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:10004702
- 负责人:
- 金额:$ 12.46万
- 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 2022-05-31
- 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 IType 2 diabeticUnited 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/摘要
候选人
我是墨西哥裔美国医学博士,从事基础科学工作。我也是一名助理教授
约翰霍普金斯医学院,儿科心脏病学部,我也在那里完成了我的职位-
博士研究生奖学金培训。我开始了对翻译和基础研究事业的兴趣和承诺
作为一名四年级的医科学生。我相信,通过NIH/NHLBI指导的职业生涯提供资金
促进生物医学研究教师多元化的发展奖将有助于实现我的
目标是成为分子心脏病学领域的独立研究者和未来的领导者
并将其转化为糖尿病心肌病和心力衰竭治疗的进展。
研究建议:用新的定量蛋白质组学方法来确定
O-GlcN酰化和磷酸化在糖尿病心脏肌丝功能障碍中的作用
在北美,2010年糖尿病患病率为3740万人(10.2%),而且还在稳步上升。
糖尿病患者死于心脏病的风险是普通人群的2到4倍。
在心血管并发症中,糖尿病心肌病指的是进行性的舒张期和收缩期
独立于冠状动脉发育的心肌收缩缺陷所致的功能障碍
疾病。虽然它存在于60%的糖尿病患者中,但目前还没有治疗方法可以停止或显著
改变糖尿病心肌病的病程18。
肌节的翻译后修饰调节心脏功能,并在失调时
会导致心脏功能不全。我们小组最近的工作集中在识别、量化和
肌丝O-GlcN酰化和磷酸化1-8的功能特征。这项提议的目标是
使用最先进的定量蛋白质组学方法广泛地定位和执行特定的位点
所有可能的O-GlcN酰化和磷酸化的肌丝蛋白的定量
糖尿病心脏在基础心功能期间以及在β肾上腺素能和力频刺激期间。通过
比较基线和增强工作负载之间O-GlcNAc/磷酸化学计量比的变化,我们将
找出糖尿病心肌病肌丝功能异常的关键部位。通过使用基因转移
技术,本提案还将在体内和体外进行功能工作,以确定
O-GlcN酰化和磷酸化的相互作用及其导致心脏损害的机制
糖尿病患者的收缩储备。这一领域的进展可能会产生糖尿病的早期诊断工具
心肌病和开辟新的治疗场所来修复
糖尿病心脏衰竭的分子马达。的具体目标
这项建议是
目标1:进行全局肌丝部位特异性O-
谷氨酰胺酰化和磷酸化定位及定量
正常心脏和2型糖尿病心脏。
目的2:鉴定O-GlcN酰化和磷酸化位点
β-肾上腺素能和
力频刺激对正常和2型糖尿病心脏的影响
肌丝。
目的3:验证O-GlcN酰化和磷酸化竞争平衡改变对功能的影响
通过基因转移操纵肌丝蛋白对心肌收缩能力的影响。
环境问题
约翰霍普金斯医学院拥有良好的环境,可以进行基础和
翻译研究。约翰霍普金斯大学在研究方面拥有雄厚的基础和设施
成人和儿童的疾病。例如,儿科目前有2700万美元
国立卫生研究院的研究经费。医学园将使候选人能够访问许多最先进的核心
设施。本申请中概述的导师、顾问和协作者将帮助成功
完成应聘者的职业生涯和研究目标。我们已经组建了一支优秀的科学家团队
拥有多年经验并在指导年轻科学家方面取得巨大成功的知名教师。我的Main
导师是安妮·M·墨菲博士,共同导师是詹妮弗·范·埃克博士。杰拉尔德·W·哈特博士和布莱恩·奥鲁尔克博士
组建顾问委员会。
项目成果
期刊论文数量(9)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Epidemiological Algorithm for Early Detection of COVID-19 Cases in a Mexican Oncologic Center.
用于早期检测墨西哥肿瘤中心的COVID-19病例的流行病学算法。
- DOI:10.3390/healthcare10030462
- 发表时间:2022-03-01
- 期刊:
- 影响因子:0
- 作者:González-Escamilla M;Pérez-Ibave DC;Burciaga-Flores CH;Ortiz-Murillo VN;Ramírez-Correa GA;Rodríguez-Niño P;Piñeiro-Retif R;Rodríguez-Gutiérrez HF;Alcorta-Nuñez F;González-Guerrero JF;Vidal-Gutiérrez O;Garza-Rodríguez ML
- 通讯作者:Garza-Rodríguez ML
Heart Failure-Related Hyperphosphorylation in the Cardiac Troponin I C Terminus Has Divergent Effects on Cardiac Function In Vivo.
- DOI:10.1161/circheartfailure.117.003850
- 发表时间:2017-09
- 期刊:
- 影响因子:0
- 作者:Li Y;Zhu G;Paolocci N;Zhang P;Takahashi C;Okumus N;Heravi A;Keceli G;Ramirez-Correa G;Kass DA;Murphy AM
- 通讯作者:Murphy AM
Risk Association of TOX3 and MMP7 Gene Polymorphisms with Sporadic Breast Cancer in Mexican Women.
- DOI:10.3390/curroncol29020086
- 发表时间:2022-02-11
- 期刊:
- 影响因子:0
- 作者:Solis-Coronado O;Villarreal-Vela MP;Rodríguez-Gutiérrez HF;González-Guerrero JF;Cerda-Flores RM;Alcorta-Núñez F;Camarillo-Cárdenas KP;Pérez-Ibave DC;Vidal-Gutiérrez O;Ramírez-Correa GA;Garza-Rodríguez ML
- 通讯作者:Garza-Rodríguez ML
Identification of a Novel Pathogenic Rearrangement Variant of the APC Gene Associated with a Variable Spectrum of Familial Cancer.
- DOI:10.3390/diagnostics11030411
- 发表时间:2021-02-28
- 期刊:
- 影响因子:0
- 作者:Garza-Rodríguez ML;Treviño V;Pérez-Maya AA;Rodríguez-Gutiérrez HF;González-Escamilla M;Elizondo-Riojas MÁ;Ramírez-Correa GA;Vidal-Gutiérrez O;Burciaga-Flores CH;Pérez-Ibave DC
- 通讯作者:Pérez-Ibave DC
Prolactin Expression in the Baboon (Papio hamadryas) Eye.
- DOI:10.3390/ani12172288
- 发表时间:2022-09-03
- 期刊:
- 影响因子:0
- 作者:
- 通讯作者:
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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:
9494653 - 财政年份:2016
- 资助金额:
$ 12.46万 - 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:
9166064 - 财政年份:2016
- 资助金额:
$ 12.46万 - 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:
$ 12.46万 - 项目类别:
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