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:
- 金额:$ 50.03万
- 依托单位:
- 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:
- 关键词:AgonistAlzheimer&aposs DiseaseAreaBiological MarkersBloodBlood VesselsCOVID-19CalciumCardiovascular DiseasesCell physiologyCellsClinicalConfocal MicroscopyContractsDataDiseaseEndothelial CellsEnsureExtracellular MatrixFeedbackFibrosisFluid BalanceFunctional disorderHealthImmuneImpairmentInflammationInflammatoryInflammatory ResponseIntercellular JunctionsIon ChannelIschemic Brain InjuryLinkLiquid substanceLymphaticLymphatic Endothelial CellsLymphatic EndotheliumLymphatic SystemLymphatic functionLymphoid TissueMediatingMetabolic dysfunctionMetabolic syndromeMusMyographyObese MiceObesityPlasminogen Activator Inhibitor 1Platelet-Derived Growth Factor alpha ReceptorPumpRegulationResearchRoleSpeedStretchingTamoxifenTestingTherapeuticThinnessTissuesVanilloidVascular DiseasesWild Type Mouseantagonistcell typediet-induced obesityimprovedin vivoinducible Creinhibitorlipid metabolismlipid transportlung injurylymphatic dysfunctionlymphatic vasculaturelymphatic vesselnovel therapeutic interventionpharmacologicpressurepreventpromoterprotein expressionreceptorwestern 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.
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.
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Jorge Augusto Castorena-Gonzalez其他文献
Jorge Augusto Castorena-Gonzalez的其他文献
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{{ truncateString('Jorge Augusto Castorena-Gonzalez', 18)}}的其他基金
Endothelial dependent mechanisms of lymphatic dysfunction in metabolic syndrome and type-2 diabetes associated with obesity
与肥胖相关的代谢综合征和 2 型糖尿病中淋巴功能障碍的内皮依赖性机制
- 批准号:
10200130 - 财政年份:2020
- 资助金额:
$ 50.03万 - 项目类别:
Endothelial dependent mechanisms of lymphatic dysfunction in metabolic syndrome and type-2 diabetes associated with obesity
与肥胖相关的代谢综合征和 2 型糖尿病中淋巴功能障碍的内皮依赖性机制
- 批准号:
10438705 - 财政年份:2020
- 资助金额:
$ 50.03万 - 项目类别:
Endothelial dependent mechanisms of lymphatic dysfunction in metabolic syndrome and type-2 diabetes associated with obesity
与肥胖相关的代谢综合征和 2 型糖尿病中淋巴功能障碍的内皮依赖性机制
- 批准号:
9919377 - 财政年份:2019
- 资助金额:
$ 50.03万 - 项目类别: