Microtubule Deficit in Glaucoma

我们的目标是为青光眼的早期发现和治疗寻找新的分子靶点。在.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)在这一过程中起着至关重要的作用。我们最近进行了演示，使用的是秒- 谐波产生显微镜作为一种新的视网膜成像方法和DBA小鼠作为遗传模型 青光眼，轴突MT的降解速度快于RGC轴突的丧失(MT缺陷)和MT缺陷 在空间上与轴突萎缩相关。我们的结果表明MT缺陷是早期青光眼的一种新的病理， 这可能与RGC轴突的缺失有共同的致病来源。在这里，我们的目标是探索 新发现的无法及早发现的病理。我们假设MT缺陷可能代表着一个可逆的 适合治疗介入的阶段，并提供分子底物使研资局对 高眼压触发病理反应。要检验这一观点，MT赤字的机制必须是 已澄清。作为一个潜在的靶点，我们将询问轴突MTS的翻译后修饰(PTM)， 也称为微管蛋白编码，它调节MTS和MT相关蛋白之间的相互作用 (地图)。我们的研究将显示在青光眼期间MT PTM是如何变化的，以及这种变化是否相关 MT缺乏症。此外，我们将测试MT缺陷作为RGC生存能力的终点标志，以评估 治疗性治疗。我们将分析接受NAD+水平增加的DBA视网膜，以保护RGC 轴突。我们的研究可以对MT缺陷的机制提供有价值的见解，并开辟一条新的路线 关于改进青光眼治疗的问题。

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.