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Regulation of mechanosensitive ion channels by membrane lipids

膜脂对机械敏感离子通道的调节

基本信息

批准号：
10200845
负责人：
Valeria Vasquez
金额：
$ 32.68万
依托单位：
UNIVERSITY OF TENNESSEE HEALTH SCI CTR
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-08-01 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10200845
关键词：
Acids Animals Architecture Arthrogryposis Ataxia Atomic Force Microscopy Binding Sites Biochemical Blood Pressure Blood Vessels Cations Cell Line Cell Volumes Cell membrane Cells Cholesterol Cues Data Defect Development Dietary Fatty Acid Dietary intake Disease Eicosapentaenoic Acid Electrophysiology (science)Embryo Endothelial Cells Erythrocyte volume Erythrocytes Family Fatty Acids Functional disorder Goals Hemolytic Anemia Hereditary Disease Human Inherited Ion Channel Knock-out Knowledge Light Lipids Mechanics Mediating Membrane Membrane Lipids Membrane Proteins Mission Modality Molecular Mus Mutation Nerve Neural Conduction Neurons Outcome Pathway interactions Permeability Phenotype Phosphatidylinositols Phosphatidylserines Phospholipids Physiological Processes Piezo 1 ion channel Piezo 2 ion channel Piezo ion channels Polyunsaturated Fatty Acids Proprioception Proteins Public Health Regulation Research Saturated Fatty Acids Signal Transduction Site-Directed Mutagenesis Stimulus Stretching Testing Text Touch sensation Translating United States National Institutes of Health Vascular Endothelial Cell base biophysical techniques cell motility dietary effective therapy gain of function human disease improved innovation liquid chromatography mass spectrometry loss of function mutation mechanical force mechanical properties member mutant neuroblastoma cell pain sensation patch clamp response stomatocytic anemia translational impact vibration

项目摘要

Mechanosensitive ion channels rely on membrane composition to transduce physical stimuli into electrical signals. Piezo channels mediate mechanoelectrical transduction to regulate crucial physiological processes, including vascular architecture and remodeling, cell migration, erythrocyte volume, touch, vibration, and proprioception. Piezo1 and Piezo2 are essential proteins in mice, as global knockouts are embryonic lethal and cell-specific knockouts result in animals with severe defects. In humans, Piezo channels gain- and loss-of-function mutations have been associated with hereditary human pathophysiologies. Mutations in Piezo1 are associated with dehydrated hereditary stomatocytosis, a hemolytic anemia characterized by increased cation permeability and dehydrated erythrocytes. Hence, it is essential to determine the proteins and lipids that regulate Piezo channels gating mechanisms. It has been shown that phosphoinositides and phosphatidylserine translocation regulate Piezo channels activity. However, it remains largely unknown how dietary fatty acids-containing phospholipids modulate Piezo1 and Piezo2 mechanical gating. Our long-term goal is to determine the mechanisms underpinning how bioactive lipids modulate mechanosensitive ion channels. In this proposal, the overall objective is to establish the molecular basis underlying Piezo channels modulation by dietary fatty acids. The central hypothesis is that Piezo channels activation and inactivation are regulated by the mechanical properties of the membrane via lipid remodeling. The rationale for the proposed research plan is that once the precise mechanisms are determined whereby fatty acids modulate Piezo channels function, it will be possible to use fatty acids to control vascular function and ameliorate the effects of hereditary disorders. The hypothesis will be tested by pursuing three Specific Aims: 1) Determine how fatty acid composition modulates Piezo1 activity through changes in membrane stiffness; 2) Determine the effect of dietary fatty acids on Piezo1 mutations causing red blood cell disorders; and 3) Test the hypothesis that saturated fatty acids decrease Piezo2 activation. We will leverage functional, biochemical, and biophysical approaches to uncover the contribution of bioactive lipids to mechanosensation. The research plan is innovative because it exploits the use of dietary fatty acids to control Piezo channels mechanical response. The proposed research is significant because it is expected to have broad translational impact in targeting Piezo channels, involved in vascular and neuronal function.

机械敏感离子通道依靠膜成分将物理刺激转化为电信号。压电通道介导机电转导来调节重要的生理过程，包括血管结构和重塑、细胞迁移、红细胞体积、触觉、振动和本体感觉。Piezo1和Piezo2在小鼠中是必需的蛋白，因为全局敲除是胚胎致命的和细胞特异性的