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：
10165728
负责人：
Daniel Sun
金额：
$ 47.77万
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/10165728
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 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 conditional knockout 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 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.

项目摘要青光眼是一种疾病，当前治疗重点是修改主要危险因素，即降低眼内压，而不是直接针对视网膜或导致神经节细胞死亡的视神经。这是因为我们仍然不完全了解基础疾病的机制。在许多情况下，仅降低眼内压还不够，并且患者继续失去视力。确定介导神经节细胞变性的新机制将受益于青光眼替代治疗的发展。青光眼病理生理学中的主要假设是视神经头内的星形胶质细胞在神经节细胞变性中起重要作用，尽管尚不清楚这种作用是什么。星形胶质细胞为a 关键重点是因为（1）它们填充视神经头，一个早期神经节细胞轴突损伤的部位，（2）视神经头中的星形胶质细胞变得高度“反应性”，这一过程改变了其形态，功能和分子表型，但在中枢神经系统的白质中尚不清楚。使用功能丧失的转基因小鼠模型，我们最近表明STAT3信号是关键敲出STAT3在青光眼视神经头内的星形胶质反应性减弱。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。星形胶质细胞反应性因此，通过某种机制来保持视觉的作用，提高了长期以来的普遍信念，即反应性是仅在疾病中有害，而治疗必须阻止这种治疗。基于这一初步观察，我们提出的研究的总体目标是研究机制星形胶质细胞反应影响神经节细胞的存活。这项研究在识别和研究了涉及青光眼的新机械途径（STAT3信号通路）。我们的方法是使用来自星形胶质细胞的两个特定基因的有针对性删除来产生功能丧失（STAT3 基因敲除小鼠）和功能获得（SOCS3基因敲除小鼠； STAT3的负反馈分子）小鼠模型并确定这些如何影响组织学，功能和分子结果测量遵循两种不同的实验青光眼模型。在最后一个实验中，我们将在商业上使用可用的药物，以测试操纵STAT3途径的治疗潜力和星形胶质细胞对有益结果的反应性。我们实现目标的具体目标是测试以下假设：（1）STAT3敲除减弱星形胶质细胞反应性的，增加了病理青光眼视神经的过程，尤其是与炎症/免疫相关的过程，（2） STAT3激活并增强星形胶质细胞反应的增加将改善组织学和功能结果。由于青光眼是全球失明的第二大主要原因，因此该提议将解决一个主要的问题公共卫生问题。