Cardiac Myosin Binding Protein-C: Structure and Function
心肌肌球蛋白结合蛋白-C:结构和功能
基本信息
- 批准号:9391433
- 负责人:
- 金额:$ 39.15万
- 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:2016-12-01 至 2020-03-31
- 项目状态:已结题
- 来源:
- 关键词:ActinsActomyosinAge-MonthsApoptosisAttenuatedBlood CirculationBundlingC2 DomainCalpainCardiacCardiac MyocytesCardiac MyosinsCardiomyopathiesCleaved cellClinicalDataDependovirusDevelopmentFailureFiberFilamentFunctional disorderGenerationsGoalsGrantHeartHeart HypertrophyHeart failureIn VitroInfarctionInjuryKineticsLeadLengthLinkMediatingMicrofilamentsMolecularMusMutationMyocardialMyocardiumMyosin ATPaseN-terminalOrganOutcomePapillaryPhosphorylationPilot ProjectsProteinsProteolysisRecombinantsRegulationReperfusion InjuryRoleSarcomeresSiteSkinStructureTestingTherapeuticThickThick FilamentThin FilamentTransgenic MiceTransgenic Organismsalpha Tropomyosinbasecitrate carrierheart functionimprovedin vivomouse modelmyosin-binding protein Cnovelpreventpublic health relevancerestoration
项目摘要
DESCRIPTION (provided by applicant): Cardiac myosin binding protein-C (cMyBP-C) is a trans-filament protein which, at its N'-region, connects thick and thin filaments to regulate cardiac contractility. The overall objective of the studies contained in this renewal of R01HL-105826 is to define the N'-region of cMyBP-C as a critical regulator of cardiac contractility. In particular, C0-C1f, which interacts only with actin, is generated by proteolysis of cMyBP-C during ischemia/reperfusion (I/R) injury and heart failure. On the other hand, C0-C2 interacts with both actin and myosin, connecting thin and thick filaments to regulate sarcomere function. On the basis of these findings, we will 1) use a novel transgenic mouse model expressing cMyBP-C (cMyBP-C110kDa) in which the C0-C1f region was ablated to study the necessity and sufficiency of this domain in regulating cardiac contractility and 2) use adeno-associated virus 9 (AAV9)-mediated expression of (i) recombinant C0-C2 to determine the sufficiency of N'-terminal C0-C2 in bundling thick and thin filaments in vivo and (ii) recombinant C0-C2ΔCTS, in which the calpain-targeted site (CTS) has been ablated, to determine its therapeutic potential in improving cardiac function pre- and post-I/R injury. The molecular mechanisms underlying the regulation of cMyBP-C and, in turn, its impact on sarcomere structure and function, are largely unknown. Our short-term goal is to elucidate the specific role(s) of the N'-region of cMyBP-C in the regulation of cardiac function, whereas our long-term goal is to determine the mechanisms by which cMyBP-C stabilizes sarcomeric structure and function, thereby conferring cardioprotection during I/R injury. SPECIFIC AIM 1 will test the hypothesis that the C0-C1f domain of cMyBP-C, which is cleaved and released during I/R injury, is necessary for regulating cardiac function. Transgenic cMyBP-C110kDa mice will be used to determine the critical role of the N'-region of cMyBP-C at the sarcomere and whole-heart levels, compared to the control non-transgenic mice. SPECIFIC AIM 2 will test the hypothesis that the C0-C2 domains of cMyBP-C are sufficient to bundle thick and thin filaments and to regulate normal cardiac function. AAV9-mediated expression of recombinant C0-C2 will be used to prevent or rescue contractile dysfunction in mouse models that lack either the N'-region (C0-C1f) or full-length cMyBP-C in vivo. SPECIFIC AIM 3 will test the hypothesis that expression of recombinant C0-C2ΔCTS in vivo confers cardioprotection during I/R injury. Recombinant C0-C2ΔCTS protein is protected from calpain-mediated degradation. We expect AAV9-mediated expression of recombinant C0-C2ΔCTS to significantly reduce infarct size and apoptosis, as well as preserve contractile function during I/R injury. Together, these studies will determine the necessity and sufficiency of the N'-region (both C0-C1f and C0-C2) of cMyBP-C to regulate cardiac function, and, hence, provide therapy for myocardial injury and heart failure occurring during I/R injury.
描述(由申请人提供):心肌肌球蛋白结合蛋白-C(cMyBP-C)是一种跨丝蛋白,在其N '区连接粗丝和细丝以调节心脏收缩力。R 01 HL-105826更新中包含的研究的总体目的是将cMyBP-C的N '区定义为心肌收缩力的关键调节因子。特别是,C 0-C1 f,它只与肌动蛋白相互作用,产生的cMyBP-C在缺血/再灌注(I/R)损伤和心力衰竭的蛋白水解。另一方面,C 0-C2与肌动蛋白和肌球蛋白相互作用,连接细丝和粗丝以调节肌节功能。根据这些调查结果,我们将1)使用表达cMyBP-C的新型转基因小鼠模型(cMyBP-C110 kDa),其中C 0-C1 f区域被切除,以研究该结构域在调节心脏收缩性中的必要性和充分性,和2)使用腺相关病毒9(AAV 9)介导的(i)重组C 0-C2的表达,以确定N ′-末端C 0-C2的充分性。C2在体内捆绑粗细细丝中的作用,以及(ii)重组C 0-C2ΔCTS,其中钙蛋白酶靶向位点(CTS)已被消融,以确定其在改善I/R损伤前后心脏功能方面的治疗潜力。cMyBP-C调控的分子机制及其对肌节结构和功能的影响在很大程度上是未知的。我们的短期目标是阐明cMyBP-C的N '区在调节心脏功能中的特定作用,而我们的长期目标是确定cMyBP-C稳定肌节结构和功能的机制,从而在I/R损伤期间赋予心脏保护作用。 特异性目的1将检验cMyBP-C的C 0-C1 f结构域在I/R损伤期间被切割和释放,是调节心脏功能所必需的假设。与对照非转基因小鼠相比,转基因cMyBP-C110 kDa小鼠将用于确定cMyBP-C的N '-区在肌节和全心脏水平的关键作用。特异性目的2将检验cMyBP-C的C 0-C2结构域足以捆绑粗丝和细丝并调节正常心脏功能的假设。AAV 9介导的重组C 0-C2表达将用于预防或挽救体内缺乏N '-区(C 0-C1 f)或全长cMyBP-C的小鼠模型中的收缩功能障碍。特异性目的3将检验重组C 0-C2ΔCTS在体内表达在I/R损伤期间赋予心脏保护的假设。重组C 0-C2ΔCTS蛋白被保护免于钙蛋白酶介导的降解。我们预期AAV 9介导的重组C 0-C2ΔCTS表达可显著减少梗死面积和细胞凋亡,并在I/R损伤期间保持收缩功能。总之,这些研究将确定cMyBP-C的N '-区(C 0-C1 f和C 0-C2)调节心脏功能的必要性和充分性,并因此为I/R损伤期间发生的心肌损伤和心力衰竭提供治疗。
项目成果
期刊论文数量(0)
专著数量(0)
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Sakthivel Sadayappan其他文献
Sakthivel Sadayappan的其他文献
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{{ truncateString('Sakthivel Sadayappan', 18)}}的其他基金
Slow myosin binding protein-C in skeletal muscle physiology
骨骼肌生理学中的慢肌球蛋白结合蛋白-C
- 批准号:
10461813 - 财政年份:2020
- 资助金额:
$ 39.15万 - 项目类别:
Slow myosin binding protein-C in skeletal muscle physiology
骨骼肌生理学中的慢肌球蛋白结合蛋白-C
- 批准号:
10673945 - 财政年份:2020
- 资助金额:
$ 39.15万 - 项目类别:
Slow myosin binding protein-C in skeletal muscle physiology
骨骼肌生理学中的慢肌球蛋白结合蛋白-C
- 批准号:
10239247 - 财政年份:2020
- 资助金额:
$ 39.15万 - 项目类别:
Proteomic approaches to validate novel cardiac biomarkers for myocardial infarcti
验证心肌梗塞新型心脏生物标志物的蛋白质组学方法
- 批准号:
8705576 - 财政年份:2012
- 资助金额:
$ 39.15万 - 项目类别:
Proteomic approaches to validate novel cardiac biomarkers for myocardial infarcti
验证心肌梗塞新型心脏生物标志物的蛋白质组学方法
- 批准号:
9122471 - 财政年份:2012
- 资助金额:
$ 39.15万 - 项目类别:
Proteomic approaches to validate novel cardiac biomarkers for myocardial infarcti
验证心肌梗塞新型心脏生物标志物的蛋白质组学方法
- 批准号:
8352638 - 财政年份:2012
- 资助金额:
$ 39.15万 - 项目类别:
Proteomic approaches to validate novel cardiac biomarkers for myocardial infarcti
验证心肌梗塞新型心脏生物标志物的蛋白质组学方法
- 批准号:
8891482 - 财政年份:2012
- 资助金额:
$ 39.15万 - 项目类别:
Proteomic approaches to validate novel cardiac biomarkers for myocardial infarcti
验证心肌梗塞新型心脏生物标志物的蛋白质组学方法
- 批准号:
8516588 - 财政年份:2012
- 资助金额:
$ 39.15万 - 项目类别:
Cardiac Myosin Binding Protein-C: Structure and Function
心肌肌球蛋白结合蛋白-C:结构和功能
- 批准号:
8600985 - 财政年份:2011
- 资助金额:
$ 39.15万 - 项目类别:
Cardiac myosin binding protein-C: Structure and Function
心肌肌球蛋白结合蛋白-C:结构和功能
- 批准号:
9104884 - 财政年份:2011
- 资助金额:
$ 39.15万 - 项目类别:
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