Mechanisms of membrane protein trafficking and AKT/mTOR signaling that promote myelin sheath stability and growth

促进髓鞘稳定性和生长的膜蛋白运输和 AKT/mTOR 信号传导机制

基本信息

批准号：
10328875
负责人：
Adam R Almeida
金额：
$ 3.4万
依托单位：
UNIVERSITY OF COLORADO DENVER
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-01 至 2023-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10328875
关键词：
Adhesions Automobile Driving Axon Back Binding Biochemical Biochemistry Cell Adhesion Molecules Cerebellum Clustered Regularly Interspaced Short Palindromic Repeats Data Disease Early Endosome Event FRAP1 gene Fishes Genetic Epistasis Growth Image Investigation Knock-out Learning Mediating Membrane Membrane Proteins Modeling Multiple Sclerosis Mus Myelin Myelin Associated Glycoprotein Myelin Proteins Myelin Sheath Oligodendroglia Pathway interactions Pharmacology Phosphatidylinositols Process Proteins Proto-Oncogene Proteins c-akt Recycling Reporter Signal Transduction Structure Testing Time Work Zebrafish design effective therapy experimental study genetic manipulation in vivo leukodystrophy live cell imaging mTOR inhibition membrane biogenesis mutant myelin biogenesis myelination protein transport trafficking tripolyphosphate

项目摘要

Project Summary Myelin sheaths are built through a dynamic process of axonal adhesion and membrane biogenesis to form a compact, multilamellar structure. Interestingly, only a fraction of sheaths that initiate at the onset of myelination will stabilize and mature to form compact myelin. We know that axonal adhesion proteins are important for determining sheath stability. However, there is a fundamental gap in our understanding of how these molecules are maintained at the myelin/axolemma interface during the dynamic process of myelin wrapping. Additionally, AKT/mTOR signaling is an important driver of membrane biogenesis in oligodendrocytes. However, we do not know whether AKT/mTOR signaling drives ensheathment events or rather this pathway acts downstream of axonal adhesion. Therefore, our objective here is to investigate the mechanisms for trafficking myelin/axonal adhesion molecules and for activating AKT/mTOR signaling to promote sheath stabilization and growth. In aim 1, we will use a combination of genetic manipulations, in vivo live-cell imaging, and biochemistry to investigate the mechanisms of membrane trafficking that localize MAG to the axolemma interface. In aim 2 we will use a MAG knockout fish line to perform genetic epistasis experiments to determine if the AKT/mTOR pathway promotes sheath stabilization downstream of axonal adhesion. Together this project will elucidate how AKT/mTOR signaling interfaces with membrane protein trafficking pathways to build a myelin sheath.

项目概要髓鞘是通过轴突粘附和膜生物发生的动态过程构建的形成致密的多层结构。有趣的是，只有一小部分鞘在开始时启动髓鞘形成将稳定并成熟，形成致密的髓鞘。我们知道轴突粘附蛋白是对于确定护套稳定性很重要。然而，我们对如何实现这一目标的理解存在根本性差距。在髓磷脂的动态过程中，这些分子维持在髓磷脂/轴膜界面包装。此外，AKT/mTOR 信号传导是细胞膜生物发生的重要驱动因素。少突胶质细胞。然而，我们不知道 AKT/mTOR 信号传导是否驱动鞘事件或相反，该途径作用于轴突粘附的下游。因此，我们这里的目标是调查运输髓磷脂/轴突粘附分子和激活 AKT/mTOR 信号传导的机制促进鞘稳定和生长。在目标 1 中，我们将结合体内基因操作活细胞成像和生物化学研究将 MAG 定位到的膜运输机制轴膜界面。在目标 2 中，我们将使用 MAG 敲除鱼线来执行遗传上位性确定 AKT/mTOR 通路是否促进轴突下游鞘稳定的实验附着力。该项目将共同阐明 AKT/mTOR 信号传导如何与膜蛋白相互作用构建髓鞘的运输途径。