PATHOGENESIS AND IN VIVO SUPPRESSION OF THIN FILAMENT-BASED CARDIOMYOPATHIES
细丝型心肌病的发病机制和体内抑制
基本信息
- 批准号:10366554
- 负责人:
- 金额:$ 59.5万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2015
- 资助国家:美国
- 起止时间:2015-09-01 至 2026-12-31
- 项目状态:未结题
- 来源:
- 关键词:AcetylationActinsActomyosinAffectAmino AcidsAnimal ModelAutomobile DrivingBindingBinding SitesBiological AssayBiological ModelsCardiacCardiomyopathiesCharacteristicsChargeCommunicationComplementComplexCryoelectron MicroscopyDefectDevelopmentDilated CardiomyopathyDiseaseDisease modelDrosophila genusDrosophila melanogasterElectrostaticsElementsEnsureEnvironmental Risk FactorF-ActinFundingGenerationsGeneticGenotypeGoalsGrowthHeartHumanHypertrophic CardiomyopathyIn VitroIndividualLaboratoriesLeadLesionLocationLysineMechanicsMediatingModelingModificationMolecularMovementMusMuscleMuscle functionMutationMyocardialMyocardial dysfunctionMyosin ATPaseOrganPathogenesisPathologicPathologyPerformancePhenotypePhysiologicalPositioning AttributePost-Translational Protein ProcessingProcessProductionPropertyProteinsRecombinantsRegulationRelaxationRestRunningSeveritiesSignal TransductionSlideSpeedStructureSurfaceTechniquesTestingThickThin FilamentTimeTissuesTransgenic OrganismsTropomyosinTroponinTroponin ITroponin TVariantVentricular RemodelingWorkalpha Tropomyosinbasebiophysical analysiscardiac muscle diseasecell motilitydisease-causing mutationflyheart functionimage reconstructionimprovedin silicoin vivoinsightinterfacialmimeticsmouse modelnovelpreventresponsetool
项目摘要
Project Summary
The thin filament is a multi-subunit regulatory machine. Proper regulation of cardiac contraction requires
communication among, and controlled movement of, individual thin filament proteins. The goal of this application
is to understand how post-translational modifications (PTMs) and human cardiomyopathy mutations, located at
conserved interfaces between thin filament subunits, affect protein-protein associations, modulate muscle
function, and/or lead to disease. Drosophila melanogaster benefits from robust experimental tools that permit
efficient, yet comprehensive, scrutiny of the most proximal consequences of thin filament perturbations. This
animal model will continue to help us discern the mechanistic basis of contractile regulation and, importantly, of
myopathic responses to molecular insults. Mice, however, are more genetically and physiologically similar to
humans. Using a unique combination of techniques including high-speed video and cryo-electron microscopy,
in silico modeling, and mechanical assays we will define, for the first time, the structural and functional effects of
specific PTMs and cardiomyopathy mutations, located at interfacial seams between thin filament subunits, from
the molecular to the tissue level. Therefore, a highly integrative approach will be employed that relies, in part, on
a pioneering strategy to express human actin variants in Drosophila for purification and biophysical analysis, and
upon several new fly models of actin and troponin T (TnT)-based cardiomyopathies. The latter will be
complemented by murine models. Aim 1 will focus on determining the effects of actin acetylation on tropomyosin
(Tm) positioning and cardiac performance using recombinant human proteins, flies, and mice. We will test the
hypothesis that acetylation of K326 and K328 on actin, residues we previously showed bind to and help orient
Tm such that it prevents actomyosin cycling, discourages inhibitory Tm positioning and promotes cardiac
contraction. For Aim 2 we will delineate how certain actin and TnT cardiomyopathy mutations uniquely affect
myocardial relaxation. We will test the hypothesis that particular actin and TnT lesions disturb distinct, critical
interfacial contacts with Tm, which differentially alters Tm-based inhibition of contraction and force production to
initiate discrete cardiac pathologies. For Aim 3, we will ascertain if the same actin PTMs investigated in Aim 1,
improve or worsen myocardial dysfunction in murine and fly cardiomyopathy models. We will test the hypothesis
that enhanced cardiac contractility, conferred by actin pseudo-acetylation, will improve and aggravate the
pathological phenotypes in models of dilated and hypertrophic cardiomyopathy, respectively. Overall, this work
is significant since it will provide critical structural and functional information necessary to understand how the
thin filament machine operates normally and during disease. Additionally, our efforts will yield genotype-
phenotype information in a less complex model system (Drosophila) that limits genetic modifiers and
environmental factors to help establish paradigms for disease processes involved in cardiac remodeling.
项目总结
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)
数据更新时间:{{ journalArticles.updateTime }}
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
Anthony Cammarato其他文献
Anthony Cammarato的其他文献
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
{{ truncateString('Anthony Cammarato', 18)}}的其他基金
Pathogenesis and in vivo suppression of thin filament based cardiomyopathies
基于细丝的心肌病的发病机制和体内抑制
- 批准号:
9302507 - 财政年份:2015
- 资助金额:
$ 59.5万 - 项目类别:
Pathogenesis and in vivo suppression of thin filament based cardiomyopathies
基于细丝的心肌病的发病机制和体内抑制
- 批准号:
9065618 - 财政年份:2015
- 资助金额:
$ 59.5万 - 项目类别:
PATHOGENESIS AND IN VIVO SUPPRESSION OF THIN FILAMENT-BASED CARDIOMYOPATHIES
细丝型心肌病的发病机制和体内抑制
- 批准号:
10544001 - 财政年份:2015
- 资助金额:
$ 59.5万 - 项目类别:
Pathogenesis and in vivo suppression of thin filament based cardiomyopathies
基于细丝的心肌病的发病机制和体内抑制
- 批准号:
8884895 - 财政年份:2015
- 资助金额:
$ 59.5万 - 项目类别:
Pathogenesis and in vivo suppression of thin filament based cardiomyopathies
基于细丝的心肌病的发病机制和体内抑制
- 批准号:
8903521 - 财政年份:2014
- 资助金额:
$ 59.5万 - 项目类别:
相似海外基金
A novel motility system driven by two classes of bacterial actins MreB
由两类细菌肌动蛋白 MreB 驱动的新型运动系统
- 批准号:
22KJ2613 - 财政年份:2023
- 资助金额:
$ 59.5万 - 项目类别:
Grant-in-Aid for JSPS Fellows
The structural basis of plasmid segregation by bacterial actins
细菌肌动蛋白分离质粒的结构基础
- 批准号:
342887 - 财政年份:2016
- 资助金额:
$ 59.5万 - 项目类别:
Operating Grants
The structural basis for plasmid segregation by bacterial actins
细菌肌动蛋白分离质粒的结构基础
- 批准号:
278338 - 财政年份:2013
- 资助金额:
$ 59.5万 - 项目类别:
Operating Grants
Cytoplasmic Actins in Maintenance of Muscle Mitochondria
细胞质肌动蛋白在维持肌肉线粒体中的作用
- 批准号:
8505938 - 财政年份:2012
- 资助金额:
$ 59.5万 - 项目类别:
Differential Expression of the Diverse Plant Actins
多种植物肌动蛋白的差异表达
- 批准号:
7931495 - 财政年份:2009
- 资助金额:
$ 59.5万 - 项目类别:
Studies on how actins and microtubules are coordinated and its relevancy.
研究肌动蛋白和微管如何协调及其相关性。
- 批准号:
19390048 - 财政年份:2007
- 资助金额:
$ 59.5万 - 项目类别:
Grant-in-Aid for Scientific Research (B)
Interaction of myosin with monomeric actins
肌球蛋白与单体肌动蛋白的相互作用
- 批准号:
5311554 - 财政年份:2001
- 资助金额:
$ 59.5万 - 项目类别:
Priority Programmes
STRUCTURE/INTERACTIONS OF ACTINS AND ACTIN-BINDING PROTEIN
肌动蛋白和肌动蛋白结合蛋白的结构/相互作用
- 批准号:
6316669 - 财政年份:2000
- 资助金额:
$ 59.5万 - 项目类别: