The Role of Bioactive Lipids in Transient Receptor Potential Channels Gating

生物活性脂质在瞬时受体电位通道门控中的作用

基本信息

批准号：
10080740
负责人：
Julio F Cordero-Morales
金额：
$ 30.4万
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：
2018
资助国家：
美国
起止时间：
2018-01-01 至 2022-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10080740
关键词：
Acids Address Adenosine Triphosphate Adult Afferent Neurons Animal Model Arachidonic Acids Behavioral Behavioral Assay Binding Biochemical Biological Assay Biosensor Blood Vessels Caenorhabditis elegans Cardiovascular Diseases Cardiovascular system Cell membrane Cell physiology Cells Consumption Coronary artery Cues Data Development Dietary Fatty Acid Differential Scanning Calorimetry Eicosanoids Eicosapentaenoic Acid Endothelial Cells Endothelium Environment Enzymes Epoxy Compounds Family Fatty Acids G-Protein-Coupled Receptors GJB6 gene Genetic Genome Goals Human Hypertension Individual Ion Channel Knowledge Lateral Lipid Binding Lipids Liposomes Location Measures Mechanical Stimulation Mechanics Mediating Membrane Membrane Fluidity Membrane Proteins Mental Depression Mission Molecular Molecular Target Nerve Neurons P2Y2 receptor Pathway interactions Pharmaceutical Preparations Phospholipase A2 Phospholipase C Phosphorylation Physiological Polyunsaturated Fatty Acids Preparation Process Protein Kinase C Public Health Rattus Receptor Activation Research Resistance Role Signal Transduction Smooth Muscle Myocytes Stimulus Stretching Supplementation Systemic blood pressure TRP channel Testing United States United States National Institutes of Health Vanilloid Variant Vascular System Vasodilation base biophysical techniques blood pressure regulation dietary hemodynamics in vivo innovation mechanical properties member mutant novel phospholipase C gamma pressure prevent receptor reconstitution recruit side effect

项目摘要

Blood pressure regulation relies on the ability of membrane proteins to transduce variations in physical stimuli (e.g., hemodynamic forces) into electrical signals. The transient receptor potential vanilloid 4 (TRPV4) is a pu- tative mechanosensitive Ca2+ channel expressed in endothelial and smooth muscle cells and in perivascular sensory neurons. Although TRPV4 has been implicated in endothelium- and perivascular nerve-dependent vasorelaxation, its precise gating mechanism remains elusive. Three mechanisms have been proposed to activate TRPV4 after mechanical stimulation: 1) downstream of the phospholipase A2 (PLA2)-dependent formation of omega (w)-6 arachidonic acid (AA) and its metabolites, epoxyeicosatrienoic acids (EETs); 2) downstream of purinergic P2Y2 receptor activation, mediated by adenosine triphosphate release; and 3) direct activation by membrane stretch. Our long-term goal is to delineate the mechanisms by which ion channels decode exogenous and endogenous stimuli to regulate cellular function. In this proposal, the overall objective is to establish the molecular basis underlying TRPV4 activation. The central hypothesis is that TRPV4 activation is regulated by the mechanical properties of the membrane via lipid remodeling. The rationale for the proposed research plan is that once the precise mechanism of TRPV4 activation has been elucidated, it will be possible to define strategies that target TRPV4 to control systemic blood pressure. The hypothesis will be tested by pursuing three Specific Aims: 1) Determine the effect of w-6 and w-3 fatty acids on TRPV4 activity in C. elegans; 2) Test the hypothesis that w-3 fatty acid derivatives enhance TRPV4 activity in vascular cells; and 3) Determine how changes in the mechanical properties of the membrane regulates TRPV4 gating. We will leverage genetic, behavioral, functional, biochemical, and biophysical approaches to uncover the contribution of fatty acids and their metabolites to TRPV4 function. The research plan is innovative because it will determine the individual contribution of w-3 and w-6 fatty acids and their eicosanoid derivatives to TRPV4 gating. The proposed research is significant because it is expected to have broad translational importance in targeting TRPV4 to regulate vascular and neuronal function.

血压调节依赖于膜蛋白传导物理刺激变化的能力（例如，血流动力学力）转换为电信号。瞬时受体电位香草酸 4 (TRPV4) 是一种内皮细胞、平滑肌细胞和血管周围表达的固有机械敏感 Ca2+ 通道感觉神经元。尽管 TRPV4 与内皮和血管周围神经依赖性有关血管舒张作用，其精确的门控机制仍然难以捉摸。人们提出了机械刺激后激活TRPV4的三种机制：1）磷脂酶A2（PLA2）下游依赖的omega（w）-6花生四烯酸（AA）及其代谢物环氧二十碳三烯酸（EET）的形成； 2) 嘌呤能 P2Y2 受体激活的下游，由三磷酸腺苷释放介导； 3）通过膜拉伸直接激活。我们的长期目标是描绘离子通道解码外源性和内源性刺激以调节细胞功能的机制。在该提案中，总体目标是建立 TRPV4 激活的分子基础。中心假设是 TRPV4 激活是通过脂质重塑受膜的机械特性调节。拟议的理由研究计划是，一旦TRPV4激活的精确机制被阐明，就有可能定义针对 TRPV4 控制全身血压的策略。该假设将通过以下方式进行检验追求三个具体目标： 1) 确定 w-6 和 w-3 脂肪酸对秀丽隐杆线虫 TRPV4 活性的影响； 2）检验w-3脂肪酸衍生物增强血管细胞中TRPV4活性的假设；和 3) 确定膜机械特性的变化如何调节 TRPV4 门控。我们将利用遗传、行为、功能、生物化学和生物物理方法来揭示脂肪酸及其代谢物对 TRPV4 功能的贡献。该研究计划具有创新性，因为它将决定 w-3 和 w-6 脂肪酸及其类二十烷酸衍生物对 TRPV4 门控的单独贡献。拟议的研究意义重大，因为预计它在靶向 TRPV4 方面具有广泛的转化重要性调节血管和神经元功能。