Molecular Regulation of Titin Elasticity by Post-Translational Modification
翻译后修饰对肌联蛋白弹性的分子调控
基本信息
- 批准号:9121728
- 负责人:
- 金额:$ 4.32万
- 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:2016-06-01 至 2019-05-31
- 项目状态:已结题
- 来源:
- 关键词:AffectAgingArchitectureAtherosclerosisAttentionCardiacCardiac MyocytesCollagenCysteineCytoskeletonDiabetes MellitusDiseaseDisulfidesElasticityElectron MicroscopyExtracellular StructureFilamentFluorescence MicroscopyGeneticGoalsHeartHeart DiseasesHypertensionImpairmentIndividualIschemiaLeadLengthLinkLocationMagnetismMeasuresMechanicsMicroscopyModificationMolecularMusMuscleMutationMyocardialMyocardial InfarctionMyocardiumMyofibrilsNitrogenOxidation-ReductionOxidative StressOxygenPerformancePeroxonitritePhenotypePhysiologicalPost-Translational Protein ProcessingProlinePropertyQuantum DotsReactionReactive Nitrogen SpeciesReactive Oxygen SpeciesRegulationReperfusion TherapyResistanceResolutionRoleS-NitrosothiolsSarcomeresSignal PathwaySkeletal MuscleStretchingStructureSulfhydryl CompoundsThick FilamentThinkingTissuesTranslatingTyrosineUrsidae FamilyVentricular RemodelingWorkconnectinexperiencefamilial dilated cardiomyopathyinsightmouse modelmutantnanoGoldnanometernitrationnoveloxidationparticlepreventpublic health relevanceresearch studysensorsingle molecule
项目摘要
DESCRIPTION (provided by applicant): During the filling of the heart or during the contraction of opposing muscle groups, the sarcomere experiences passive stretch that increases its overall length by several hundred nanometers. In the past, it was believed that extracellular structures, mainly collagen, were responsible for the integrity of the sarcomere and provided resistance to prevent over-stretching of the sarcomere. Within the past thirty years, it has become clear that titin, the third filament of the sarcomere, bears the majority of the force during passive stretch f muscle tissue, and is responsible for setting the optimal working length of the sarcomere. Only in 2012, after genetic sequencing of hundreds of individuals, was it shown that mutations in titin are the leading cause of inherited dilated cardiomyopathy. Now that there exists a clear link between titin mutations and disease, attention has turned towards identifying the normal physiological role of titin. Besides organizing the thick filament, the I-band segment of titin deforms to accommodate stretching of the sarcomere. Unstructured regions of titin rich in proline extend like molecular springs. Structured Ig domains, on the other hand, unfold at forces of several piconewtons to reveal cryptic residues that can undergo post-translational modification. The I-band of titin is unusually rich in cryptic cysteine residues, which can react with both oxidative and nitrosylative species when exposed by force. Hence, titin is thought to be an important redox sensor in skeletal and cardiac muscle. I propose to study the effects of post-translational modifications on titin elasticity and folding. These studies have important implications for how myocardial mechanics change after myocardial infarction, or in the setting of diseases such as diabetes, hypertension, and atherosclerosis. Aim 1 will study how reactive oxygen species alter the stability of titin Ig domain by blocking folding or inducing disulfide formation. Aim 2 is to determine if reactive nitrogen species react with residues in titin Ig domains alter titin mechanics and how mechanical stability depends on the location of the modification within the Ig fold. Aim 3 seeks to utilize a novel mouse model containing a genetically encoded tag in titin to measure the extent of titin Ig unfolding in muscle tissue using
super-resolution and electron microscopy. This unique combination of single molecule and single myofibril experiments will demonstrate how changes at the molecular level translate into a "mechanical phenotype." These studies provide insights into how oxidative insults, such as those present in ischemia/reperfusion tend to affect the cytoskeleton of muscle, altering myocardial mechanics, and initiating signaling pathways that lead to remodeling and further impairment of cardiac function and diastolic performance.
描述(申请人提供):在心脏充盈或相反肌肉群收缩期间,肌节经历被动拉伸,使其总长度增加数百纳米。在过去,人们认为细胞外结构,主要是胶原,负责肌节的完整性,并提供抵抗,以防止肌节过度伸展。在过去的30年里,肌节的第三细丝Titin在肌肉组织被动拉伸过程中承担着大部分的力,并负责设定肌节的最佳工作长度。直到2012年,在对数百名个体进行基因测序后,才发现肌联蛋白的突变是遗传性扩张型心肌病的主要原因。既然在肌动蛋白突变和疾病之间存在明确的联系,人们的注意力就转向了识别肌动蛋白的正常生理作用。除了组织粗丝外,Titin的I带片段也发生变形,以适应肌节的伸展。富含脯氨酸的Titin的非结构化区域就像分子弹簧一样延伸。另一方面,结构化的Ig结构域在几皮牛顿的力下展开,揭示了可以进行翻译后修饰的神秘残基。Titin的I-带异常富含隐蔽的半胱氨酸残基,当被强行暴露时,这些残基可以与氧化和亚硝基物种反应。因此,肌动蛋白被认为是骨骼肌和心肌中重要的氧化还原感受器。我建议研究翻译后修饰对肌动蛋白弹性和折叠的影响。这些研究对心肌梗死后或在糖尿病、高血压和动脉粥样硬化等疾病的背景下如何改变心肌力学有重要意义。目的1研究活性氧如何通过阻断折叠或诱导二硫键形成来改变Titin Ig结构域的稳定性。目的2是确定活性氮物种是否与titin Ig结构域中的残基反应改变了titin的机制,以及机械稳定性如何依赖于修饰在Ig折叠中的位置。Aim 3试图利用一种新的小鼠模型,该模型包含在肌动蛋白中的遗传编码标签,以测量肌动蛋白Ig在肌肉组织中展开的程度
超分辨率和电子显微镜。这种单分子和单肌原纤维实验的独特组合将展示分子水平上的变化如何转化为“机械表型”。这些研究为了解氧化损伤(如缺血/再灌流中存在的氧化损伤)如何影响肌肉的细胞骨架、改变心肌力学并启动导致重塑和进一步损害心功能和舒张期功能的信号通路提供了深入的见解。
项目成果
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