Modification of Troponin T to Improve Cardiac Function in Heart Failure
肌钙蛋白 T 的修饰可改善心力衰竭患者的心脏功能
基本信息
- 批准号:10392565
- 负责人:
- 金额:$ 39.98万
- 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:2021-05-05 至 2025-02-28
- 项目状态:未结题
- 来源:
- 关键词:ATP phosphohydrolaseAdrenergic AgentsBindingC-terminalCalmodulinCardiacCardiac Muscle ContractionCardiovascular DiseasesChronicClinicalClinical TreatmentComplexCongestive Heart FailureDevelopmentEpitopesExhibitsFamilyGenesGoalsHeartHeart RateHeart failureHypertrophic CardiomyopathyImmunoglobulin Variable RegionIschemiaKineticsLeftLinkLong-Term EffectsMicrofilamentsModelingModificationMolecularMolecular ConformationMolecular TargetMusMutationMyocardialMyocardial IschemiaMyocardial dysfunctionMyocardiumMyosin Light ChainsN-terminalOrganPhasePhysiologic intraventricular pressurePhysiologicalPhysiological AdaptationPlant RootsPositioning AttributePost-Translational Protein ProcessingPost-Translational RegulationProtein SubunitsProteolysisRegulationRelaxationReperfusion TherapyRepressionResearchStressStriated MusclesStroke VolumeStructureTestingThin FilamentTimeTransgenic MiceTranslatingTranslationsTropomyosinTroponinTroponin CTroponin ITroponin TVentricularWild Type Mouseeffectiveness evaluationgenetic regulatory proteinheart functionimprovedin vivomouse modelnovelnovel strategiespreservationpressurereceptorresponsetranslational study
项目摘要
Project Title: Modification of Troponin T to Improve Cardiac Function in Heart Failure
Project Summary
Cardiac muscle contraction is regulated via the troponin complex in sarcomeric thin filaments. Troponin
consists of three protein subunits: troponin C (TnC), troponin I (TnI), and troponin T (TnT). A restrictive
cleavage that selectively removes the N-terminal variable region of cardiac TnT (cTnT) naturally occurs as
an adaptation to myocardial energetic crisis such as ischemia or pressure overload. The N-terminal
truncated cTnT (cTnT-ND) remains in the cardiac myofilaments with altered functionality to physiologically
tune down left ventricular systolic velocity, which elongates the phase of rapid ejection, thereby increasing
stroke volume and improving the energetic efficiency of the heart. The proposed research will characterize
the mechanism by which cTnT-ND alters the kinetics of myofilament activity to allow the heart to
physiologically compensate for energetic crisis, and will ultimately lay groundwork for the development of
new targeted treatments for heart failure. Three Specific Aims are proposed:
Aim I is to characterize how the deletion of the N-terminal variable region of cTnT restores a repressed
TnI-like C-terminal conformation to result in a conditional inhibition of myofilament ATPase and contractile
kinetics.
Aim II is to assess the effectiveness of cTnT-ND on compensating for cardiac dysfunction and
improving cardiac efficiency in heart failure mouse models with in vivo and ex vivo functional studies.
Aim III is to assess the long-term effects of cTnT-ND on cardiac function, reserve and remodeling in
normal and failing mouse hearts for translation to new treatments for heart failure.
Significance: Heart failure is a major challenge in the management of cardiovascular diseases. While
b-adrenergic blockade has proven to be clinically effective in treating chronic congestive heart failure, the
long-term benefit of decreasing contractile kinetics remains incompletely understood. The restrictive
deletion of the N-terminal segment of cTnT naturally occurs during myocardial ischemia and pressure
overload as a posttranslational regulation to selectively tune down contractile velocity of cardiac muscle and
elongate the rapid ejection phase to increase stroke volume and cardiac efficiency. This mechanism
provides a novel and specifically targeted approach to sustain baseline cardiac function during energetic
crisis and heart failure. Using multi-level and integrative approaches, our study will lay the groundwork for
translating this molecular mechanism into a new clinical treatment for heart failure.
项目名称: 肌钙蛋白T修饰对心力衰竭患者心功能的影响
项目摘要
通过肌节细丝中的肌钙蛋白复合物调节心肌收缩。
由三种蛋白质亚基组成:肌钙蛋白C(TnC)、肌钙蛋白I(TnI)和肌钙蛋白T(TnT)。
选择性去除心肌肌钙蛋白T(cTnT)的N端可变区的切割天然发生,
对心肌能量危机如缺血或压力超负荷的适应。
截短的cTnT(cTnT-cTn ND)保留在心肌肌丝中,其功能改变,
降低左心室收缩期速度,延长快速射血期,从而增加
每搏输出量和提高心脏的能量效率。拟议的研究将表征
cTnT-β 2-ND改变肌丝活性动力学以使心脏
生理上弥补能量危机,并最终为发展奠定基础。
心力衰竭的新靶向治疗。提出了三个具体目标:
目的I是表征cTnT N端可变区的缺失如何恢复受抑制的
TnI-β样C-β末端构象导致肌丝ATP酶和收缩功能的条件性抑制,
动力学。
目的二是评价cTnT-BND对心功能不全的代偿作用,
通过体内和离体功能研究改善心力衰竭小鼠模型的心脏效率。
目的III是评估cTnT-β 2-ND对心脏功能、储备和重塑的长期影响,
正常和衰竭的小鼠心脏,用于转化为心力衰竭的新疗法。
意义:心力衰竭是心血管疾病管理的主要挑战。
B β-肾上腺素能阻滞剂已被证明在治疗慢性充血性心力衰竭方面是临床有效的,
降低收缩动力学的长期益处仍不完全清楚。
cTnT的N端缺失在心肌缺血和压力升高时自然发生
超负荷作为翻译后调节以选择性地下调心肌的收缩速度,
延长快速射血期以增加每搏输出量和心脏效率。
提供了一种新的和特别有针对性的方法,以维持基线心脏功能,
采用多层次、综合性的研究方法,
将这种分子机制转化为心力衰竭的新临床治疗方法。
项目成果
期刊论文数量(3)
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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Jian-Ping Jin其他文献
Jian-Ping Jin的其他文献
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{{ truncateString('Jian-Ping Jin', 18)}}的其他基金
Regulation of Troponin I in Cardiac Adaptation & Failure
肌钙蛋白 I 在心脏适应中的调节
- 批准号:
10349218 - 财政年份:2016
- 资助金额:
$ 39.98万 - 项目类别:
C-terminal Peptide of Cardiac Troponin I for the Treatment of Diastolic Hear Failure
心肌肌钙蛋白 I C 端肽治疗舒张性心力衰竭
- 批准号:
10658193 - 财政年份:2016
- 资助金额:
$ 39.98万 - 项目类别:
C-terminal Peptide of Cardiac Troponin I for the Treatment of Diastolic Hear Failure
心肌肌钙蛋白 I C 端肽治疗舒张性心力衰竭
- 批准号:
10850280 - 财政年份:2016
- 资助金额:
$ 39.98万 - 项目类别:
Regulation of Troponin I in Cardiac Adaptation & Failure
肌钙蛋白 I 在心脏适应中的调节
- 批准号:
9053622 - 财政年份:2016
- 资助金额:
$ 39.98万 - 项目类别:
Detection of Host Response In Clostridium Difficile Infection
艰难梭菌感染中宿主反应的检测
- 批准号:
8859073 - 财政年份:2015
- 资助金额:
$ 39.98万 - 项目类别:
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