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Function and Regulation of PMP22 in CMT1A and HNPP

PMP22 在 CMT1A 和 HNPP 中的功能和调控

基本信息

批准号：
10684083
负责人：
Kathryn Renae Moss
金额：
$ 23.6万
依托单位：
JOHNS HOPKINS UNIVERSITY
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：
2021-09-21 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10684083
关键词：
Acceleration Adherens Junction Adhesions Affect Aging Award Axon Biophysics Canis familiaris Career Transition Award Cell Adhesion Cell membrane Cell model Cells Charcot-Marie-Tooth Disease Complement Complex Confocal Microscopy Development Disease Electrical Resistance Electron Microscopy Gene Dosage Genes Goals Hereditary Motor and Sensory Neuropathy Type I Hereditary neuropathy with liability to pressure palsies Human Inherited Intercellular Junctions Investigation Knowledge Label MDCK cell Membrane Membrane Microdomains Mentorship Microscopy Modeling Modification Molecular Neurobiology Morphology Myelin Nerve Nerve Fibers PMP22 gene Pathogenesis Peripheral Peripheral Nerves Peripheral Nervous System Diseases Phase Phenotype Positioning Attribute Regulation Research Research Personnel Role Schwann Cells System Tamoxifen Technical Expertise Techniques Therapeutic Tight Junctions Training Transfection Vesicle Work biophysical properties biophysical techniques career confocal imaging dosage dysmyelination improved inducible Cre kidney epithelial cell mouse model mutant myelination overexpression palmitoylation protein function success superresolution microscopy therapeutically effective therapy development ultra high resolution

项目摘要

Project Summary/Abstract The fact that both duplication and deletion of the Peripheral Myelin Protein 22 (PMP22) gene cause dysmyelinating peripheral neuropathy illustrates the importance of PMP22 for peripheral myelin integrity. PMP22 duplication causes Charcot-Marie-Tooth Disease Type 1A (CMT1A) and PMP22 deletion causes Hereditary Neuropathy with Liability to Pressure Palsies (HNPP). Although CMT1A and HNPP are the most common inherited peripheral neuropathies, research on them is underfunded and there are currently no disease-modifying treatments. This is largely due to the fact that PMP22 function and the consequence of altered PMP22 expression remain unclear. Thus, there is a critical need to expand knowledge of what PMP22 does in myelin, how it is regulated and when precise expression is required as a means to improve therapeutic potential of CMT1A and HNPP. This proposal aims to utilize cutting-edge techniques, including conditional mouse models and super resolution microscopy, and knowledge of cell adhesion and membrane biophysics to advance understanding of CMT1A and HNPP pathomechanisms. My central hypothesis is that PMP22 gene dosage and lipid raft association govern localization and organization of myelin adherens and tight junctions; a function that is most critical during development. In Aim 1, I will determine how PMP22 regulates adhesion junction organization in peripheral nerve myelin during development and aging with super resolution and electron microscopy. I will aid the interpretation of these studies by evaluating the effects of altered PMP22 expression on prototypical adherens and tight junctions in Madin-Darby Canine Kidney (MDCK) epithelial cells. The temporal requirement for precise PMP22 expression in myelin will also be defined by generating powerful conditional mouse models of CMT1A and HNPP. In Aim 2, I will determine how palmitoylation impacts PMP22 lipid raft association and regulation of adhesion junctions and define the biophysical properties of PMP22 within the plasma membrane using MDCK and Schwann cell models of CMT1A and HNPP and advanced biophysical methods. This K22 Career Transition Award will provide me with additional training, mentorship and expertise in cell adhesion, membrane biophysics and microscopy, thereby enabling my proposed research and facilitating my transition to independence. This training will complement my previous training in cell and molecular neurobiology and my current peripheral nerve training, and the expertise acquired during Phase I will be applied to more complex models in Phase II to expand mechanistic details. Completion of these aims will accelerate progress towards my long-term goal of developing an independent academic research career studying pathomechanisms of CMT1A and HNPP as a means to improve their therapeutic potential. The training and mentorship provided by this award will expand my technical skills and expertise, positioning me for success as an independent investigator.

项目总结/文摘