A Pathogenic Role for Natriuretic Peptide Receptor-C in Pulmonary Hypertension and Heart Failure with Preserved Ejection Fraction
钠尿肽受体-C 在肺动脉高压和射血分数保留的心力衰竭中的致病作用
基本信息
- 批准号:10463813
- 负责人:
- 金额:$ 15.84万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2021
- 资助国家:美国
- 起止时间:2021-08-10 至 2026-07-31
- 项目状态:未结题
- 来源:
- 关键词:Advisory CommitteesAffectAgonistAnimal ModelBiogenesisBiopsy SpecimenCardiac MyocytesCardiovascular systemCatheterizationCause of DeathCell LineCell modelCellsClustered Regularly Interspaced Short Palindromic RepeatsCommunicationCyclic AMPCyclic AMP-Dependent Protein KinasesCyclic GMPDataDevelopmentDiagnosisDiseaseEFRACElectron MicroscopyEnzyme-Linked Immunosorbent AssayFailureFoundationsFundingGenerationsGenesGenus HippocampusGoalsHeartHeart failureHigh Fat DietHospitalizationHumanHypertrophyImpairmentIn VitroKnock-outKnockout MiceMeasurementMediatingMedicineMentorsMentorshipMetabolicMetabolic dysfunctionMetabolismMitochondriaModelingMorbidity - disease rateMyoblastsMyocardialNatriuresisNatriuretic PeptidesObesityOutcomePathogenesisPathogenicityPatientsPeptide ReceptorPersonsPhysiciansPlasmidsPreventionPrincipal InvestigatorPulmonary HypertensionRegulationRelaxationResearchResourcesRespirationRight Ventricular DysfunctionRight Ventricular FunctionRoleScientistSignal PathwaySignal TransductionSurfaceTamoxifenTechniquesTestingTissuesTrainingTraining SupportTransgenic MiceVentricularWestern BlottingWorkcareercareer developmentepidemiology studyfatty acid oxidationimprovedimproved outcomein vivoinduced pluripotent stem cellinduced pluripotent stem cell derived cardiomyocytesknock-downmetabolomicsmitochondrial dysfunctionmortalitymyocardial biopsynew therapeutic targetnovelnovel therapeuticsobesity treatmentoverexpressionpatient populationpreservationpreventprotein expressionreceptorreceptor expressionright ventricular failureskillstherapeutic evaluationtherapeutic target
项目摘要
Project Summary/Abstract:
Heart failure with preserved ejection fraction (HFpEF) affects over 3 million people nationwide and carries a
75% 5-year mortality. Unlike other forms of heart failure, there are currently no treatment options for HFpEF
that reduce mortality. A common cause of morbidity and mortality in HFpEF is right ventricular (RV) failure, and
there are currently no therapies directly targeting RV failure in heart failure. Regardless of the cause, studies
have shown that the failing RV undergoes a metabolic shift characterized by decreased utilization of fatty acid
oxidation for energy generation and increased mitochondrial dysfunction. While restoring fatty acid oxidation
and mitochondrial function are thought to be beneficial, there are currently no therapies that can successfully
do so in the failing RV. The goal of the proposal is to support the career development of Dr. Vineet Agrawal by
providing him the training, mentorship, and resources to pursue a career in identifying mechanisms by which
obesity and metabolic dysfunction fundamentally alter RV metabolism to promote failure, and secondarily
identify viable therapies to improve outcomes in a patient population that currently has none. This work is
supported by primary mentor, Dr. Anna Hemnes, and a complementary research advisory committee. Dr.
Agrawal will leverage their combined mentorship to study the role of a novel therapeutic target, natriuretic
peptide clearance receptor NPRC, in the treatment of obesity-induced HFpEF. The central hypothesis of this
proposal is that increased NPRC expression in the HFpEF RV results in RV failure through impaired
mitochondrial biogenesis and fatty acid oxidation. This central hypothesis will be tested in two specific aims
that will test the following hypotheses: (1) that knockdown of NPRC in a model of obesity-induced HFpEF
prevents and reverses RV failure by restoring fatty acid oxidation and mitochondrial biogenesis, and (2) NPRC
directly inhibits mitochondrial biogenesis and fatty acid oxidation in vitro through cAMP and cGMP-mediated
regulation of PGC1α. This proposal will utilize a novel transgenic mouse in which NPRC can inducibly be
knocked out to study the role of NPRC in vivo, and CRISPR edited human induced pluripotent stem cells and
H9C2 cardiomyocyte-like cells to study the role of NPRC in modulating cardiomyocyte function in vitro.
Through the studies proposed to test the hypotheses above, Dr. Agrawal will also accomplish the following
career development and training objectives to: (1) master techniques to study mitochondrial function and
metabolism of tissue and cells, (2) master techniques to generate and differentiate human induced pluripotent
stem cells and cardiomyocytes (hiPSCs), (3) master techniques in gene editing in vitro, and (4) refine
professional development and communication skills to achieve goals of academic progress, effective
communication, and successful R01 submission.
项目概要/摘要:
射血分数正常的心力衰竭(HFpEF)影响着全国300多万人,
5年死亡率为75%。与其他形式的心力衰竭不同,目前没有HFpEF的治疗选择
从而降低死亡率。HFpEF发病和死亡的常见原因是右心室(RV)衰竭,
目前没有直接靶向心力衰竭中RV衰竭的疗法。不管是什么原因,研究
已经表明,失败的RV经历了以脂肪酸利用率降低为特征的代谢转变
用于能量产生的氧化和增加的线粒体功能障碍。同时恢复脂肪酸氧化
和线粒体功能被认为是有益的,目前还没有治疗方法可以成功地
在失败的RV中这样做。该提案的目标是通过以下方式支持Vineet Agrawal博士的职业发展:
为他提供培训、指导和资源,以从事确定机制的职业,
肥胖和代谢功能障碍从根本上改变RV代谢,促进衰竭,
确定可行的治疗方法,以改善目前没有治疗方法的患者群体的结局。这项工作是
由主要导师安娜赫姆尼斯博士和一个补充研究咨询委员会支持。博士
Agrawal将利用他们的联合指导来研究一种新的治疗靶点,利钠剂的作用
肽清除受体NPRC,治疗肥胖诱导的HFpEF。这个问题的核心假设是
建议HFpEF RV中NPRC表达增加导致RV衰竭,
线粒体生物合成和脂肪酸氧化。这一中心假设将在两个具体目标中得到检验
这将测试以下假设:(1)在肥胖诱导的HFpEF模型中,NPRC的敲除
通过恢复脂肪酸氧化和线粒体生物合成来预防和逆转RV衰竭,以及(2)NPRC
在体外通过cAMP和cGMP介导直接抑制线粒体生物合成和脂肪酸氧化
PGC 1 α的调节该建议将利用一种新的转基因小鼠,其中NPRC可以诱导
敲除以研究NPRC在体内的作用,CRISPR编辑人诱导多能干细胞,
H9 C2心肌样细胞,以研究NPRC在体外调节心肌细胞功能中的作用。
通过上述研究,Agrawal博士还将完成以下工作:
职业发展和培养目标:(1)掌握研究线粒体功能的技术,
组织和细胞的代谢,(2)掌握技术,以产生和分化的人诱导多能
干细胞和心肌细胞(hiPSC),(3)掌握体外基因编辑技术,以及(4)完善
专业发展和沟通能力,以实现目标的学术进步,有效
沟通,并成功提交R 01。
项目成果
期刊论文数量(1)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
The Latest in Animal Models of Pulmonary Hypertension and Right Ventricular Failure.
最新的肺动脉高压和右心室衰竭动物模型。
- DOI:10.1161/circresaha.121.319971
- 发表时间:2022-04-29
- 期刊:
- 影响因子:20.1
- 作者:Boucherat O;Agrawal V;Lawrie A;Bonnet S
- 通讯作者:Bonnet S
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Vineet Agrawal其他文献
Vineet Agrawal的其他文献
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{{ truncateString('Vineet Agrawal', 18)}}的其他基金
A Pathogenic Role for the Natriuretic Peptide Clearance Receptor in Heart Failure with Preserved Ejection Fraction.
钠尿肽清除受体在射血分数保留的心力衰竭中的致病作用。
- 批准号:
10589324 - 财政年份:2023
- 资助金额:
$ 15.84万 - 项目类别:
A Pathogenic Role for Natriuretic Peptide Receptor-C in Pulmonary Hypertension and Heart Failure with Preserved Ejection Fraction
钠尿肽受体-C 在肺动脉高压和射血分数保留的心力衰竭中的致病作用
- 批准号:
10301687 - 财政年份:2021
- 资助金额:
$ 15.84万 - 项目类别:
ECM Degradation and Macrophage Polarization in Endogenous Stem Cell Recruitment
内源干细胞招募中的 ECM 降解和巨噬细胞极化
- 批准号:
7912172 - 财政年份:2010
- 资助金额:
$ 15.84万 - 项目类别:
ECM Degradation and Macrophage Polarization in Endogenous Stem Cell Recruitment
内源干细胞招募中的 ECM 降解和巨噬细胞极化
- 批准号:
8296675 - 财政年份:2010
- 资助金额:
$ 15.84万 - 项目类别:
ECM Degradation and Macrophage Polarization in Endogenous Stem Cell Recruitment
内源干细胞招募中的 ECM 降解和巨噬细胞极化
- 批准号:
8122283 - 财政年份:2010
- 资助金额:
$ 15.84万 - 项目类别:
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