The mechanisms of cardiac thin filament regulation in health and disease.
健康和疾病中心脏细丝调节的机制。
基本信息
- 批准号:10544527
- 负责人:
- 金额:$ 57.99万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2022
- 资助国家:美国
- 起止时间:2022-01-01 至 2025-12-31
- 项目状态:未结题
- 来源:
- 关键词:3-DimensionalActinsAffectAlgorithmsBepridilBindingBinding SitesCardiacCardiac Muscle ContractionCardiomyopathiesCardiovascular DiseasesCommunicationComplexComputing MethodologiesCryoelectron MicroscopyDataDevelopmentDilated CardiomyopathyDiseaseDistalDistantElectron MicroscopyEquilibriumFilamentGeneticGoalsHealthHeart DiseasesHypertrophic CardiomyopathyIncubatedKnowledgeLobeMissionModelingMolecularMolecular ConformationMuscle functionMutationMyocardiumMyosin ATPasePathogenesisPathogenicityPhenotypePhosphorylationPhysiologicalRegulationResearchSideSiteStriated MusclesStructureSurfaceTailTestingTherapeutic InterventionThickThin FilamentThinnessTimeTropomyosinTroponinTroponin CTroponin ITroponin TUnited States National Institutes of HealthVariantgenetic regulatory proteinimprovedindividualized medicineinherited cardiomyopathyinnovationinterdisciplinary approachmultidisciplinarymuscle physiologymutantoutcome predictionpublic health relevancerational designreconstructiontool
项目摘要
Project Summary
Cardiomyopathies are the most common genetic cardiovascular disease worldwide. The presence of cardiac
troponin variants accounts for at least 15% of all familial cardiomyopathy cases. Cardiac muscle contraction is
regulated by free intracellular Ca2+ concentration via two thin filament regulatory proteins – tropomyosin and
troponin complex. Ca2+ binding to troponin displaces tropomyosin from myosin-binding sites and allows formation
of myosin cross-bridges, which on their own contribute to thin filament activation. Troponin complex is composed
of Ca2+ sensing troponin C, actin-binding troponin I, and Tm-bound troponin T. For decades, the helical approach
to electron microscopy reconstruction of the thin filament eliminated information on the structure of the Tn
complex. Hence, the complex interactions among components of the thin filament remained unknown. We
developed cryo-EM non-helical algorithm to the reconstruction of native cardiac thin filaments to reveal the
structure of the whole troponin complex at physiological Ca2+ levels. We show that the thin filament is comprised
of an array of Ca2+-free and Ca2+-bound non-equivalent troponin complexes with short-range cooperativity
between adjacent units. Troponin variants associated with inherited cardiomyopathies affect thin filament Ca2+-
dependent activation. We hypothesize that: (1) dilated (DCM) or hypertrophic (HCM) cardiomyopathy variants in
troponin affect thin filament regulation by: (a) altering the equilibrium between Ca2+-free and Ca2+-bound troponin
complexes via conformational changes in Ca2+-sensing troponin C unit; and/or (b) altering the distribution of
Ca2+-free and Ca2+-bound troponin complexes by changing communication between the adjacent troponins
along and across the thin filament. To test our hypothesis we chose 4 strategically located mutations. In Aim 1
we will utilize pathogenic variants in troponin C located in distal parts of Ca2+-sensing troponin N-lobe to evaluate
how they affect the equilibrium between Ca2+-free and Ca2+-bound troponin complexes, and if they affect
communication between troponin units that may curb activating effect of rigor myosin-S1. In Aim 2 we will focus
on highly penetrant pathogenic variants in troponin T located in N-terminus of troponin T, which stabilizes the
interaction between tropomyosin cables belonging to adjacent troponin units. We will evaluate how these
mutations affect the communication between neighboring troponins and activation by myosin-S1. To reveal how
distal parts of the troponin complex (Ca2+ sensing troponin C and N-terminus of troponin T) communicate, we
will use a Ca2+ sensitizer, which binds to troponin C to revert effects of a troponin T variant. Our multidisciplinary,
multi-PI approach with collective expertise in structural, functional and computational methods will reveal how
the complex interactions between components of the thin filament make heartbeats possible. Successful
execution of the aims may set the ground for the development of tailored therapies that could potentially modulate
the structure of the thin filament to treat various forms of heart disease.
项目摘要
心肌病是全世界最常见的遗传性心血管疾病。心脏疾病的存在
肌钙蛋白变异至少占所有家族性心肌病病例的15%。心肌收缩是
受两种细丝调节蛋白-原肌球蛋白和细胞内游离钙离子浓度的调节
肌钙蛋白复合体。钙离子与肌钙蛋白结合取代肌球蛋白结合部位的原肌球蛋白并允许形成
肌球蛋白的跨桥,它们本身就有助于细丝的激活。肌钙蛋白复合体由
钙离子感应肌钙蛋白C、肌动蛋白结合的肌钙蛋白I和TM结合的肌钙蛋白T。
用电子显微镜重建细丝消除了TN的结构信息
很复杂。因此,细丝成分之间复杂的相互作用仍然未知。我们
开发了冷冻-EM非螺旋算法来重建天然心脏细丝以揭示
整个肌钙蛋白复合体在生理钙离子水平的结构。我们发现细丝是由
具有短程协同作用的无钙和结合钙的非等效肌钙蛋白复合体的阵列
在相邻单元之间。与遗传性心肌病相关的肌钙蛋白变异影响细丝钙离子
依赖激活。我们假设:(1)扩张型(DCM)或肥厚型(HCM)心肌病变异
肌钙蛋白通过以下方式影响细丝调节:(A)改变无钙和结合钙的肌钙蛋白之间的平衡
通过钙离子感受型肌钙蛋白C单位的构象变化;和/或(B)改变肌钙蛋白C的分布
通过改变相邻肌钙蛋白之间的通讯改变无钙和结合钙的肌钙蛋白复合体
沿着细丝和穿过细丝。为了验证我们的假设,我们选择了4个位于战略位置的突变。在目标1中
我们将利用位于钙离子敏感的肌钙蛋白N叶远端的肌钙蛋白C的致病变异体来评估
它们如何影响无钙和结合钙的肌钙蛋白复合体之间的平衡,以及它们是否影响
肌钙蛋白单位之间的通讯可能抑制僵直肌球蛋白-S1的激活效应。在《目标2》中,我们将专注于
肌钙蛋白T N端高穿透性致病变异体的研究
属于相邻肌钙蛋白单位的原肌球蛋白缆线之间的相互作用。我们将评估这些
突变会影响相邻肌钙蛋白之间的通讯和肌球蛋白-S1的激活。为了揭示如何
肌钙蛋白复合体的远端部分(钙离子感应肌钙蛋白C和肌钙蛋白T的N端)相互通信,我们
将使用一种钙离子增敏剂,它与肌钙蛋白C结合,以逆转肌钙蛋白T变体的影响。我们的多学科,
结合结构、功能和计算方法的集体专业知识的多PI方法将揭示
细丝各组成部分之间的复杂相互作用使心跳成为可能。成功
这些目标的实现可能会为开发可能调节
细丝的结构可以治疗各种形式的心脏病。
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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P. Bryant Chase其他文献
Aberrant Cardiac Muscle Mechanics in a Hypertrophic Cardiomyopathy Troponin T ILE79ASN Transgenic Mouse
- DOI:
10.1016/j.bpj.2017.11.2744 - 发表时间:
2018-02-02 - 期刊:
- 影响因子:
- 作者:
Karissa M. Dieseldorff Jones;David Gonzalez-Martinez;Maicon Landim-Vieira;Yeojung Koh;Bjorn C. Knollmann;P. Bryant Chase;Hyun S. Hwang;Jose R. Pinto - 通讯作者:
Jose R. Pinto
Thin Filament Regulation Blends Thermodynamic and Mechanical Mechanisms
- DOI:
10.1016/j.bpj.2018.11.986 - 发表时间:
2019-02-15 - 期刊:
- 影响因子:
- 作者:
Henry G. Zot;P. Bryant Chase;Javier E. Hasbun;J. Renato Pinto - 通讯作者:
J. Renato Pinto
Clinical and Biophysical Characterization of a Mutation in the N-Helix Region of Cardiac Troponin C: Evidence for an Allosteric Mechanism of Contractile Dysfunction
- DOI:
10.1016/j.bpj.2017.11.3109 - 发表时间:
2018-02-02 - 期刊:
- 影响因子:
- 作者:
Jamie R. Johnston;Mayra de A. Marques;David Gonzalez-Martinez;Guilherme A.P. de Oliveira;Einat Birk;Nili Zucker;Maicon Landim-Vieira;Adolfo H. Moraes;P. Bryant Chase;Jerson L. Silva;Yael Wilnai;Jose R. Pinto - 通讯作者:
Jose R. Pinto
Mechanical Properties of Human Cardiac Tropomyosin in Familial Hypertrophic Cardiomyopathy (FHC) Probed by Atomic Force Microscopy
- DOI:
10.1016/j.bpj.2009.12.1897 - 发表时间:
2010-01-01 - 期刊:
- 影响因子:
- 作者:
Campion Loong;P. Bryant Chase - 通讯作者:
P. Bryant Chase
Molecular Function of the C-terminal Domain of Cardiac Troponin I
- DOI:
10.1016/j.bpj.2009.12.1927 - 发表时间:
2010-01-01 - 期刊:
- 影响因子:
- 作者:
Danamarie Moonoo;Nancy L. Meyer;Vanessa Inchausti;Nicolas M. Brunet;Vincent LaBarbera;P. Bryant Chase;Brenda Schoffstall - 通讯作者:
Brenda Schoffstall
P. Bryant Chase的其他文献
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{{ truncateString('P. Bryant Chase', 18)}}的其他基金
The mechanisms of cardiac thin filament regulation in health and disease.
健康和疾病中心脏细丝调节的机制。
- 批准号:
10343934 - 财政年份:2022
- 资助金额:
$ 57.99万 - 项目类别:
Micro-Hall magnetometry for detection of bio-molecular interactions
用于检测生物分子相互作用的微霍尔磁力测定法
- 批准号:
7192325 - 财政年份:2007
- 资助金额:
$ 57.99万 - 项目类别:
Micro-Hall magnetometry for detection of bio-molecular interactions
用于检测生物分子相互作用的微霍尔磁力测定法
- 批准号:
7586241 - 财政年份:2007
- 资助金额:
$ 57.99万 - 项目类别:
Micro-Hall magnetometry for detection of bio-molecular interactions
用于检测生物分子相互作用的微霍尔磁力测定法
- 批准号:
7373491 - 财政年份:2007
- 资助金额:
$ 57.99万 - 项目类别:
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