retinal ganglion cells (RGCs) and their axons, will affect an estimated 100 million people worldwide by the year 2040. Sensitivity to intraocular pressure (IOP) is the only modifiable risk factor in glaucoma. IOP can be reduced by a number of hypotensive therapies, which often slow progression, but many patients continue to lose vision despite significant pressure control. IOP-related stress is conveyed by mechanisms that pique RGC axons within the optic nerve head. Thus, the first cellular responders to stress likely reside in the optic nerve head and represent primary targets for neuroprotective treatment. In this region, axons are located in close proximity to astrocytes. Astrocytes are intimately involved in the response to neurodegenerative stress and have become an attractive target for the development of neuroprotective therapies. Astrocytes are densely interconnected by gap junctions, primarily composed of the protein connexin-43 (Cx43), and can function as a broader network of cells. Such networks are capable of enhancing astrocyte homeostatic capacities, including metabolite distribution and extracellular ionic buffering, but their role in neurodegenerative disease is an emerging field. Early glaucomatous degeneration is characterized in part by enhanced RGC excitability and a reduction in axon function. Interestingly, a subset of RGCs which produce sustained responses at light offset (αOFF-S) appear to be more vulnerable to IOP-related stress. Astrocytic networks play key roles at this early stage of glaucoma. Work in the Calkins lab demonstrated that astrocyte-specific deletion of Cx43 grossly accelerates degenerative changes in a mouse model of glaucoma. Preliminary experiments indicate that astrocytic Cx43 deletion preferentially alters the firing properties of αOFF-S RGCs. This proposal expands upon these findings, aiming to illuminate the mechanisms underlying the differential susceptibility of RGC types and to explore the importance of astrocyte networks in enhancing one neuroprotective function – buffering the contents of the extracellular environment. Electrophysiologic, pharmacologic, and cell imaging techniques, alongside a mouse model of glaucoma, will be employed to accomplish these aims. These studies will provide important insight into the early physiologic events in glaucomatous neurodegeneration and establish a framework for future neuroprotective therapies targeting astrocytes. The training plan outlined in this proposal is strengthened by an abundance of resources and expertise, as well as strong mentorship and a commitment to training an independent physician scientist.

项目摘要/摘要 青光眼是不可逆转视力丧失的主要原因，其特征是残留神经节的变性 到2040年，细胞（RGC）及其轴突将影响全球范围内约1亿人。 对眼内压（IOP）的敏感性是青光眼中唯一可改变的危险因素。 IOP可以通过 降压疗法的数量通常会减慢进展，但许多患者继续失去视力 尽管有重大压力控制。与IOP相关的应力是通过刺激RGC轴突的机制传达的 在视神经头内。那就是第一个细胞反应者对压力的反应者可能存在于视神经头部 并代表神经保护治疗的主要靶标。在该区域，轴突位于近距离 到星形胶质细胞。星形胶质细胞与对神经退行性应激的反应密切相关，并已成为 神经保护疗法发展的有吸引力的靶标。星形胶质细胞不互连 间隙连接，主要由蛋白质连接蛋白43（CX43）组成，并且可以充当更广泛的网络 细胞。这样的网络能够增强星形胶质细胞稳态容量，包括代谢物 分布和细胞外离子缓冲，但它们在神经退行性疾病中的作用是一个新兴领域。 早期的青光眼变性部分以增强的RGC令人兴奋和减少 轴突功能。有趣的是，在光偏移时产生持续反应的RGC子集（αOff-S） 似乎更容易受到与IOP相关的压力的影响。星形胶质细胞网络在这个早期阶段扮演关键角色 青光眼。 Calkins实验室的工作表明，CX43的星形胶质细胞特异性缺失非常加速 青光眼小鼠模型的退化变化。初步实验表明星形胶质细胞CX43 删除优先改变了αOff-S RGC的发射特性。该建议扩展了这些发现， 旨在阐明RGC类型差异敏感性的基础机制并探索 星形胶质细胞网络在增强一个神经保护功能方面的重要性 - 缓冲含量 细胞外环境。电生理，药理和细胞成像技术，以及小鼠 这些研究将提供重要的见解 进入青光眼神经退行性的早期生理事件，并为未来建立框架 针对星形胶质细胞的神经保护疗法。该提案中概述的培训计划得到了加强 资源和专业知识的抽象以及强大的精神训练以及对培训的承诺 独立的物理科学家。