Targeting Macrophage Lysosome Biogenesis Program in Cardiomyopathy and Heart Failure
心肌病和心力衰竭中的靶向巨噬细胞溶酶体生物发生程序
基本信息
- 批准号:9898259
- 负责人:
- 金额:--
- 依托单位:
- 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:2018-04-01 至 2022-03-31
- 项目状态:已结题
- 来源:
- 关键词:AblationAffectAnimal ModelAnti-Inflammatory AgentsAtherosclerosisAttenuatedAutophagocytosisBiogenesisCardiacCardiac MyocytesCardiomyopathiesCause of DeathCell DeathCellsCessation of lifeChestCoronary ArteriosclerosisDataDevelopmentDiabetes MellitusDiseaseEpidemicExcisionFamily memberGenetic TranscriptionGrowthHeartHeart failureHyperlipidemiaHypertensionIncidenceInfarctionInfiltrationInflammationInflammatoryInflammatory ResponseIntermittent fastingLeft Ventricular RemodelingLigaseLipidsLysosomesMediatingMethodsMitochondriaModelingMusMyocardialMyocardial InfarctionMyocardial IschemiaMyocarditisMyocardiumNon-Insulin-Dependent Diabetes MellitusObesityPathway interactionsPeripheralPhagocytesPhagocytosisPhasePhenotypePlayPopulation GroupPrevalencePreventionPublishingQuality ControlReperfusion InjuryRisk FactorsRoleSecondary Myocardial DiseasesSecondary toSignal TransductionStressTFE3 geneTestingTherapeuticTranscription CoactivatorTranscriptional RegulationTransgenic OrganismsTrehaloseUnited StatesVeteransage groupaging populationattenuationbasecardiogenesischemokine receptordiabetic cardiomyopathygain of functioninflammatory markerloss of functionmacrophagemonocytemortalitymouse modelmyocardial infarct sizingoverexpressionpreventprogramsrecruitsedentary lifestyletherapeutic targettranslational approachvascular inflammation
项目摘要
Heart failure due to myocardial infarction (MI) is leading cause of death in the United States. Infiltration of
peripheral monocytes and resident cardiac macrophages are postulated to play a dual role in the post-MI
period, characterized by pro-inflammatory signaling and phagocytic removal of dead cells in the early phase
and a shift towards anti-inflammatory signaling to promote reparative phase. Persistence of pro-inflammatory
macrophages correlates with maladaptive left ventricular remodeling and progressive heart failure. Obesity and
resultant (type II) diabetes have reached epidemic proportions and predispose to development of heart failure
by provoking development of lipid overload in myocardium, i.e. cardiac lipotoxicity; and by promoting coronary
artery disease in concert with other risk factors such as hypertension, hyperlipidemia and a sedentary lifestyle.
Early macrophage recruitment drives inflammation and promotes development of lipotoxic cardiomyopathy in
animal models. These observations indicate that strategies to modulate macrophage inflammatory phenotype
may be of therapeutic benefit. Emerging data point to a critical role for lysosomal function in macrophage
inflammatory responses. TFEB and TFE3, two closely related family members have been demonstrated to
function as the master transcriptional activators of the lysosomal biogenesis program in macrophages, acting
in a mutually redundant fashion; and activation of TFEB and TFE3 is essential for sustaining macrophage
phagocytosis. Our preliminary and published findings demonstrate that macrophage TFEB expression
attenuates post-MI remodeling and protects against lipotoxic cell death. We have previously found that
intermittent fasting activates TFEB to stimulate lysosome function in the myocardium and attenuate cardiac
myocyte death during MI. Our preliminary data demonstrate that intermittent fasting rescues mortality and
attenuates the inflammatory response to prevent cardiomyopathy and heart failure in MHC-ACSL1 mice with
cardiac lipotoxicity due to transgenic expression of acylCoA-synthetase 1 (ACSL1); suggesting that intermittent
fasting may also modulate macrophage lysosome function and the inflammatory response. In this proposal, we
hypothesize that TFEB/TFE3-mediated transcriptional regulation of the macrophage lysosome biogenesis
program is critical to attenuate inflammatory responses in the myocardium, post-MI and under lipotoxic stress;
and can be harnessed therapeutically to prevent heart failure. In aim 1, we will examine the role of the
macrophage lysosome biogenesis program in preventing post-MI heart failure in a closed chest model of
cardiac ischemia-reperfusion injury and attenuating cardiomyopathy secondary to lipotoxicity in the MHC-ACS
mouse model. In aim 2, we will examine the mechanisms for TFEB/TFE3-mediated modulation of macrophage
phenotype. In aim 3, we will evaluate the efficacy of trehalose, an activator of TFEB/TFE3-induced lysosomal
biogenesis, in attenuating the macrophage inflammatory response and cardiomyopathy, post-MI and under
lipotoxic stress. These studies will identify TFEB/TFE3-transcriptional program as a potential therapeutic target
to modulate cardiac macrophage function in post-MI heart failure and lipotoxic cardiomyopathy. Administration
of trehalose, a naturally occurring and safe compound, has tremendous potential as a therapy to activate this
pathway for prevention and/or treatment of cardiomyopathy and heart failure.
在美国,由心肌梗死(MI)引起的心力衰竭是导致死亡的主要原因。的渗透
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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Abhinav Diwan其他文献
Abhinav Diwan的其他文献
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{{ truncateString('Abhinav Diwan', 18)}}的其他基金
Mitophagy pathways in cellular cross-talk in the myocardium
心肌细胞串扰中的线粒体自噬途径
- 批准号:
10486506 - 财政年份:2022
- 资助金额:
-- - 项目类别:
Harnessing the Lysosome Machinery to Counter Metal Toxicity
利用溶酶体机制对抗金属毒性
- 批准号:
10689401 - 财政年份:2022
- 资助金额:
-- - 项目类别:
Maternal obesity and cardiometabolic health in the offspring
母亲肥胖与后代心脏代谢健康
- 批准号:
9925261 - 财政年份:2018
- 资助金额:
-- - 项目类别:
Maternal obesity and cardiometabolic health in the offspring
母亲肥胖与后代心脏代谢健康
- 批准号:
10206245 - 财政年份:2018
- 资助金额:
-- - 项目类别:
Maternal obesity and cardiometabolic health in the offspring
母亲肥胖与后代心脏代谢健康
- 批准号:
9762209 - 财政年份:2018
- 资助金额:
-- - 项目类别:
Targeting Macrophage Lysosome Biogenesis Program in Cardiomyopathy and Heart Failure
心肌病和心力衰竭中的靶向巨噬细胞溶酶体生物发生程序
- 批准号:
10265358 - 财政年份:2018
- 资助金额:
-- - 项目类别:
Innate Immunity Pathways in Autophagy Signaling in Cardiac Myocytes
心肌细胞自噬信号传导的先天免疫途径
- 批准号:
9492022 - 财政年份:2017
- 资助金额:
-- - 项目类别:
Targeting TFEB To Microglia and Monocytes to Enhance Amyloid Degradation
将 TFEB 靶向小胶质细胞和单核细胞以增强淀粉样蛋白降解
- 批准号:
10191054 - 财政年份:2017
- 资助金额:
-- - 项目类别:
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