Trpv4 regulation of lymphatic vascular function: Implications in metabolic syndrome

Trpv4 对淋巴管功能的调节：对代谢综合征的影响

基本信息

批准号：
10638806
负责人：
Jorge Augusto Castorena-Gonzalez
金额：
$ 50.03万
依托单位：
TULANE UNIVERSITY OF LOUISIANA
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-03-20 至 2028-02-29
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10638806
关键词：
Agonist Alzheimer&apos s Disease Area Biological Markers Blood Blood Vessels COVID-19 Calcium Cardiovascular Diseases Cell physiology Cells Clinical Confocal Microscopy Contracts Data Disease Endothelial Cells Ensure Extracellular Matrix Feedback Fibrosis Fluid Balance Functional disorder Health Immune Impairment Inflammation Inflammatory Inflammatory Response Intercellular Junctions Ion Channel Ischemic Brain Injury Link Liquid substance Lymphatic Lymphatic Endothelial Cells Lymphatic Endothelium Lymphatic System Lymphatic function Lymphoid Tissue Mediating Metabolic dysfunction Metabolic syndrome Mus Myography Obese Mice Obesity Plasminogen Activator Inhibitor 1 Platelet-Derived Growth Factor alpha Receptor Pump Regulation Research Role Speed Stretching Tamoxifen Testing Therapeutic Thinness Tissues Vanilloid Vascular Diseases Wild Type Mouse antagonist cell type diet-induced obesity improved in vivo inducible Cre inhibitor lipid metabolism lipid transport lung injury lymphatic dysfunction lymphatic vasculature lymphatic vessel novel therapeutic intervention pharmacologic pressure prevent promoter protein expression receptor western diet

项目摘要

PROJECT SUMMARY A major function of the lymphatic system is fluid transport, which is critical for fluid homeostasis, lipid transport and metabolism, and the transport of immune cells and pro-inflammatory molecules. Lymphatic vessels contract spontaneously to pump fluid, while intraluminal one-way valves ensure net forward flow. Our group and others have shown that obesity and metabolic syndrome can cause different forms of lymphatic vascular dysfunction. In fact, this connection is a dysfunction- and disease-promoting feedback loop, as lymphatic dysfunction also contributes to obesity. This suggests pharmacological improvement of lymphatic function as a potential therapeutic alternative in obesity and metabolic syndrome. Relevant to this proposal, transient receptor potential vanilloid 4 (Trpv4) channels are key regulators of vascular function, and their activity is dysregulated in various inflammatory diseases, including obesity and metabolic syndrome; however, the role of Trpv4 channels in regulating lymphatic vascular function in health and disease remains unexplored. Our preliminary studies show that overactivity of Trpv4 channels in a variety of cell types within and around the lymphatic wall is detrimental to different aspects of the function of the lymphatic vasculature, including impairment of contractility and compromised barrier function. Importantly, partial deficiency of Trpv4 channels in the lymphatic endothelium prevented significant impairment of lymphatic function upon stimulation of Trpv4 channels. Trpv4 channels have also been implicated in regulatory mechanisms of tissue fibrosis via activation of the Plasminogen Activator Inhibitor-1 (PAI-1) leading to remodeling of the extracellular matrix. PAI-1 is an important biomarker for disease, fibrosis, and inflammation. We recently showed that PAI-1 is significantly increased in the lymphatic vasculature of diet-induced obese mice; and globally deficient PAI-1 mice are significantly protected against diet-induced obesity and metabolic dysfunction; however, the underlying mechanisms remain unknown. In line with the emerging significant role of the lymphatic system in lipid metabolism, we hypothesize that, in obesity and metabolic syndrome, increased PAI-1 can be a key modulator of Trpv4 overactivity, and this is detrimental for lymphatic vascular function, which reciprocally exacerbates obesity. We propose evaluating PAI-1 as a long-term therapeutic alternative for direct or indirect modulation of Trpv4 activity. We anticipate that reducing inflammation and fibrosis via PAI-1 inhibition will decrease direct activation of Trpv4 channels in two ways, 1) by decreasing inflammatory molecules; and 2) by reducing stiffening of the extracellular matrix, and therefore decreasing stretch-mediated activation. As important regulators of inflammatory responses, dual targeting of Trpv4 and PAI-1 may offer synergistic therapeutic benefits, to be evaluated in this proposal. This project will provide fundamental information about Trpv4 channels in the regulation of lymphatic vascular function and will identify the role of lymphatic Trpv4 channels in obesity and metabolic syndrome.

项目概要淋巴系统的主要功能是液体运输，这对于液体稳态、脂质运输至关重要和新陈代谢，以及免疫细胞和促炎分子的运输。淋巴管收缩自发地泵送流体，而腔内单向阀确保净向前流动。我们组和其他人研究表明，肥胖和代谢综合征可引起不同形式的淋巴血管功能障碍。事实上，这种联系是一个促进功能障碍和疾病的反馈循环，因为淋巴功能障碍也会导致肥胖。这表明改善淋巴功能的药理作用是一种潜在的治疗方法。肥胖和代谢综合征的替代治疗方法。与该提案相关的是，瞬时受体电位 vanilloid 4 (Trpv4) 通道是血管功能的关键调节因子，其活性在多种疾病中失调。炎症性疾病，包括肥胖和代谢综合征；然而，Trpv4 通道的作用在健康和疾病中调节淋巴管功能仍有待探索。我们的初步研究表明淋巴壁内部和周围多种细胞类型中 Trpv4 通道的过度活跃对淋巴管系统功能的不同方面有害，包括收缩力受损以及屏障功能受损。重要的是，淋巴内皮中 Trpv4 通道部分缺乏防止 Trpv4 通道刺激后淋巴功能的显着损害。 Trpv4 频道有还通过纤溶酶原激活剂的激活参与组织纤维化的调节机制 Inhibitor-1 (PAI-1) 导致细胞外基质重塑。 PAI-1是疾病的重要生物标志物，纤维化和炎症。我们最近发现淋巴脉管系统中的 PAI-1 显着增加饮食诱导的肥胖小鼠；全面缺乏 PAI-1 的小鼠可显着免受饮食诱导的影响肥胖和代谢功能障碍；然而，其根本机制仍然未知。符合淋巴系统在脂质代谢中的重要作用正在显现，我们假设，在肥胖和代谢综合征中，PAI-1 增加可能是 Trpv4 过度活跃的关键调节剂，这是不利于淋巴血管功能，进而加剧肥胖。我们建议评估 PAI-1 作为直接或间接调节 Trpv4 活性的长期治疗替代方案。我们预计通过抑制 PAI-1 减少炎症和纤维化将减少 Trpv4 的直接激活通过两种方式调节通道，1）通过减少炎症分子； 2）通过减少细胞外的僵硬基质，从而减少拉伸介导的激活。作为炎症反应的重要调节因子， Trpv4 和 PAI-1 的双重靶向可能会提供协同治疗益处，这一点将在本提案中进行评估。该项目将提供Trpv4通道在淋巴管调节中的基础信息功能，并将确定淋巴 Trpv4 通道在肥胖和代谢综合征中的作用。