Protective function of STAT3-mediated astrocyte reactivity in experimental glaucoma: mechanism of action

STAT3介导的星形胶质细胞反应性在实验性青光眼中的保护功能：作用机制

基本信息

批准号：
9764368
负责人：
Daniel Sun
金额：
$ 49.25万
依托单位：
SCHEPENS EYE RESEARCH INSTITUTE
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-09-01 至 2023-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9764368
关键词：
Address Affect Astrocytes Attenuated Axon Axonal Transport Belief Blindness CISH gene Carrier Proteins Cell Death Cell Survival Characteristics Chronic Complement Data Development Disease Dyes Feedback Functional disorder Genes Genetic Glaucoma Goals Growth Factor Histologic Hypertrophy Immune Immunity Infiltration Inflammation Injections Injury Knock-out Knockout Mice Lead Leukocytes Link Mediating Methods Microglia Modeling Molecular Morphology Nerve Crush Neurobiology Optic Disk Optic Nerve Optic Nerve Injuries Outcome Outcome Measure Pathologic Processes Pathway interactions Patients Phagosomes Pharmacology Phenotype Physiologic Intraocular Pressure Play Prevention Process Public Health Receptor Signaling Retina Retinal Retinal Ganglion Cells Risk Factors Role Savings Severities Signal Pathway Signal Transduction Signaling Molecule Site Stat3 protein TNF gene Testing Therapeutic Therapeutic Intervention Toll-like receptors Tracer Transgenic Mice Transgenic Organisms Vision Visual Western Blotting Work alternative treatment axon injury axonal degeneration base cell injury experimental study falls functional outcomes gain of function ganglion cell improved in vivo inflammatory marker interest intravitreal injection loss of function macrophage migration molecular phenotype monocyte mouse model novel preservation prevent promoter protein transport targeted treatment therapeutic evaluation transcriptome sequencing white matter

项目摘要

Project Summary Glaucoma is a disease in which current treatments focus on modifying a major risk factor, that is lowering intraocular pressure, rather than directly targeting the pathophysiological mechanisms in the retina or optic nerve that lead to ganglion cell death. This is because we still do not fully understand the underlying mechanisms of the disease. In many cases, lowering the intraocular pressure alone is not sufficient, and patients continue to lose their vision. Identifying new mechanisms that mediate ganglion cell degeneration will benefit the development of alternative treatments for glaucoma. A leading hypothesis in the pathophysiology of glaucoma is that astrocytes within the optic nerve head play an important role in the ganglion cell degeneration, albeit it is not clear what this role is. Astrocytes are a key focus because (1) they populate the optic nerve head, a site where early ganglion cell axon injury occurs, and (2) astrocytes in the optic nerve head become highly “reactive”, a process that changes their morphology, function and molecular phenotype, but in the white matter of the CNS is not well understood. Using a loss-of-function transgenic mouse model, we recently showed that STAT3 signaling is a critical regulator of astrocyte reactivity within the glaucomatous optic nerve head. Knocking out STAT3 attenuates astrocyte reactivity, increasing ganglion cell degeneration and visual function loss. Astrocyte reactivity therefore functions by some mechanism to preserve vision, upturning the long prevailing belief that reactivity is simply detrimental in disease and that treatments must prevent it. Based on this initial observation, the overall goal of our proposed study is to investigate the mechanism by which astrocyte reactivity affects ganglion cell survival. This study is unique and novel in identifying and investigating a novel mechanistic pathway (the STAT3 signaling pathway) involved in glaucoma. Our method is to use targeted deletion of two specific genes from astrocytes to generate a loss-of-function (STAT3 knockout mice) and gain-of-function (SOCS3 knockout mice; the negative feedback molecule of STAT3) mouse model and determine how these affect histological, functional and molecular outcome measures following two different models of experiment glaucoma. In a final experiment, we will use a commercially available pharmacological agent to test the therapeutic potential of manipulating the STAT3 pathway and astrocyte reactivity towards a beneficial outcome. Our specific aims to accomplish our goal are to test the following hypotheses: (1) that STAT3 knockout, which attenuates astrocyte reactivity, increases pathological processes in the glaucomatous optic nerve, particularly processes related to inflammation/immunity, and (2) that increasing STAT3 activation and enhancing astrocyte reactivity will improve histological and functional outcome. As glaucoma is the second leading cause of blindness worldwide, this proposal will address a major public health concern.

项目概要青光眼是一种目前的治疗重点是改变主要危险因素的疾病，即降低眼压，而不是直接针对视网膜的病理生理机制或视神经导致神经节细胞死亡，这是因为我们还没有完全了解其背后的原因。在许多情况下，仅降低眼压是不够的，并且识别介导神经节细胞变性的新机制将导致患者继续丧失视力。有利于青光眼替代疗法的开发。青光眼病理生理学的一个主要假设是视神经头内的星形胶质细胞尽管星形胶质细胞的作用尚不清楚，但它在神经节细胞变性中发挥着重要作用。关键焦点是因为（1）它们位于视神经乳头，这是早期神经节细胞轴突损伤发生的部位， (2) 视神经乳头中的星形胶质细胞变得高度“反应”，这是一个改变其形态的过程，功能和分子表型，但在中枢神经系统白质中尚不清楚。使用功能丧失的转基因小鼠模型，我们最近表明 STAT3 信号传导是一个关键青光眼视神经乳头内星形胶质细胞反应性的调节因子敲除 STAT3 会减弱。星形胶质细胞反应性，增加神经节细胞变性和视觉功能丧失。因此，通过某种机制发挥作用来保持视力，颠覆了长期以来盛行的信念，即反应性是只是疾病中的疾病，治疗必须预防它。基于这一初步观察，我们提出的研究的总体目标是调查其机制星形胶质细胞反应性影响神经节细胞存活的研究在识别和识别方面是独特且新颖的。我们的方法研究了一种与青光眼有关的新机制途径（STAT3 信号途径）。是利用星形胶质细胞中两个特定基因的定向删除来产生功能丧失（STAT3 基因敲除小鼠）和功能获得性小鼠（SOCS3 基因敲除小鼠；STAT3 的负反馈分子）小鼠模型并确定它们如何影响组织学、功能和分子结果测量以下是两种不同的青光眼实验模型在最后一个实验中，我们将使用商业化的模型。可用的药物来测试操纵 STAT3 通路的治疗潜力我们实现目标的具体目标是测试星形胶质细胞对有益结果的反应。以下假设：(1) STAT3 敲除会减弱星形胶质细胞的反应性，从而增加病理性青光眼视神经的过程，特别是与炎症/免疫相关的过程，以及（2）增加 STAT3 激活并增强星形胶质细胞反应性将改善组织学和功能由于青光眼是全球第二大失明原因，因此该提案将解决一个重大问题。公共卫生问题。