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Stretch-activated ion channels in human neural stem cell mechanotransduction

人神经干细胞机械转导中的拉伸激活离子通道

基本信息

批准号：
8997126
负责人：
Francesco Tombola
金额：
$ 19.31万
依托单位：
UNIVERSITY OF CALIFORNIA-IRVINE
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-02-01 至 2018-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8997126
关键词：
Affect Alzheimer&apos s Disease Astrocytes Biocompatible Materials Biophysics Brain Brain Injuries Cell Culture Techniques Cell Differentiation process Cell Fate Control Cell Transplants Cell membrane Cell physiology Cells Complex Cues Data Detection Development Disease Drug Targeting Environment Event Exclusion Future Genetic Glass Goals Health Human In Vitro Injury Ion Channel Lead Light Link Mechanics Mediating Memory Molecular Neuraxis Neurons Nuclear Oligodendroglia Outcome Parkinson Disease Property Regenerative Medicine Role Signal Transduction Signaling Molecule Specific qualifier value Spinal cord injury Stem cell transplant Stem cells Stimulus Stretching Swelling Testing Therapeutic Tissues Transplantation base brain tissue cell motility cell type in vivo insight knock-down nerve stem cell neurogenesis novel relating to nervous system repaired research study stem stem cell biology stem cell differentiation stem cell fate transcription factor

项目摘要

DESCRIPTION (provided by applicant): Mechanical forces powerfully modulate stem cell fate. Despite the emerging importance of these forces in stem cell differentiation, the molecular mechanisms by which mechanical cues direct cell fate remain unknown. We propose that the stretch-activated ion channels (SACs) transduce mechanical information sensed at the plasma membrane to downstream signaling molecules that control cell fate. In this revised application we will test this hypothesis in light of new preliminary data from our group demonstrating that the recently-identified SAC Piezo1 underlies mechanotransduction currents in human neural stem/progenitor cells and influences neuronal-glial lineage choice. In Aim 1 we will directly test the hypothesis that Piezo1 links mechanical signals to downstream transcription factor activity and mechanosensitive lineage specification. In Aim 2 we will determine whether Piezo1 activity is involved in lineage specification in vivo. Together, the two Aims will establish Piezo1 as a ke signaling molecule in mechanoregulation of human neural stem/progenitor cell fate. In summary, this proposal brings together our expertise in ion channel biophysics, mechanics, biomaterials and stem cell biology to uncover a new molecular player with implications for both, basic stem cell biology and future developments in regenerative medicine.

描述(申请人提供)：机械力有力地调节干细胞的命运。尽管这些力量在干细胞分化中的重要性正在显现，但机械信号决定细胞命运的分子机制仍不清楚。我们认为，拉伸激活离子通道(SACs)将质膜上感受到的机械信息传递到控制细胞命运的下游信号分子。在这个修订的应用中，我们将根据我们团队的新的初步数据来检验这一假设，该数据表明，最近发现的SAC Piezo1是人类神经干细胞/祖细胞的机械转导电流的基础，并影响神经元-神经胶质谱系的选择。在目标1中，我们将直接测试假设Piezo1将机械信号与下游转录因子活性和机械敏感谱系规范联系起来。在目标2中，我们将确定Piezo1的活性是否与体内的谱系指定有关。这两个目标将共同确立Piezo1作为KE信号分子在人类神经干细胞/祖细胞命运的机械调节中的作用。总而言之，这项建议汇集了我们在离子通道生物物理学、力学、生物材料和干细胞生物学方面的专业知识，以揭示一个新的分子参与者，对基础干细胞生物学和再生医学的未来发展都有影响。