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：
10327700
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 2023-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10327700
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 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 control blood pressure regulation dietary hemodynamics in vivo innovation mechanical properties mechanical stimulus 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在物理刺激中转变变化的能力（例如，血液动力）进入电信号。瞬态受体电势香草素4（TRPV4）是PU- 在内皮和平滑肌细胞中表达的机械敏感Ca2+通道以及血管周围感觉神经元。尽管TRPV4与内皮和周神经有关血管征，其精确的门控机制仍然难以捉摸。已经提出了三种机制来激活机械刺激后激活TRPV4：1）磷脂酶A2（PLA2）依赖性形成欧米茄（W）-6蛛网膜酸（AA）及其代谢产物，环氧酸氧甲酸（Eets）的下游； 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述离子通道解码外源和内源性刺激以调节细胞功能的机制。在此提案中，总体目标是建立分子基础TRPV4激活。中心假设是TRPV4激活是通过脂质重塑受膜的机械性能调节。提议的理由研究计划是，一旦阐明了TRPV4激活的确切机制，就有可能定义靶向TRPV4以控制全身血压的策略。该假设将通过追求三个特定目的：1）确定W-6和W-3脂肪酸对秀丽隐杆线虫中TRPV4活性的影响； 2）检验以下假设：W-3脂肪酸衍生物增强了血管细胞中的TRPV4活性； 3）确定膜的机械性能的变化如何调节TRPV4门控。我们将利用遗传，行为，功能，生化和生物物理方法来发现脂肪酸及其代谢物对TRPV4功能的贡献。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eicosanoid衍生物对TRPV4门控的个人贡献。拟议的研究很重要，因为它有望在靶向TRPV4方面具有广泛的翻译重要性调节血管和神经元功能。

项目成果

期刊论文数量（10）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Human Dental Pulp Stem Cells and Gingival Mesenchymal Stem Cells Display Action Potential Capacity In Vitro after Neuronogenic Differentiation.

DOI：
10.1007/s12015-018-9854-5
发表时间：
2019-03
期刊：
Stem cell reviews and reports
影响因子：
4.8
作者：
Li D;Zou XY;El-Ayachi I;Romero LO;Yu Z;Iglesias-Linares A;Cordero-Morales JF;Huang GT
通讯作者：
Huang GT

Genetic- and diet-induced ω-3 fatty acid enrichment enhances TRPV4-mediated vasodilation in mice.

DOI：
10.1016/j.celrep.2022.111306
发表时间：
2022-09-06
期刊：
CELL REPORTS
影响因子：
8.8
作者：
Caires, Rebeca;Garrud, Tessa A. C.;Romero, Luis O.;Fernandez-Pena, Carlos;Vasquez, Valeria;Jaggar, Jonathan H.;Cordero-Morales, Julio F.
通讯作者：
Cordero-Morales, Julio F.

Expression and Purification of the Pain Receptor TRPV1 for Spectroscopic Analysis.

用于光谱分析的疼痛受体 TRPV1 的表达和纯化。

DOI：
10.1038/s41598-017-10426-7
发表时间：
2017
期刊：
Scientific reports
影响因子：
4.6
作者：
Velisetty,Phanindra;Stein,RichardA;Sierra-Valdez,FranciscoJ;Vásquez,Valeria;Cordero-Morales,JulioF
通讯作者：
Cordero-Morales,JulioF

Omega-3 Fatty Acids Modulate TRPV4 Function through Plasma Membrane Remodeling.

DOI：
10.1016/j.celrep.2017.09.029
发表时间：
2017-10-03
期刊：
Cell reports
影响因子：
8.8
作者：
Caires R;Sierra-Valdez FJ;Millet JRM;Herwig JD;Roan E;Vásquez V;Cordero-Morales JF
通讯作者：
Cordero-Morales JF

TRPV6 channel mediates alcohol-induced gut barrier dysfunction and systemic response.

DOI：
10.1016/j.celrep.2022.110937
发表时间：
2022-06-14
期刊：
CELL REPORTS
影响因子：
8.8
作者：
Meena, Avtar S.;Shukla, Pradeep K.;Bell, Briar;Giorgianni, Francesco;Caires, Rebeca;Fernandez-Pena, Carlos;Beranova, Sarka;Aihara, Eitaro;Montrose, Marshall H.;Chaib, Mehdi;Makowski, Liza;Neeli, Indira;Radic, Marko Z.;Vasquez, Valeria;Jaggar, Jonathan H.;Cordero-Morales, Julio F.;Rao, RadhaKrishna
通讯作者：
Rao, RadhaKrishna