Thick and Thin Filament Mutations that cause Distal Arthrogryposis
导致远端关节弯曲的粗丝和细丝突变
基本信息
- 批准号:8734213
- 负责人:
- 金额:$ 3.5万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2012
- 资助国家:美国
- 起止时间:2012-04-30 至 2015-04-29
- 项目状态:已结题
- 来源:
- 关键词:AccountingActinsAdultAffectAreaArthrogryposisBindingBiomedical ResearchBiopsyChildCodeCongenital clubfootContractureDataDistalEconomic BurdenEtiologyExhibitsFaceGenesGeneticGoalsHumanKineticsLeadLearningLegLifeLigamentsLive BirthMolecularMorbidity - disease rateMuscleMuscle FibersMutationMyofibrilsMyosin ATPasePathogenesisPatientsProductionProteinsRelaxationReportingSarcomeresSkeletal MuscleSkinSpecimenSyndromeTendon structureThick FilamentThin FilamentTimeUnited StatesUpper ExtremityVariantanalogfootfunctional restorationmalformationproband
项目摘要
DESCRIPTION (provided by applicant): Arthrogryposis is a congenital contracture syndrome that affects 1 of 3000 live births. While the genetic causes of DA are in discovery, the biophysical mechanisms of how these mutations cause life-long contractures remains unknown. We have recently acquired and reported on contractile characterization for one DA patient, exhibiting an MYH3 R672C mutation. This mutation decreased steady state force production and increased relaxation time in single skinned myofibers from a human skeletal muscle biopsy, and our data suggest this may occur via altered crossbridge binding and cycling kinetics. The mechanism of how this occurs remains unknown. As such, there is much to be learned from contractile assessments from patient biopsies containing mutations in both thin and thick filament sarcomere proteins. I hypothesize that there are differences in how thin filament protein mutations and thick filament protein mutations result in altered contractures. Specifically, I expect thick filament mutations, such as MYH3 R672C and MYH8 R672H, to lead to direct changes in myosin (crossbridge) binding, detachment and interaction with actin. These mutations lead to a severe form of DA, Freeman-Sheldon Syndrome. In contrast, I expect thin filament mutations, such as TNNI2 R174Q andTNNT3 R63H, to lead to changes crossbridge binding via altered Ca2+ sensitivity and cooperativity of thin filament activation. These mutations
lead to a slightly less severe form of DA, Sheldon-Hall syndrome. By determining functional changes and the causal mechanisms, we can begin to develop targeted therapies that would restore function on the molecular and cellular level. I plan to do so with three aims, focusing on muscle contractility of muscle fibers and muscle myofibrils. I will use muscle fibers to determine maximal force production, crossbridge binding, and Ca2+ sensitivity of force. I will use muscle myofibrils to determine thin filament activation and relaxation kinetics from single isolated myofibrils from human skeletal muscle biopsies. Finally, I will use muscle fibers and potentially myofibrils to determine if modulation of crossbridge binding or thin filament activation through use of an ATP analogue (2-deoxyATP) or TnC variants with altered Ca2+ binding, respectively, can restore function to human adult DA skeletal muscle.
描述(由申请人提供):关节挛缩是一种先天性挛缩综合征,影响1/3000的活产婴儿。虽然DA的遗传原因正在发现中,但这些突变如何导致终身挛缩的生物物理机制仍然未知。我们最近获得并报告了一名DA患者的收缩特征,表现出MYH 3 R672 C突变。这种突变降低了稳态力的产生,增加了松弛时间,在单一皮肤肌纤维从人骨骼肌活检,我们的数据表明,这可能是通过改变横桥结合和循环动力学。这是如何发生的机制仍然未知。因此,从包含薄和厚丝肌节蛋白突变的患者活检的收缩评估中有很多东西要学。我推测,有不同的细丝蛋白突变和粗丝蛋白突变如何改变挛缩。具体来说,我预计粗丝突变,如MYH 3 R672 C和MYH 8 R672 H,导致肌球蛋白(横桥)结合,分离和与肌动蛋白相互作用的直接变化。这些突变会导致严重的DA,Freeman-Sheldon综合征。相比之下,我预计细纤维突变,例如TNNI 2 R174 Q和TNTT 3 R63 H,会通过改变Ca 2+敏感性和细纤维激活的协同性来导致跨桥结合的变化。这些突变
导致轻微程度较轻形式的DA,谢尔顿-霍尔综合征。通过确定功能变化和因果机制,我们可以开始开发靶向治疗,在分子和细胞水平上恢复功能。我计划这样做有三个目标,重点是肌肉纤维和肌肉肌原纤维的肌肉收缩性。我将使用肌纤维来确定最大的力产生,横桥结合和力的Ca 2+敏感性。我将使用肌肉肌原纤维,以确定细丝激活和松弛动力学从单一的分离肌原纤维从人类骨骼肌活检。最后,我将使用肌纤维和潜在的肌原纤维,以确定是否通过使用ATP类似物(2-deoxyATP)或TnC变异体与改变的Ca 2+结合,分别调制横桥结合或细丝激活,可以恢复功能的人成年DA骨骼肌。
项目成果
期刊论文数量(0)
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科研奖励数量(0)
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Alice Ward Racca其他文献
Functional Implications of Dcm End-to-End Bond Mutation in A-Tropomyosin
- DOI:
10.1016/j.bpj.2018.11.989 - 发表时间:
2019-02-15 - 期刊:
- 影响因子:
- 作者:
Alice Ward Racca;Nicholas LaFave;Stephanie Jones;Michael J. Rynkiewicz;William Lehman;Jeffrey R. Moore - 通讯作者:
Jeffrey R. Moore
Alice Ward Racca的其他文献
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{{ truncateString('Alice Ward Racca', 18)}}的其他基金
Thick and Thin Filament Mutations that cause Distal Arthrogryposis
导致远端关节弯曲的粗丝和细丝突变
- 批准号:
8734889 - 财政年份:2012
- 资助金额:
$ 3.5万 - 项目类别:
Thick and Thin Filament Mutations that cause Distal Arthrogryposis
导致远端关节弯曲的粗丝和细丝突变
- 批准号:
8317383 - 财政年份:2012
- 资助金额:
$ 3.5万 - 项目类别:
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