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

基本信息

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
项目类别：
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&apos 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

项目摘要

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。

项目成果

期刊论文数量（4）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Retinal ganglion cells adapt to ionic stress in experimental glaucoma.

DOI：
10.3389/fnins.2023.1142668
发表时间：
2023
期刊：
FRONTIERS IN NEUROSCIENCE
影响因子：
4.3
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。

DOI：
10.3389/fncel.2022.966425
发表时间：
2022
期刊：
Frontiers in cellular neuroscience
影响因子：
5.3
作者：
通讯作者：

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。

DOI：
10.1016/j.ymthe.2023.03.035
发表时间：
2023
期刊：
Molecular therapy : the journal of the American Society of Gene Therapy
影响因子：
0
作者：
McGrady,NolanR;Boal,AndrewM;Risner,MichaelL;Taiel,Magali;Sahel,JoseA;Calkins,DavidJ
通讯作者：
Calkins,DavidJ

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