Novel quantitative proteomic approaches to define the altered interplay between OGlcNAcylation and Phosphorylation in myofilament dysfunction of diabetic hearts
新的定量蛋白质组学方法来定义糖尿病心脏肌丝功能障碍中 OGlcNAc 酰化和磷酸化之间相互作用的改变
基本信息
- 批准号:9494653
- 负责人:
- 金额:$ 12.47万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2016
- 资助国家:美国
- 起止时间:2016-09-01 至 2018-09-17
- 项目状态:已结题
- 来源:
- 关键词:Adrenergic AgentsAdultAlanineAnabolismAspartic AcidBasic ScienceBiomedical ResearchCalciumCardiacCardiac healthCardiologyCardiovascular systemChildComplicationCore FacilityCoronary ArteriosclerosisDataDepressed moodDiabetes MellitusDiagnosticDiseaseDoctor of PhilosophyEchocardiographyEnvironmentEquilibriumEtiologyFacultyFellowshipFoundationsFrequenciesFunctional disorderFundingFutureGene TransferGene Transfer TechniquesGlucoseGoalsHeartHeart DiseasesHeart failureHexosaminesHumanImpairmentIn VitroIndividualIonsK-Series Research Career ProgramsKnowledgeLabelLeadLinkMapsMass Spectrum AnalysisMeasurementMedicalMedical StudentsMentorsMexican AmericansMicrofilamentsMolecularMolecular MotorsMuscleMyocardialMyocardial dysfunctionMyocardiumNational Heart, Lung, and Blood InstituteNorth AmericaPathway interactionsPatientsPediatric cardiologyPhosphorylationPhosphorylation SitePhysiologicalPlayPost-Translational Protein ProcessingPostdoctoral FellowPrevalencePropertyProteinsProteomicsReportingResearchResearch PersonnelResearch ProposalsRiskRoleSarcomeresSchemeScientistSerineSiteTechniquesTestingThreonineTimeTrainingTraining SupportTranslational ResearchTranslationsTroponin IUnited States National Institutes of HealthUniversitiesVariantWorkWorkloadadeno-associated viral vectorcareerdiabeticdiabetic cardiomyopathydiabetic patientexperiencegene transfer vectorglucose metabolismheart functionimprovedin vivoinorganic phosphateinterestmedical schoolsmitochondrial dysfunctionmultiple reaction monitoringmuscle physiologymutantnovelnovel therapeuticspandemic diseasepediatric departmentprofessorresponseskillsstoichiometrysuccesstitanium dioxidetool
项目摘要
Project Abstract/Summary
The candidate
I am a Mexican-American MD/PhD who works as a basic scientist. I am also an Assistant Professor in
the Johns Hopkins School of Medicine, Division of Pediatric Cardiology where I also completed my post-
doctoral fellowship training. My interest in and commitment to a translational and basic research career started
as a 4th year medical student. I am convinced that funding through the NIH/NHLBI Mentored Career
Development Award to Promote Faculty Diversity in Biomedical Research will be instrumental to achieve my
goal, which is to become an independent investigator and a future leader in the field of molecular cardiology
and its translation into the advancement of therapies of diabetic cardiomyopathy and heart failure.
Research Proposal: Novel quantitative proteomic approaches to define the altered interplay between
O-GlcNAcylation and Phosphorylation in myofilament dysfunction of diabetic hearts
In North America, the 2010 prevalence of diabetes was 37.4 million (10.2%) and is on a steady rise16.
Diabetic patients are 2 to 4 times more at risk of dying from heart disease than the general population17.
Among cardiovascular complications, diabetic cardiomyopathy refers to a progressive diastolic and systolic
dysfunction due to a contractile deficit of the cardiac muscle that develops independently from coronary artery
disease. While it is present in 60% of diabetic patients, no therapy is currently available to halt or significantly
alter the course of diabetic cardiomyopathy18.
Post-translational modifications of the sarcomere regulate cardiac function and when dysregulated
contribute to cardiac dysfunction. Recent work in our group has focused on the identification, quantification and
functional characterization of myofilament O-GlcNAcylation and Phosphorylation1-8. The goal of this proposal is
to use state of the art quantitative proteomic approaches to extensively map and perform site-specific
quantification of all potentially O-GlcNAcylated and Phosphorylated myofilament proteins of normal and
diabetic hearts during baseline cardiac function and during β-adrenergic and force-frequency stimulation. By
comparing O-GlcNAc/Phosphate stoichiometry changes between baseline and enhanced workload we will
identify key sites for abnormal myofilament function in diabetic cardiomyopathy. By using gene transfer
techniques, the present proposal also will perform in vivo and in vitro functional work to define the role of the
interplay between O-GlcNAcylation and Phosphorylation and the mechanisms that lead to impaired cardiac
contractile reserve in diabetes. Advances in this field can potentially generate early diagnostic tools for diabetic
cardiomyopathy and open new therapeutic venues to fix the
molecular motors of a failing diabetic heart. The specific aims of
this proposal are
Aim 1: To perform global myofilament site-specific O-
GlcNAcylation and Phosphorylation mapping and quantification in
normal and type 2 diabetic hearts.
Aim 2: To identify O-GlcNAcylated and Phosphorylated sites with
the greatest stoichiometric variation during β-adrenergic and
force-frequency stimulation in normal and type 2 diabetic heart
myofilaments.
Aim 3: To validate the functional impact of altered balance of O-GlcNAcylation and Phosphorylation competing
sites on cardiac contractility by manipulating myofilament proteins with gene transfer.
The environment
The Johns Hopkins School of Medicine possesses an excellent environment to perform basic and
translational research. Johns Hopkins University has a strong foundation and facilities in research focused on
diseases of adults and children. For example, the Department of Pediatrics presently has 27 million dollars in
NIH research dollars. The medical campus will enable the candidate to access numerous state-of-the-art core
facilities. The mentors, advisors and collaborators outlined in this application will assist in a successful
completion of the candidate career and research goals. We have assembled a superb team of fine scientist
and established faculty with many years of experience and great success mentoring young scientists. My main
mentor is Dr. Anne M Murphy, co-mentor is Dr. Jennifer Van Eyk. Dr. Gerald W. Hart and Dr. Brian O'Rourke
form the advisor committee.
项目摘要/总结
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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Genaro Antonio Ramirez-Correa其他文献
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{{ truncateString('Genaro Antonio Ramirez-Correa', 18)}}的其他基金
Novel quantitative proteomic approaches to define the altered interplay between OGlcNAcylation and Phosphorylation in myofilament dysfunction of diabetic hearts
新的定量蛋白质组学方法来定义糖尿病心脏肌丝功能障碍中 OGlcNAc 酰化和磷酸化之间相互作用的改变
- 批准号:
9166064 - 财政年份:2016
- 资助金额:
$ 12.47万 - 项目类别:
Novel quantitative proteomic approaches to define the altered interplay between OGlcNAcylation and Phosphorylation in myofilament dysfunction of diabetic hearts
新的定量蛋白质组学方法来定义糖尿病心脏肌丝功能障碍中 OGlcNAc 酰化和磷酸化之间相互作用的改变
- 批准号:
10004702 - 财政年份:2016
- 资助金额:
$ 12.47万 - 项目类别:
Novel quantitative proteomic approaches to define the altered interplay between OGlcNAcylation and Phosphorylation in myofilament dysfunction of diabetic hearts
新的定量蛋白质组学方法来定义糖尿病心脏肌丝功能障碍中 OGlcNAc 酰化和磷酸化之间相互作用的改变
- 批准号:
9336333 - 财政年份:2016
- 资助金额:
$ 12.47万 - 项目类别:
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