Microtubule Deficit in Glaucoma

我们的目标是确定新的分子靶点，用于青光眼的早期检测和治疗。期间 随着青光眼的进展，视网膜神经节细胞（RGC）的轴突逐渐丧失。我们的假设是 轴突微管（MT）在该过程中起关键作用。我们最近演示了，使用第二- 谐波发生（SHG）显微镜作为一种新的视网膜成像和DBA小鼠作为遗传性视网膜病变的模型， 在青光眼中，轴突MT降解比RGC轴突的损失（“MT缺陷”）更快，并且MT缺陷是 空间上与轴突萎缩相关。我们的研究结果表明，MT缺陷是早期青光眼的一种新病理， 其可能具有与RGC轴突缺失相同的致病性起源。在这里，我们的目标是探索能力， 新发现的病理学而无法早期发现我们假设MT缺陷可能代表了一种可逆的 阶段适合于治疗性干预，并为RGC的敏感性提供分子底物。 IOP升高引发病理反应。为了检验这一概念，MT缺陷的机制必须是 阐明。作为一个潜在的目标，我们将询问轴突MT的翻译后修饰（PTM）， 也称为微管蛋白编码，其调节MT和MT相关蛋白之间的相互作用 （地图）。我们的研究将显示MT PTM在青光眼期间是如何改变的，以及这种变化是否与青光眼相关。 MT赤字此外，我们将测试MT缺陷作为RGC活力的终点标志物，以评估 治疗性治疗我们将分析接受增加水平的NAD+以保护RGC的DBA视网膜 轴突我们的研究将有助于深入了解MT缺陷的机制，并为MT治疗开辟一条新的途径。 青光眼的治疗方法

Our objective is to identify new molecular targets for early detection and treatment of glaucoma. During the progression of glaucoma, the axons of the retinal ganglion cells (RGCs) are gradually lost. Our hypothesis is that axonal microtubules (MTs) are critically involved in the process. We demonstrated recently, using second- harmonic generation (SHG) microscopy as a novel retinal imaging and DBA mice as a model of inherited glaucoma, that axonal MTs degrade more rapidly than the loss of RGC axons (‘MT deficit’) and MT deficit is spatially correlated with axonal atrophy. Our results suggest that MT deficit is a new pathology of early glaucoma, which may have a common pathogenic origin as the loss of RGC axons. Here we aim to explore the capacities of newly discovered pathology beyond early detection. We hypothesize that MT deficit may represent a reversible stage suitable for therapeutic intervention and provide the molecular substrate for the RGC’s sensitivity to the elevated IOP triggering the pathological response. To test this notion, the mechanism of MT deficit must be elucidated. As a potential target, we will interrogate the posttranslational modifications (PTMs) of axonal MTs, also known as the tubulin codes, which modulate the interaction between MTs and MT-associated proteins (MAPs). Our research will show how MT PTMs are altered during glaucoma and whether the change is correlated with MT deficit. Also, we will test MT deficit as an endpoint marker of the RGC viability evaluating the efficacy of therapeutic treatments. We will analyze the DBA retina receiving an increased level of NAD+ to protect the RGC axons. Our research can yield valuable insights into the mechanism of MT deficit and open a new line of questions toward improved glaucoma therapy.