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.

机械敏感的离子通道依靠膜组成将物理刺激转移到电信号中。压电通道介导机械转导的机械转导，以调节关键的生理过程，包括血管结构和重塑，细胞迁移，红细胞体积，触摸，振动和前置感受。压电1和压电2是小鼠中必不可少的蛋白敲除导致患有严重缺陷的动物。在人类中，压电通道获得了功能丧失突变与遗传性人类病理生理有关。压电1中的突变与脱水的遗传性气孔病，这是一种溶血性贫血，其特征是阳离子渗透性增加和脱水红细胞。因此，必须确定调节压电通道的蛋白质和脂质机制。已经表明，磷酸肌醇和磷脂酰丝氨酸易位调节压电通道活动。然而，在很大程度上尚不清楚含饮食脂肪酸的磷脂如何调节压电1和压电2机械门控。我们的长期目标是确定基础的机制生物活性脂质如何调节机械敏感的离子通道。在此提案中，总体目标是建立通过饮食脂肪酸调节的分子基础压电通道。中心假设是压电通道激活和灭活受膜的机械性能调节脂质重塑。拟议的研究计划的理由是，一旦确定了脂肪酸调节压电通道功能的精确机制，就可以使用脂肪酸来控制血管功能并改善遗传性疾病的作用。该假设将通过追求来检验三个具体目的：1）确定脂肪酸成分如何通过变化调节压电1的活性膜刚度； 2）确定饮食脂肪酸对导致红细胞的压电1突变的影响疾病； 3）检验饱和脂肪酸减少压电2激活的假设。我们将利用功能性，生化和生物物理方法，以发现生物活性脂质对机械敏的贡献。该研究计划具有创新性，因为它利用使用饮食脂肪酸来控制压电通道机械响应。拟议的研究很重要，因为预计它将在靶向涉及血管和神经元功能的压电通道中具有广泛的翻译影响。