Dissecting the complex role of microglia states in glaucoma

剖析小胶质细胞状态在青光眼中的复杂作用

• 批准号: 10650571
• 负责人: Gareth R Howell
• 金额: $ 65.05万
• 依托单位: UNIVERSITY OF ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-06-01 至 2027-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10650571
• 关键词: Ablation; Acceleration; Acute; Aging; Alzheimer' s Disease; Amyloid; Amyotrophic Lateral Sclerosis; Animal Model; Astrocytes; Automobile Driving; Blindness; Brain Diseases; CSF1R gene; Cell Death; Cell Survival; Cells; Central Nervous System; Cessation of life; Chronic; Classical Complement Pathway; Complement 1q; Complex; Data; Disease; Disease associated microglia; Event; Functional disorder; Gene Expression; Genes; Genetic; Genetic Transcription; Glaucoma; Goals; Human Anti-Mouse Antibody; Huntington gene; IL1A gene; Immune; Injury; Interferons; Mediating; Mediator; Microglia; Modeling; Modernization; Molecular; Mus; Myeloid Cells; Nerve Degeneration; Neurodegenerative Disorders; Neuronal Injury; Ocular Hypertension; Optic Disk; Optic Nerve; Outcome; Outcome Measure; Parkinson Disease; Pathologic; Patients; Peptide Initiation Factors; Phagocytosis; Phenotype; Physiologic Intraocular Pressure; Physiological; Play; Population; Prevalence; Process; Reporting; Research; Retina; Retinal Ganglion Cells; Risk Factors; Role; Senile Plaques; Site; Structure; Synapses; System; TNF gene; TREM2 gene; Technology; Testing; Transcript; Work; age related; age related neurodegeneration; axon injury; cell type; cytokine; disorder risk; glial activation; inhibitor; intravitreal injection; migration; mouse model; nerve damage; neuroinflammation; neuronal cell body; neuroprotection; neurotoxic; new therapeutic target; novel; novel therapeutic intervention; prevent; receptor; receptor expression; response; sight restoration; single cell sequencing; single-cell RNA sequencing; targeted treatment; therapeutic candidate; therapeutic evaluation; therapy development; transcriptome sequencing

Glaucoma is a very common age-related neurodegenerative disease characterized by the death of the retinal ganglion cells. Despite its prevalence, there are no neuroprotective treatments for glaucoma. The only current treatment is lowering intraocular pressure which unfortunately does not prevent or restore vision loss in many patients. Due to extensive research in both glaucoma patients and animal models of glaucoma, much is known about glaucomatous neurodegeneration, both at the physiological and molecular levels. However, despite this, we still lack a molecular understanding of the early pathological events that injure RGCs as a result of ocular hypertension. Microglia cells are a major component of the neuroinflammatory response in neurodegenerative diseases and after injury to the central nervous system. In fact, microglia cell response is thought to play key roles in many neurodegenerative diseases, including, Alzheimer’s disease, Parkinson’s disease, Huntingtin disease, and Amyotrophic Lateral Sclerosis. Work in other systems has shown that microglia can act be both protective and detrimental in the disease process, and possibly these two actions could take place sequentially in the same disease. Recent studies using modern sequencing technology has shown that microglia exist in different molecular states which correspond to their role in disease. A major, well-supported hypothesis in glaucoma research is that microglial cells are critical for maintaining retinal ganglion cell viability after a glaucomatous insult. However, the importance of microglia in an ocular hypertensive model of glaucoma has not been critically tested. In this application we propose to test the hypothesis that different activated states of microglia play distinct roles in glaucoma dependent upon stage of disease. Specifically, in two ocular hypertensive glaucoma mouse models, we will: (1) Determine if the role of microglia activation varies with disease stage, (2) define and test the importance of different molecular states, and (3) determine the role of microglial derived neurotoxic cytokines. Overall, this proposal we will define novel mechanisms by which microglia states modulate glaucoma onset and progression leading to novel candidates for therapeutic evaluation.

青光眼是一种非常常见的与年龄相关的神经退行性疾病，其特征是视网膜死亡 神经节细胞。尽管有盛行的率，但仍未针对青光眼治疗神经保护治疗。唯一的电流 治疗正在降低眼内压，不幸的是，这并不能阻止或恢复许多人的视力丧失 患者。由于对青光眼患者和青光眼动物模型的广泛研究，众所周知 在物理和分子水平上，关于青光眼的神经退行性。但是，要求这个， 我们仍然缺乏对因眼损伤RGC的早期病理事件的分子理解 高血压。小胶质细胞是神经退行性反应的主要组成部分 疾病和中枢神经系统受伤后。实际上，认为小胶质细胞响应被认为播放键 在许多神经退行性疾病中的作用，包括阿尔茨海默氏病，帕金森氏病，亨廷顿 疾病和肌萎缩性侧索硬化症。在其他系统中的工作表明，小胶质细胞可以行为 在疾病过程中保护和有害，这两个动作可能会顺序进行 在同一疾病中。使用现代测序技术的最新研究表明，小胶质细胞存在于 与它们在疾病中的作用相对应的不同分子状态。一个主要的，有充分支持的假设 青光眼研究是，小胶质细胞对于维持视网膜神经节细胞活力至关重要 青光眼侮辱。但是，小胶质细胞在青光眼高血压模型中的重要性尚未 我们经过了严格的测试。在此应用中，我们建议检验以下假设 小胶质细胞在依赖疾病阶段的青光眼中起着不同的作用。具体而言，在两个眼中 高血压青光眼小鼠模型，我们将：（1）确定小胶质细胞激活变化是否与 疾病阶段，（2）定义和测试不同分子状态的重要性，（3）确定 小胶质细胞衍生的神经毒性细胞因子。总体而言，这一建议我们将定义新的机制 小胶质细胞状态调节青光眼的发作和进展，导致新的治疗候选者 评估。