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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.

项目总结