Microtubule Deficit in Glaucoma

青光眼的微管缺陷

基本信息

批准号：
10468950
负责人：
Hyungsik Lim
金额：
$ 22.7万
依托单位：
HUNTER COLLEGE
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-09-01 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10468950
关键词：
Acetylation Active Biological Transport Age Age-Months Animals Apoptosis Atrophic Axon Axonal Transport Biological Assay Blindness Brain Cell Survival Code Cytoskeleton Data Diet Disease Early Diagnosis Early treatment Elements Female Generations Glaucoma Impairment Inbred DBA Mice Inherited Intervention Measures Mechanics Metabolic Metabolic stress Microscopy Microtubule-Associated Proteins Microtubules Modeling Modulus Molecular Molecular Motors Molecular Target Morphology Mus Nerve Fibers Neurodegenerative Disorders Neurons Niacinamide Nicotinamide adenine dinucleotide Optic Disk Oral Administration Pathogenesis Pathogenicity Pathologic Pathology Physiologic Intraocular Pressure Play Post-Translational Protein Processing Process Proteins Research Retina Retinal Ganglion Cells Role Stains Testing Therapeutic Therapeutic Intervention Treatment Efficacy Tubulin Tyrosine base effective therapy efficacy evaluation glycoprotein NMB improved innovation insight male mouse model novel prevent response retinal axon retinal imaging second harmonic second harmonic generation imaging side effect

项目摘要

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.

我们的目标是确定青光眼早期检测和治疗的新分子靶标。随着青光眼的进展，视网膜神经节细胞（RGC）的轴突逐渐丢失。我们最近使用第二个方法证明了轴突微管（MT）在该过程中发挥着至关重要的作用。谐波发生 (SHG) 显微镜作为一种新型视网膜成像，DBA 小鼠作为遗传模型青光眼中，轴突 MT 的降解速度比 RGC 轴突的损失（“MT 缺陷”）更快，并且 MT 缺陷是我们的结果表明 MT 缺陷是早期青光眼的一种新病理学。其可能具有共同的致病起源，即 RGC 轴突的丢失。在这里，我们旨在探索其能力。我们发现 MT 缺陷可能代表着一种可逆的病理现象。适合治疗干预的阶段，并为 RGC 对治疗的敏感性提供分子底物眼压升高引发病理反应为了验证这一观点，必须了解 MT 缺陷的机制。作为一个潜在的目标，我们将探究轴突 MT 的翻译后修饰 (PTM)，也称为微管蛋白代码，调节 MT 和 MT 相关蛋白之间的相互作用（MAP）。我们的研究将展示 MT PTM 在青光眼期间如何改变以及这种变化是否相关。此外，我们将测试 MT 缺陷作为 RGC 活力的终点标记，评估其功效。我们将分析接受增加水平的 NAD+ 以保护 RGC 的 DBA 视网膜。我们的研究可以对 MT 缺陷的机制产生有价值的见解，并开辟一条新的路线。关于改善青光眼治疗的问题。