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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.

项目总结