Lipid Deposition in the Right Ventricle in Pulmonary Arterial Hypertension
肺动脉高压右心室脂质沉积
基本信息
- 批准号:9474720
- 负责人:
- 金额:$ 15.8万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2015
- 资助国家:美国
- 起止时间:2015-01-01 至 2019-12-31
- 项目状态:已结题
- 来源:
- 关键词:AffectAnimal ModelApoptosisAutopsyCD36 AntigensCD36 geneCardiacCardiac MyocytesCardiomyopathiesCause of DeathCell Culture TechniquesCeramidesDNA Sequence AlterationDataDepositionDiagnosisDietDisease MarkerEnhancersExcisionFDA approvedFailureFatty AcidsFatty acid glycerol estersFinancial compensationFunctional disorderGoalsGrantHeart failureHumanHuman RightsImpairmentInsulin ResistanceInterventionIntracellular Accumulation of LipidsLipidsMagnetic Resonance SpectroscopyMeasuresMediatingMetabolicMetabolismMetforminModelingMusMuscle CellsMutant Strains MiceMutationMyocardialMyocardial dysfunctionMyocardiumOilsPatientsPharmacologyPulmonary HypertensionPulmonary artery structureRegulator GenesRight Ventricular DysfunctionRight Ventricular FunctionRight Ventricular HypertrophyRight ventricular structureRodent ModelStaining methodStainsStressTechnologyTestingTissuesTransgenic OrganismsTranslatingTriglyceridesVentricularVentricular Ejection FractionsWild Type MouseWorkbasebone morphogenic proteinembryonic stem cellfatty acid oxidationfatty acid transporthemodynamicshuman diseaseimprovedlipid metabolismlipid transportmortalitymouse modelmutantpromoterpublic health relevancepulmonary arterial hypertensionreceptorresponsethermozymocidintoolwestern diet
项目摘要
DESCRIPTION (provided by applicant): Right ventricular failure is the primary cause of mortality in patients with pulmonary arterial hypertension and there currently are no therapies to reverse right ventricular dysfunction. Other's work and our own preliminary data have suggested altered metabolism including decreased fatty acid oxidation and lipid deposition may contribute to right ventricular failure in both human pulmonary arterial hypertension and in rodent models of RV dysfunction associated with pulmonary arterial hypertension. We have identified both fatty acid oxidation and increased lipid transport into cardiomyocytes as mechanisms that promote right ventricular lipid accumulation. Moreover, in preliminary data we have used MR spectroscopy to measure lipid deposition in the right ventricle of a patient with pulmonary arterial hypertension and found 10 fold higher percent triglyceride compared with controls. Based on these preliminary data, we now hypothesize that cardiomyocyte lipid deposition promotes RV failure in pulmonary arterial hypertension. Multiple mechanisms may result in right ventricular myocyte lipid deposition including Western diet resulting in increased lipid import or genetic mutations associated with impaired fatty acid oxidation with resultant accumulation of fatty acid metabolites and we propose two specific aims to study the mechanisms leading to lipid accumulation and the effect of deposition on right ventricular dysfunction. Our third specifi aim will translate these findings to humans in a trial of metabolic therapy for right ventricular failure with metformin and test the effect of this fatty acid oxidation enhancer on right ventriculr lipid measured by cardiac magnetic resonance spectroscopy. We will use cell culture, rodent model and human studies to study the mechanisms by which lipid deposition occurs, the functional consequences of lipid accumulation and if metabolic interventions to decrease lipid accumulation will improve right ventricular function in both rodent models and human disease. The long-term goal of these studies is to develop effective metabolic therapy for right heart failure in pulmonary arterial hypertension.
描述(由申请人提供):右心室衰竭是肺动脉高压患者死亡的主要原因,目前尚无逆转右心室功能障碍的治疗方法。其他人的工作和我们自己的初步数据表明,代谢的改变,包括减少脂肪酸氧化和脂质沉积可能有助于右心室衰竭在人类肺动脉高压和啮齿动物模型的RV功能障碍与肺动脉高压。我们已经确定了脂肪酸氧化和增加脂质转运到心肌细胞的机制,促进右心室脂质积聚。此外,在初步数据中,我们使用MR光谱测量了肺动脉高压患者右心室的脂质沉积,发现甘油三酯百分比比对照组高10倍。基于这些初步数据,我们现在假设心肌细胞脂质沉积促进肺动脉高压时右心室衰竭。多种机制可能导致右心室肌细胞脂质沉积,包括西方饮食导致脂质输入增加或与脂肪酸氧化受损相关的基因突变,从而导致脂肪酸代谢产物的积累,我们提出了两个具体的目标来研究导致脂质积累的机制和沉积对右心室功能障碍的影响。我们的第三个具体目标是在二甲双胍治疗右心室衰竭的代谢治疗试验中将这些发现转化为人类,并通过心脏磁共振波谱测量来测试这种脂肪酸氧化增强剂对右心室脂质的影响。我们将使用细胞培养、啮齿动物模型和人体研究来研究脂质沉积发生的机制、脂质积聚的功能后果以及减少脂质积聚的代谢干预是否会改善啮齿动物模型和人类疾病中的右心室功能。这些研究的长期目标是开发有效的代谢治疗肺动脉高压右心衰竭。
项目成果
期刊论文数量(0)
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Anna R Hemnes其他文献
Future treatment paradigms in pulmonary arterial hypertension: a personal view from physicians, health authorities, and patients
肺动脉高压未来治疗模式:来自医生、卫生当局和患者的个人观点
- DOI:
10.1016/s2213-2600(24)00425-9 - 发表时间:
2025-04-01 - 期刊:
- 影响因子:32.800
- 作者:
Franck F Rahaghi;Marc Humbert;Marius M Hoeper;R James White;Robert P Frantz;Paul M Hassoun;Anna R Hemnes;Steven M Kawut;Vallerie V McLaughlin;Gergely Meszaros;Peter G M Mol;Steven D Nathan;Mitchel A Psotka;Farbod N Rahaghi;Olivier Sitbon;Norman Stockbridge;Jason Weatherald;Faiez Zannad;Sandeep Sahay - 通讯作者:
Sandeep Sahay
Anna R Hemnes的其他文献
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{{ truncateString('Anna R Hemnes', 18)}}的其他基金
Genomic and Circulating Predictors of PAH response
PAH 反应的基因组和循环预测因子
- 批准号:
10166908 - 财政年份:2019
- 资助金额:
$ 15.8万 - 项目类别:
Genomic and Circulating Predictors of PAH response
PAH 反应的基因组和循环预测因子
- 批准号:
9926307 - 财政年份:2019
- 资助金额:
$ 15.8万 - 项目类别:
Genomic and Circulating Predictors of PAH response
PAH 反应的基因组和循环预测因子
- 批准号:
10402363 - 财政年份:2019
- 资助金额:
$ 15.8万 - 项目类别:
Genomic and Circulating Predictors of PAH response
PAH 反应的基因组和循环预测因子
- 批准号:
10393072 - 财政年份:2019
- 资助金额:
$ 15.8万 - 项目类别:
Lipid Deposition in the Right Ventricle in Pulmonary Arterial Hypertension
肺动脉高压右心室脂质沉积
- 批准号:
9197665 - 财政年份:2015
- 资助金额:
$ 15.8万 - 项目类别:
A molecular phenotype of combined pulmonary hypertension
合并性肺动脉高压的分子表型
- 批准号:
8796005 - 财政年份:2014
- 资助金额:
$ 15.8万 - 项目类别:
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