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:改良肌钙蛋白T改善心力衰竭患者心功能
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)
数据更新时间:{{ journalArticles.updateTime }}
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
Jian-Ping Jin其他文献
Jian-Ping Jin的其他文献
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
{{ 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:
相似海外基金
Preclinical test for the efficacy of adrenergic agents in treatment of AD
肾上腺素能药物治疗AD疗效的临床前试验
- 批准号:
8358448 - 财政年份:2012
- 资助金额:
$ 39.98万 - 项目类别:
Preclinical test for the efficacy of adrenergic agents in treatment of AD
肾上腺素能药物治疗AD疗效的临床前试验
- 批准号:
8517552 - 财政年份:2012
- 资助金额:
$ 39.98万 - 项目类别:
MODULATING FLUID THERAPY WITH ADRENERGIC AGENTS AND CYCLIC AMP ENHANCERS IN
使用肾上腺素能药物和环放大器增强剂调节液体治疗
- 批准号:
7952159 - 财政年份:2009
- 资助金额:
$ 39.98万 - 项目类别:
THE EFFECT OF BETA-ADRENERGIC AGENTS AND FLUID THERAPY IN HUMANS
β-肾上腺素能药物和液体疗法对人体的影响
- 批准号:
7952152 - 财政年份:2009
- 资助金额:
$ 39.98万 - 项目类别:
MODULATING FLUID THERAPY WITH ADRENERGIC AGENTS AND CYCLIC AMP ENHANCERS IN
使用肾上腺素能药物和环放大器增强剂调节液体治疗
- 批准号:
7719194 - 财政年份:2008
- 资助金额:
$ 39.98万 - 项目类别:
THE EFFECT OF BETA-ADRENERGIC AGENTS AND FLUID THERAPY IN HUMANS
β-肾上腺素能药物和液体疗法对人体的影响
- 批准号:
7605416 - 财政年份:2007
- 资助金额:
$ 39.98万 - 项目类别:
MODULATING FLUID THERAPY WITH ADRENERGIC AGENTS AND CYCLIC AMP ENHANCERS IN
使用肾上腺素能药物和环放大器增强剂调节液体治疗
- 批准号:
7605425 - 财政年份:2007
- 资助金额:
$ 39.98万 - 项目类别:
THE EFFECT OF BETA-ADRENERGIC AGENTS AND FLUID THERAPY IN HUMANS
β-肾上腺素能药物和液体疗法对人体的影响
- 批准号:
7378753 - 财政年份:2006
- 资助金额:
$ 39.98万 - 项目类别:
Adrenergic Agents for Methamphetamine: Outpatient Trials
甲基苯丙胺肾上腺素药物:门诊试验
- 批准号:
6825160 - 财政年份:2004
- 资助金额:
$ 39.98万 - 项目类别:
ADRENERGIC AGENTS FOR CARDIOPULMONARY RESUSCITATION
用于心肺复苏的肾上腺素能药物
- 批准号:
2702283 - 财政年份:1997
- 资助金额:
$ 39.98万 - 项目类别: