Dissecting the complex role of microglia states in glaucoma

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。尽管青光眼很普遍，但目前还没有针对青光眼的神经保护性治疗方法。唯一的电流 治疗正在降低眼压，不幸的是，这并不能防止或恢复许多人的视力丧失。 病人。由于对青光眼患者和青光眼动物模型的广泛研究，人们已经知道了很多。 关于青光眼神经退行性变，从生理和分子水平。然而，尽管如此， 我们仍然缺乏对由于眼球损伤视网膜节细胞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变中神经炎性反应的主要成分 疾病和受伤后对中枢神经系统的影响。事实上，小胶质细胞的反应被认为起着关键作用 在许多神经退行性疾病中发挥作用，包括阿尔茨海默病、帕金森氏病、亨廷顿 疾病和肌萎缩侧索硬化症。在其他系统中的研究表明，小胶质细胞既可以起作用，也可以起作用 在疾病过程中具有保护性和破坏性，这两种行为可能会相继发生 在同样的疾病中。最近使用现代测序技术的研究表明，小胶质细胞存在于 不同的分子状态与它们在疾病中的作用相对应。一个重要的、得到充分支持的假说 青光眼研究表明，小胶质细胞是维持视网膜神经节细胞活性的关键。 青光眼的侮辱。然而，小胶质细胞在青光眼高眼压模型中的重要性还没有 经过了严格的测试。在这个应用程序中，我们建议测试假设不同的激活状态 小胶质细胞在青光眼发病机制中的作用因疾病分期不同而不同。具体地说，两只眼睛 建立高血压性青光眼小鼠模型后，我们将：(1)确定小胶质细胞激活的作用是否因 疾病阶段，(2)定义和测试不同分子状态的重要性，以及(3)确定 小胶质细胞衍生的神经毒性细胞因子。总体而言，这项提议我们将定义新的机制， 小胶质细胞状态调节青光眼的发生和发展，导致新的治疗候选 评估。

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.