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Piezo1 in neural stem cell mechano-regulation

Piezo1 在神经干细胞机械调节中的作用

基本信息

批准号：
10092758
负责人：
Medha M Pathak
金额：
$ 2.15万
依托单位：
UNIVERSITY OF CALIFORNIA-IRVINE
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：
2020-04-01 至 2022-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10092758
关键词：
Actins Actomyosin Age Alzheimer&apos s Disease Astrocytes Back Biochemical Biocompatible Materials Biological Assay Biomedical Engineering Biophysics Brain Cell Lineage Cell membrane Cells Cues Cytoskeleton Data Development Disease Embryo Engraftment Environment Extracellular Matrix Feeds Filament Generations Genetic Goals Image In Vitro Injury Integrins Ion Channel Knock-out Knockout Mice Measurement Measures Mechanics Microscopy Modeling Molecular Motor Mus Myosin Type II Neuraxis Neurodegenerative Disorders Neuroglia Neurons Nonmuscle Myosin Type IIB Oligodendroglia Organ Parkinson Disease Pharmacology Phenocopy Physiological Piezo 1 ion channel Preparation Process Regulation Reporting Role Shapes Signal Transduction Spinal cord injury Stem cell transplant Structure System Therapeutic Tissues Traction Transplantation Work axon guidance base behavior in vitro brain abnormalities cell motility cell type experience genetic approach high resolution imaging imaging approach in vivo insight mechanical force mechanical properties mechanotransduction nerve stem cell nervous system disorder neurodevelopment neuroregulation novel relating to nervous system repaired single molecule stem stem cells

项目摘要

Project Summary/Abstract Mechanical signals are an important influence on the development, structure, and function of the central nervous system. Neural stem/progenitor cells (NSPCs), which generate neurons, astrocytes, and oligodendrocytes, are particularly sensitive to mechanical cues. During development, mechanical signals drive NSPC lineage specification, cell migration, and axon guidance. In stem cell transplant therapy, mechanical cues experienced by stem cells both in vitro before transplantation and in vivo after transplantation influence engraftment. Despite their manifest importance, the processes by which NSPCs detect, transduce, and generate mechanical forces remain poorly understood. Our overall objective is to uncover novel molecular mechanisms underlying NPSC mechano-regulation that could be harnessed for therapeutic strategies against neurodevelopmental and neurodegenerative diseases. We recently reported that the mechanically-activated ion channel Piezo1 generates Ca2+ flickers in NSPCs, and showed that its activity promotes differentiation into neurons rather than glia. Our new preliminary data also shows that Piezo1 knockout in mice results in gross abnormalities of the brain. Intriguingly, Piezo1 is active even in the absence of externally-applied mechanical force and this activity is triggered by cellular traction forces – intracellular forces generated by the cell’s acto-myosin cytoskeleton to probe mechanical properties of the extracellular matrix. Here we examine the functional dynamics between traction forces and Piezo1 in NSPCs. Aim 1 examines how traction forces activate Piezo1; Aim 2 asks whether Piezo1 activity feeds back to modulate Myosin II activity; and Aim 3 examines the role of the mechanical signaling between Piezo1 and Myosin II in neural tissue mechanics during development. These studies will provide a mechanistic insight into Piezo1’s role in regulating NSPC behavior in vitro and in vivo.

项目总结/文摘