AS160 as a nodal regulator of the cardiac response to metabolic stress
AS160 作为心脏对代谢应激反应的节点调节剂
基本信息
- 批准号:10518319
- 负责人:
- 金额:$ 56.32万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2022
- 资助国家:美国
- 起止时间:2022-08-01 至 2027-07-31
- 项目状态:未结题
- 来源:
- 关键词:ADRBK1 geneAdipocytesAdipose tissueAdultAdverse effectsAffectAmericanBindingBiological MarkersBiologyBody mass indexCardiacCardiac MyocytesCardiometabolic DiseaseCardiovascular systemCause of DeathCentral obesityChronicCo-ImmunoprecipitationsComplexConsensusCountryCuesDataDiabetes MellitusDietDiseaseEpidemicFunctional disorderG protein coupled receptor kinaseGLUT 4 proteinGoalsHeartHeart DiseasesHeart failureHigh Fat DietHomeostasisHumanImmunoprecipitationInsulinInsulin ResistanceInsulin Signaling PathwayIntervention StudiesInvestigationKnock-inKnock-outKnowledgeLeftLengthLife StyleLinkMass Spectrum AnalysisMediatingMembraneMetabolicMetabolic DiseasesMetabolic stressMetabolic syndromeMetabolismMitochondriaModelingMusMutationMyocardial dysfunctionN-terminalNodalNon-Insulin-Dependent Diabetes MellitusObesityOrganOutcomePathogenesisPathway AnalysisPathway interactionsPatientsPeptidesPerformancePhenotypePhosphorylationPhosphotransferasesPhysiologicalProtein InhibitionProteinsProteomicsProto-Oncogene Proteins c-aktRegulationResearchRespirationRoleSamplingSeverity of illnessSignal TransductionSkeletal MuscleStressStrokeTertiary Protein StructureTherapeutic InterventionTissue SampleTranslatingUnited StatesVentricularVesicleWomanWorkabdominal fatadipokinesatherosclerosis riskcardiometabolismcardioprotectioncardiovascular disorder riskcardiovascular risk factorcrosslinkdiet-induced obesitydriving forceflexibilitygenetic risk factorglucose uptakeheart functionheart metabolismimprovedinhibitorinsightinsulin receptor substrate 1 proteininsulin regulationinsulin sensitivityinsulin signalinginterestknock-downmenmortalitymouse modelnegative affectnovel strategiesnovel therapeutic interventionobese personpreservationpressurerecruitresponsesmall moleculesystemic inflammatory responsetargeted treatmenttherapeutic targettraffickinguptake
项目摘要
PROJECT SUMMARY
Heart disease is the leading cause of death for both men and women in the United States. Cardiovascular
mortality rates positively correlate with the presence of diabetes, obesity and metabolic syndrome, which are
rising in epidemic proportions and leading to poor outcomes including heart failure. There is a consensus that
abdominal obesity is a major driving force in the pathogenesis of metabolic syndrome, with severe adverse
effects on cardiovascular risk factors. In the midst of a growing recognition of how adipose tissue dysfunction
and adipokine imbalance affect cardiac disease in the obese population, a less-well understood mechanism is
the effect of cardiac metabolism and function on systemic metabolic homeostasis. In fact, little is known about
the factors that link cardiac dysfunction and systemic metabolism. I have a long-standing interest in translational
cardiovascular research, with previous investigations showing that elevated GRK2 activity and expression occurs
early in disease and contributes to progression. Recently, my lab has shown that cardiac restricted expression
of a short, amino terminal fragment of GRK2 (βARKnt) is cardioprotective. Further, while GRK2 negatively affects
insulin signaling through a direct interaction with and phosphorylation of insulin receptor substrate-1 (IRS1),
βARKnt enhances activation of the insulin signaling pathway and mitochondrial efficiency. Our preliminary data
also show that βARKnt reduces abdominal fat content and preserves systemic insulin responsiveness during
high fat diet-induced obesity. Currently, we discovered selective interactions of endogenous GRK2 and βARKnt
with Akt substrate of 160kDa (AS160). Pathway analysis of this proteomic data confirmed an AS160/GRK2 link
and involved numerous regulators of insulin signaling. AS160 has been identified as nodal regulator between
insulin signaling and glucose uptake, but research into its physiological role in cardiomyocyte metabolism has
been hampered by limitations of available or selected models. We hypothesize that enhancing AS160 signaling
in cardiomyocytes improves their metabolic flexibility in a cardioprotective manner and translates these to
beneficial effects on systemic insulin responsiveness. Aim 1 will interrogate the physiological role of cardiac
AS160 in insulin-stimulated GLUT4 membrane trafficking and the functional consequences for metabolite uptake
and mitochondrial respiration in the heart. Aim 2 will elucidate the composition of the cardiac AS160 regulatory
complex using cross-linking/mass spectrometry to visualize the components and their interactions in human left
ventricular samples from patients with heart failure with or without diabetes compared to murine mimics of
disease. These studies seek to fill important gaps in our knowledge regarding the composition of the cardiac
AS160 regulatory complex, how it is altered during cardiometabolic stress, how it regulates cardiomyocyte
metabolite utilization, and whether it translates this to influencing systemic metabolic performance. Our overall
goal is to gain a better understanding of the regulation and relevance of AS160 in cardiomyocyte insulin-
responsiveness and whether it represents a therapeutic target for cardiometabolic disease.
项目总结
项目成果
期刊论文数量(0)
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科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Sarah Marie Bass其他文献
Sarah Marie Bass的其他文献
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{{ truncateString('Sarah Marie Bass', 18)}}的其他基金
AS160 as a nodal regulator of the cardiac response to metabolic stress
AS160 作为心脏对代谢应激反应的节点调节器
- 批准号:
10674917 - 财政年份:2022
- 资助金额:
$ 56.32万 - 项目类别:
Unique Domain Features of GRK2 and Roles in Cardiovascular Disease
GRK2 的独特结构域特征及其在心血管疾病中的作用
- 批准号:
9332419 - 财政年份:2016
- 资助金额:
$ 56.32万 - 项目类别:
Unique Domain Features of GRK2 and Roles in Cardiovascular Disease
GRK2 的独特结构域特征及其在心血管疾病中的作用
- 批准号:
9899299 - 财政年份:2016
- 资助金额:
$ 56.32万 - 项目类别:
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