The Role of Cardiomyopathic Troponin C Mutations in Skeletal and Cardiac Muscle C
心肌病肌钙蛋白 C 突变在骨骼肌和心肌 C 中的作用
基本信息
- 批准号:8528011
- 负责人:
- 金额:$ 24.9万
- 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:2010-08-20 至 2015-05-31
- 项目状态:已结题
- 来源:
- 关键词:ATP phosphohydrolaseActomyosinAddressAffectAffinityArrhythmiaBindingBody WeightBuffersCalciumCardiacCardiac Muscle ContractionCardiomyopathiesChelating AgentsCircular DichroismComplexCongestive Heart FailureDevelopmentDilated CardiomyopathyDiseaseDissociationFiberFibrosisFluorescenceFunctional disorderGenerationsGenesGrantHeartHeart DiseasesHereditary DiseaseHypertrophic CardiomyopathyIn SituIn VitroInvestigationKineticsKnock-in MouseKnowledgeLabelLaboratoriesLeadLinkMeasurementMeasuresMicrofilamentsMolecularMonitorMorphologyMuscleMuscle CellsMuscle ContractionMuscle FibersMutationMyocardiumMyopathyPapillaryPatientsPhenotypePhysiologicalPlayProcessPropertyProteinsRecombinantsRegulationRelaxationReportingRoleSkeletal MuscleSkeletal systemSkinSoleus MuscleStriated MusclesStructureSystemThick FilamentThin FilamentTroponinTroponin CTroponin ITroponin TVentricularin vivoinnovationinsightmouse modelmutantnovel strategiesprotein protein interactionreconstitutionresearch studysensorskeletalskeletal abnormalitystopped-flow fluorescencesudden cardiac deaththerapeutic development
项目摘要
Project Summary
The cardiac troponin complex (CTn) is made up of cardiac troponin T (CTnT), that attaches the
complex to the thin filament; cardiac troponin I (CTnI), involved in the inhibition of muscle contraction
and cardiac/slow skeletal troponin C (CTnC), that binds Ca2+ and triggers contraction. Altogether, the
CTn, regulates muscle contraction, i.e., Ca2+ sensitivity of force development, maximal force
development and basal force. Cardiac/Slow Skeletal Troponin C (C/SSTnC) is the only component of
CTn that is expressed and present in both cardiac and slow skeletal muscles. It is considered the
primary Ca2+ sensor of striated muscle and has been a target of Hypertrophic (HCM) and Dilated
(DCM) Cardiomyopathies. HCM or DCM are genetic disorders caused by the mutations in the TnC
gene that are characterized by morphological changes in the ventricular walls and altered Ca2+
handling of the diseased heart. HCM mutations in troponin cause the cardiac myofilament to become
sensitized to Ca2+ which is implicated as causing arrhythmias and sudden cardiac death. In contrast,
troponin mutations related to DCM desensitize myofilaments to Ca2+ which often leads to congestive
heart failure. CTn mutations related to cardiomyopathy have been extensively studied in the cardiac
system. However, the functional consequences of cardiomyopathic C/SSTnC mutants also
present in slow skeletal muscle are unknown. The question to be addressed in this grant is: What
are the functional consequences of C/SSTnC mutations linked to HCM and DCM in the regulation of
slow skeletal muscle contraction? How do they compare to those found in cardiac muscle? To
accomplish this, in vitro systems will be utilized as well as skinned fibers which will be used to
measure the force/pCa relationship. These measurements will be performed in both skeletal and
cardiac muscles. An HCM CTnC knock-in mouse generated in the laboratory will be characterized to
determine the in vivo consequences of the mutation in intact and skinned fibers. The aims of this
proposal address the functional differences that underlie the phenotypes of C/SSTnC mutations in
cardiac and skeletal muscles. These studies will investigate whether slow skeletal muscle containing
C/SSTnC mutations develops skeletal abnormalities similar to those seen in the heart and whether
the function of skeletal muscle is altered in the mutation-knock in mouse model. The questions that
are being addressed are: Is the change that occurs in the skeletal system comparable to changes
that occur in cardiac muscle? If the functional changes in slow skeletal muscle appear minimal what
additional components absent in the regulation of cardiac muscle assist in rescuing the effects of the
mutation? Successful execution of these aims will lead to a better understanding of cardiac versus
slow skeletal muscle disorders associated with mutations in the TnC gene.
项目成果
期刊论文数量(0)
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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Jose Renato Pinto其他文献
Jose Renato Pinto的其他文献
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{{ truncateString('Jose Renato Pinto', 18)}}的其他基金
Isolation, Characterization and Reconstruction of Vertebrate Striated Muscle Myosin Filaments
脊椎动物横纹肌肌球蛋白丝的分离、表征和重建
- 批准号:
10043292 - 财政年份:2020
- 资助金额:
$ 24.9万 - 项目类别:
Isolation, Characterization and Reconstruction of Vertebrate Striated Muscle Myosin Filaments
脊椎动物横纹肌肌球蛋白丝的分离、表征和重建
- 批准号:
10268975 - 财政年份:2020
- 资助金额:
$ 24.9万 - 项目类别:
The Role of Cardiomyopathic Troponin C Mutations in Skeletal and Cardiac Muscle C
心肌病肌钙蛋白 C 突变在骨骼肌和心肌 C 中的作用
- 批准号:
8130800 - 财政年份:2010
- 资助金额:
$ 24.9万 - 项目类别:
The Role of Cardiomyopathic Troponin C Mutations in Skeletal and Cardiac Muscle C
心肌病肌钙蛋白 C 突变在骨骼肌和心肌 C 中的作用
- 批准号:
8532964 - 财政年份:2010
- 资助金额:
$ 24.9万 - 项目类别:
The Role of Cardiomyopathic Troponin C Mutations in Skeletal and Cardiac Muscle C
心肌病肌钙蛋白 C 突变在骨骼肌和心肌 C 中的作用
- 批准号:
7962716 - 财政年份:2010
- 资助金额:
$ 24.9万 - 项目类别:
The Role of Cardiomyopathic Troponin C Mutations in Skeletal and Cardiac Muscle C
心肌病肌钙蛋白 C 突变在骨骼肌和心肌 C 中的作用
- 批准号:
8677956 - 财政年份:2010
- 资助金额:
$ 24.9万 - 项目类别:
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