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: 10693858
• 负责人: Andrew M Boal
• 金额: $ 5.21万
• 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/10693858
• 关键词: Acceleration; 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 Study; Physicians; Physiologic Intraocular Pressure; Physiological; Physiological Processes; Play; Potassium; Predisposition; Process; Property; Proteins; Regulation; Resources; Retina; Retinal Ganglion Cells; Risk Factors; Role; Scientist; Signal Transduction; Stress; Synapses; Testing; Training; Vision; Work; cell type; cellular imaging; cellular targeting; deprivation; experimental study; extracellular; functional decline; genetic predictors; imaging study; insight; modifiable risk; mouse model; neuronal excitability; neuroprotection; patch clamp; pharmacologic; 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.

项目概要/摘要 青光眼，以视网膜神经节退化为特征的不可逆视力丧失的主要原因 到 2040 年，视网膜神经细胞 (RGC) 及其轴突将影响全球约 1 亿人。 对眼压 (IOP) 的敏感性是青光眼唯一可改变的危险因素，可通过以下方法降低。 降压疗法的数量通常会减缓病情进展，但许多患者仍会丧失视力 尽管有显着的控制，但与 IOP 相关的应激压力是通过激怒 RGC 轴突的机制来传递的。 因此，对压力的第一个细胞反应可能位于视神经乳头内。 并代表神经保护治疗的主要目标 在该区域，轴突位置非常接近。 星形胶质细胞密切参与对神经退行性应激的反应，并已成为 星形胶质细胞是神经保护疗法开发的一个有吸引力的目标，其紧密相连。 间隙连接主要由蛋白质 connexin-43 (Cx43) 组成，可以作为更广泛的网络 这种网络能够增强星形胶质细胞的稳态能力，包括代谢产物。 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。 早期青光眼变性的部分特征是 RGC 兴奋性增强和 RGC 兴奋性降低 轴突功能，是 RGC 的一个子集，在光偏移 (αOFF-S) 下产生持续反应。 星形胶质细胞网络似乎更容易受到 IOP 相关压力的影响。 Calkins 实验室的工作表明，星形胶质细胞特异性删除 Cx43 会大大加速青光眼的发生。 青光眼小鼠模型的退行性改变表明星形细胞 Cx43。 删除优先改变 αOFF-S RGC 的发射特性该提案扩展了这些发现， 旨在阐明 RGC 类型差异易感性的机制并探索 星形胶质细胞网络在增强一种神经保护功能方面的重要性——缓冲神经细胞的内容 细胞外环境，以及小鼠。 青光眼模型将用于实现这些目标，这些研究将提供重要的见解。 研究青光眼神经变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通过以下内容得到加强： 丰富的资源和专业知识，以及强有力的指导和对培训人员的承诺 独立医师科学家。

项目成果

Ocular stress enhances contralateral transfer of lenadogene nolparvovec gene therapy through astrocyte networks.

眼部应激通过星形胶质细胞网络增强 lenadogene nolparvovec 基因治疗的对侧转移。

• 发表时间: 2023-07-05
• 作者: McGrady, Nolan R;Boal, Andrew M;Risner, Michael L;Taiel, Magali;Sahel, Jose A;Calkins, David J
• 通讯作者: Calkins, David J

Retinal ganglion cells adapt to ionic stress in experimental glaucoma.

视网膜神经节细胞适应实验性青光眼中的离子应激。

• 发表时间: 2023
• 作者: Boal, Andrew M;McGrady, Nolan R;Holden, Joseph M;Risner, Michael L;Calkins, David J
• 通讯作者: Calkins, David J

Sensitivity to extracellular potassium underlies type-intrinsic differences in retinal ganglion cell excitability.

对细胞外钾的敏感性是视网膜神经节细胞兴奋性类型内在差异的基础。

• 发表时间: 2022
• 作者: Boal, Andrew M;McGrady, Nolan R;Risner, Michael L;Calkins, David J
• 通讯作者: Calkins, David J

Axon hyperexcitability in the contralateral projection following unilateral optic nerve crush in mice.

小鼠单侧视神经挤压后对侧投射的轴突过度兴奋。

• 发表时间: 2022
• 影响因子: 4.8
• 作者: McGrady, Nolan R;Holden, Joseph M;Ribeiro, Marcio;Boal, Andrew M;Risner, Michael L;Calkins, David J
• 通讯作者: Calkins, David J