Pathophysiological Regulation of Metabolism and Energy Use during Heart Failure
Pathophysiological Regulation of Metabolism and Energy Use during Heart Failure
批准号:
10227925
负责人:
Gregory Aubert
金额:
$15.94万
依托单位国家:
美国
项目类别:
财政年份:
2019
资助国家:
美国
项目状态:
已结题
起止时间:
2019-08-15 至 2022-07-31
关键词:
ABCC9 geneAdultAffectAnimalsArrhythmiaBiological SciencesCantu syndromeCardiacCardiac MyocytesCardiomegalyCardiomyopathiesCardiovascular DiseasesCell RespirationCellsClinicalClinical SciencesCommunicationCost of IllnessDataDevelopmentDilated CardiomyopathyDiseaseDown-RegulationEnergy MetabolismExhibitsFacultyFailureGene MutationGenerationsGenesGenetic studyGenetically Engineered MouseGlucoseGlycolysisHealthcareHeartHeart failureHumanHuman GeneticsImpairmentIndividualInstitutesIschemiaLeadLinkMentorshipMetabolicMetabolismMethodsMitochondriaMolecularMusMuscle CellsMutationMyocardialMyocardial dysfunctionMyocardiumNeonatalOutcomePathway interactionsPatientsPerinatal mortality demographicsPhenotypePhysiciansPhysiologicalPopulationPotassiumPrevalenceProductionProteinsRNAReactive Oxygen SpeciesRegulationResearchResearch PersonnelRodentRoleScientistStructureTestingTherapeuticTissuesTranslational ResearchUnited StatesVariantVentricular ArrhythmiaWorkcardiogenesisconstrictiondesignfunctional lossgenetic variantheart functionheart metabolismimprovedin vivoinduced pluripotent stem cellmedical schoolsmetabolic abnormality assessmentmouse modelnovel therapeuticsoxidationphysiologic stressorpressurepreventprogramsreceptorresponseskillsstressorsulfonylurea receptortargeted treatmenttherapy developmenttranslational medicine
中文摘要
项目总结/文摘
英文摘要
PROJECT SUMMARY/ABSTRACT
The objectives of this proposal are to 1) nurture the development of Dr. Gregory Aubert to become a successful
physician scientist investigator in the field of cardiovascular disease with focus on cardiac metabolism, and 2) to
better outline the role of the sulfonylurea receptor 2 (SUR2) in the control of cardiomyocyte metabolism under
physiological stressors, and more specifically in the development of heart failure. This application has been
designed to help Dr. Aubert succeed in his transition to an independent investigator through 1) graduate level
and junior faculty coursework in the Loyola Stritch School of medicine and Northwestern Clinical and
Translational Sciences Institute and the Interdisciplinary Biological Sciences program 2) development of
proficiency in new scientific methods such as human induced pluripotent stem cell (hiPSC) derived
cardiomyocyte and gene editing, 3) improvement of skills in scientific communication and translational medicine
through structured mentorship. Many current therapies for heart failure are directed at disturbances in the
neurohormonal axis and do not directly target the cardiomyocyte. Evidence is emerging that alterations in
myocyte energy metabolism and substrate utilization are key components of the heart failure development.
Nonetheless, the exact mechanisms leading to this metabolic shift are not well delineated. Human genetic
studies have identified mutations in the ABCC9 gene, which encodes SUR2, in the development of dilated
cardiomyopathy and ventricular arrhythmias. Mice globally deleted for Abcc9/SUR2 develop heart failure in the
neonatal window with a failure to transition normally to oxidative metabolism. Given the role of SUR2 and its
partner proteins to modulate cardiac energetics, we believe that this protein could serve as a new target in the
treatment of heart failure. The rationale for the proposed research is to better understand SUR2 regulation of
cardiomyocyte metabolism in order to manipulate energy expenditure in heart failure. To prove this hypothesis,
we will use a genetically engineered mouse model with downregulation of SUR2 as well as human induced
pluripotent stem cells-derived cardiomyocytes derived from patients having ABCC9 genetic variants with heart
failure and arrhythmia phenotypes. This will provide us with the unique opportunity to corroborate the findings
from animals with those from human cardiomyocytes. As a consequence of the work proposed, we expect to
determine the cellular and physiological role of SUR2 in rodent and human cardiomyocyte. Combining in vivo
genetically modified mouse models and human derived cells is expected to vertically advance understanding of
how SUR2 can be better manipulated for therapeutic purpose.
期刊论文(2)
专著(0)
科研奖励(0)
会议论文
DOI:
10.3389/fcvm.2023.1105581
发表时间:
2023
期刊:
FRONTIERS IN CARDIOVASCULAR MEDICINE
影响因子:
3.6
作者:
[Hatahet, Jomana, Cook, Tyler M., Bonomo, Raiza R., Elshareif, Nadia, Gavini, Chaitanya K., White, Chelsea R., Jesse, Jason, Mansuy-Aubert, Virginie, Aubert, Gregory]
通讯作者:
Aubert, Gregory
海外基金