The Role of TP-R on Alcohol-Induced Multi-Organ Damage: Liver and Heart
The Role of TP-R on Alcohol-Induced Multi-Organ Damage: Liver and Heart
批准号:
10526258
负责人:
Saraswathi Viswanathan
金额:
$24.18万
依托单位国家:
美国
项目类别:
财政年份:
2023
资助国家:
美国
项目状态:
未结题
起止时间:
2023-02-28 至 2028-01-31
关键词:
AffectAlcohol consumptionAlcohol-Related DisordersAlcoholic CardiomyopathyAlcoholic Liver DiseasesAlcoholsAttenuatedAutoimmune DiseasesCardiac MyocytesCardiomyopathiesCardiovascular DiseasesChronicCollecting CellCongestive Heart FailureDataDevelopmentDietEchocardiographyEicosanoidsEthanolEventExposure toFatty AcidsFatty LiverFatty acid glycerol estersFunctional disorderG-Protein-Coupled ReceptorsGeneral PopulationGeneticHabitsHealthHeartHeart DiseasesHeart InjuriesHeavy DrinkingHepaticHepatocyteHigh Fat DietHumanImpairmentIncidenceIndividualInflammationInflammatoryInflammatory ResponseIsoprostanesKnockout MiceLinkLinoleic AcidsLiverLiver diseasesMeasurementMeasuresMediatingMetabolicMitochondriaMolecularMusMyocardialNebraskaNutritionalObesityOrganOxidative StressPatientsPeripheral Blood Mononuclear CellPolyunsaturated Fatty AcidsProstaglandinsRattusReportingResearchRoleTherapeutic AgentsThromboxane A2ThromboxanesTissuesTriglyceridesWild Type Mouseantagonistchronic alcohol ingestionchronic inflammatory diseasecomparison controlconditional knockoutfeedingheart functionhemodynamicsimprovedin vivolipid metabolismliver inflammationliver injurymitochondrial dysfunctionmultiorgan damagenon-alcoholic fatty liver diseaseobese patientsorgan injuryoxidant stressreceptorreceptor expressiontherapeutically effective
中文摘要
众所周知,肝脏是乙醇作用和酒精相关肝脏的主要靶点
英文摘要
It is well-established that liver is the primary target of ethanol action and alcohol-associated liver
disease (AALD) is a major health concern in general population. It should also be noted that the
incidence of heart disease due to chronic alcohol consumption continues to rise owing to the
increased chronic alcohol drinking habits among humans. It is becoming increasingly evident that a
strong positive correlation exists between alcohol-associated liver injury (AALD) and alcoholic
cardiomyopathy (ACM). It has recently become clear that the combination of obesity with heavy
drinking exacerbates ethanol-induced organ injury. Thus, there is an urgent need to define
mechanisms by which obesity and alcohol either individually or in combination, promote liver and
cardiac injury. Central to our hypothesis is that thromboxane-prostanoid receptor (TP-R) is a
common link between AALD and ACM. TP-R is a G-protein coupled receptor, expressed in all
tissues, and is activated by thromboxane A2 as well as isoprostanes, eicosanoids mediating
inflammatory response and oxidative stress. TP-R is known to play a role in the pathophysiology of
several chronic inflammatory diseases, such as cardiovascular disease and certain autoimmune
diseases. Little is known, however about a role for TP-R in modulating obesity and alcohol-related
disorders. We present exciting preliminary data in this proposal that ethanol-induced hepatic
inflammation is greatly attenuated in TP-R-KO mice. Interestingly, our preliminary data also show
that TP-R expression is significantly higher in human peripheral blood mononuclear cells (PBMCs)
collected from patients with obesity or CVD compared to control subjects and therefore, its
involvement in both AALD and ACM might be important, and present opportunities for treatment.
Based on previous reports and our preliminary data, we hypothesize that in the presence of obesity,
chronic alcohol consumption promotes liver and cardiac injury and this effect is mediated at least in
part, via activation of TP-R through its effects on inflammation and oxidative stress. We will use
nutritional, genetic, and molecular approaches to determine the role of TP-R in altering AALD and
ACM. In Aim 1, we will define the role of hepatocyte-TP-R in modulating ethanol- and/or obesity-
induced liver injury and cardiomyopathy in mice. In Aim 2, we will assess the role of cardiomyocyte-
TP-R in modulating ethanol- and/or obesity-induced liver injury and cardiomyopathy in mice. Overall,
the proposed research will uncover the role of TP-R in modulating AALD and ACM in the presence
or absence of obesity, to identify potential mechanisms, and to set the stage for the development of
effective therapeutic agents for human patients affected by the metabolic complications of obesity
and/or excess ethanol consumption.
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The Effectiveness of NanoSOD in Ameliorating Ethanol-induced Liver Injury in Obesity
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批准号:9388032
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项目类别:
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资助金额:$18.11万
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财政年份:2017
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负责人:Saraswathi Viswanathan
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依托单位:
Project 10 - The role of nanoformulated Cu/ZnSOD in reducing systemic hypertensi
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批准号:8730202
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项目类别:
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资助金额:$22.58万
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财政年份:--
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负责人:Saraswathi Viswanathan
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依托单位:
Project 10 - The role of nanoformulated Cu/ZnSOD in reducing systemic hypertensi
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批准号:8601985
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项目类别:
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资助金额:$22.45万
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财政年份:--
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负责人:Saraswathi Viswanathan
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依托单位:
海外基金