Proteolytic Regulation of Troponin T & Cardiac Function

肌钙蛋白 T 的蛋白水解调节

基本信息

  • 批准号:
    8291272
  • 负责人:
  • 金额:
    $ 51.92万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2010
  • 资助国家:
    美国
  • 起止时间:
    2010-07-01 至 2014-06-30
  • 项目状态:
    已结题

项目摘要

DESCRIPTION (provided by applicant): Cardiac muscle contraction is regulated by Ca2+ through the troponin complex that consists of three protein subunits: troponin C, troponin I, and troponin T (TnT). This research project investigates the role of a novel posttranslational modification of cardiac TnT (cTnT) in myocardial adaptation to energetic crisis. We recently reported a restricted N-terminal proteolysis of cTnT in myocardial ischemia-reperfusion (Zhang et al., Biochemistry 45:11681-94, 2006) and pressure overload (Feng et al., J. Physiol. 586:3537-50, 2008). This modification selectively removes the N-terminal variable region of cTnT but keeps the conserved middle and C-terminal regions intact. Initial studies in transgenic mouse hearts showed that the N-terminal truncated cTnT (cTnT-ND) remains functional in the myofilaments and alters myocardial contractility. This finding has lead to a hypothesis that the proteolytic removal of the N-terminal variable region of cTnT produces a functional state in cardiac muscle thin filaments as acute adaptation to energetic crisis. To test this hypothesis and understand the physiological and pathophysiological significance of cTnT- ND, three Specific Aims are proposed in this research project: Aim I will characterize the effects of the selective deletion of the N-terminal variable region on the function of cTnT. We will examine the interactions of cTnT-ND with other thin filament regulatory proteins and its functional impacts on the Ca2+ activation of myofibril ATPase and the contractility of cardiac muscle. Aim II will study the role of N-terminal truncated cTnT in compensating cardiac function and providing myocardial protection against ischemia-reperfusion injury. The acute and chronic effects of cTnT-ND on heart function and its role in overcoming energetic crisis will be investigated in ex vivo working hearts and in vivo. Aim III will investigate the role of mechanical stretch of the cardiac muscle in inducing the restricted proteolytic cleavage of cTnT N-terminal segment in order to understand the mechanisms that regulates this posttranslational regulation. Using integrated experimental systems, this study will gain new knowledge for the structure-function relationships of TnT and lay a foundation for future development of new treatment of ischemic heart disease and heart failure. PUBLIC HEALTH RELEVANCE: Myocardial contraction is essential for heart function. The contraction of cardiac muscle is regulated by calcium via the function of troponin, a protein complex in muscle cells. Cardiac troponin T (cTnT) is a subunit of the troponin complex in cardiac muscle. In a recent study, we found a restricted cleavage of cTnT in stress conditions such as acute myocardial ischemia. This modification of cTnT selectively removes the N-terminal variable region and keeps the remaining conserved structure in the myofibrils with functional consequences. Initial studies of transgenic mouse hearts showed that the N-terminal truncated cTnT (cTnT- ND) has a beneficial effect on the pumping efficiency of the heart. This observation lead us to propose a novel hypothesis that the removal of the N-terminal segment of cTnT is a rapid posttranslational mechanism to produce a transient functional state in the cardiac muscle for coping with energetic crisis. In the present study, we will characterize the physiological and pathophysiological functions of cTnT-ND. We shall examine the effects of restricted N-terminal truncation on the biochemical function of cTnT, the calcium activation of myofibril motors and the contractility of cardiac muscle. The potential role of cTnT-ND in reducing myocardial dysfunction and protecting the cardiac muscle during ischemia will be studied in isolated working hearts and in living animals. The mechanisms for mechanical stretch to induce the production of cTnT-ND will also be investigated. These experiments will provide new information for understanding the role of cTnT-ND in myocardial adaptation to energetic crisis. Using integrated physiological systems, this experimental research will also contribute key information for the structure-function relationship of TnT and lay a foundation for future development of new treatment of ischemic heart diseases and heart failure.
描述(由申请人提供): 肌钙蛋白复合体由肌钙蛋白C、肌钙蛋白I和肌钙蛋白T三个亚基组成,钙离子通过肌钙蛋白复合体调节心肌收缩。本研究项目探讨了一种新的心脏TnT翻译后修饰(CTnT)在心肌对能量危机适应中的作用。我们最近报道了心肌缺血-再灌注(Zhang等人,生物化学45:11681-94,2006年)和压力超负荷(冯等人,J.Physiol)中cTnT的N端限制性蛋白分解。586:3537-50,2008)。该修饰选择性地去除了cTnT的N-末端可变区,但保留了保守的中间和C-末端区域。对转基因小鼠心脏的初步研究表明,N端截断的cTnT(cTnT-ND)在肌丝中仍具有功能,并改变心肌的收缩能力。这一发现导致了一种假说,即cTnT N端可变区的蛋白水解性移除会在心肌细丝中产生一种功能状态,作为对能量危机的急性适应。为了验证这一假说,了解cTnT-ND的生理和病理生理学意义,本研究提出了三个具体的目标:目的研究选择性缺失N端可变区对cTnT功能的影响。我们将研究cTnT-ND与其他细丝调节蛋白的相互作用,以及它对肌原纤维ATPase的钙激活和心肌收缩的功能影响。目的研究N端截短型cTnT在代偿心功能和抗心肌缺血再灌注损伤中的作用。CTnT-ND对心脏功能的急性和慢性影响及其在克服能量危机中的作用将在体外工作心脏和体内进行研究。目的研究机械牵张心肌在诱导cTnT N末端限制性蛋白水解性切割中的作用,以了解这种翻译后调控的机制。 利用集成的实验系统,本研究将对TNT的结构与功能关系获得新的认识,并为未来开发治疗缺血性心脏病和心力衰竭的新方法奠定基础。 公共卫生相关性: 心肌收缩对心脏功能是必不可少的。心肌收缩是由钙通过肌钙蛋白调节的,肌钙蛋白是肌肉细胞中的一种蛋白质复合体。心肌肌钙蛋白T(CTnT)是心肌肌钙蛋白复合体的一个亚单位。在最近的一项研究中,我们发现在应激条件下,如急性心肌缺血,cTnT存在限制性切割。CTnT的这种修饰选择性地去除了N-末端可变区,并保留了肌原纤维中剩余的保守结构,从而产生了功能上的后果。对转基因小鼠心脏的初步研究表明,N端截断的cTnT(cTnT-ND)对心脏的泵浦效率有有益的影响。这一观察结果使我们提出了一个新的假说,即cTnT N末端片段的去除是一种快速的翻译后机制,可以在心肌中产生一过性的功能状态,以应对能量危机。在本研究中,我们将对cTnT-ND的生理和病理生理功能进行研究。我们将研究限制性N端截断对cTnT的生化功能、肌原纤维马达的钙激活和心肌收缩的影响。CTnT-ND在减少心肌功能障碍和在缺血期间保护心肌方面的潜在作用将在分离的工作心脏和活体动物中进行研究。此外,还将探讨机械拉伸诱导cTnT-ND产生的机制。这些实验将为了解cTnT-ND在心肌能量危机适应中的作用提供新的信息。利用集成的生理系统,本实验研究还将为TNT的结构-功能关系提供关键信息,并为未来开发治疗缺血性心脏病和心力衰竭的新方法奠定基础。

项目成果

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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

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
  • 批准号:
    10392565
  • 财政年份:
    2021
  • 资助金额:
    $ 51.92万
  • 项目类别:
Rabbit model for cystic fibrosis
兔囊性纤维化模型
  • 批准号:
    10420741
  • 财政年份:
    2021
  • 资助金额:
    $ 51.92万
  • 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:
    10349218
  • 财政年份:
    2016
  • 资助金额:
    $ 51.92万
  • 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:
    $ 51.92万
  • 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:
    $ 51.92万
  • 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:
    $ 51.92万
  • 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:
    $ 51.92万
  • 项目类别:
Detroit Cardiovascular Training Program
底特律心血管培训计划
  • 批准号:
    8608043
  • 财政年份:
    2014
  • 资助金额:
    $ 51.92万
  • 项目类别:
Detroit Cardiovascular Training Program
底特律心血管培训计划
  • 批准号:
    8984910
  • 财政年份:
    2014
  • 资助金额:
    $ 51.92万
  • 项目类别:
Detroit Cardiovascular Training Program
底特律心血管培训计划
  • 批准号:
    8786903
  • 财政年份:
    2014
  • 资助金额:
    $ 51.92万
  • 项目类别:
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