Regulation of Ion Channels at BIN1-induced T-tubule Microdomains
BIN1 诱导的 T 管微区离子通道的调节
基本信息
- 批准号:10219035
- 负责人:
- 金额:$ 38.13万
- 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:2016-07-01 至 2022-04-30
- 项目状态:已结题
- 来源:
- 关键词:ActinsAdrenergic AgentsAdultAffectAlternative SplicingAmericanArrhythmiaBiochemicalBiologicalCalciumCardiacCardiac MyocytesCellsChronicComplexCouplingCytoskeletonDataDevelopmentDiffusionEpidemicF-ActinGenetic TranscriptionGoalsHeartHeart DiseasesHeart failureHumanImageImpairmentInfusion proceduresIon ChannelIonsIsoproterenolL FormsL-Type Calcium ChannelsMedicalMembraneMembrane MicrodomainsMethodsMissionModelingMolecularMusOrganOutcomePathologicPathway interactionsPhysiologicalPositioning AttributePredispositionProtein IsoformsProteinsPublic HealthRNA SplicingRegulationResearchResolutionRoleRyanodine ReceptorsSarcoplasmic ReticulumSignal TransductionStressStructureSurfaceSyndromeTestingTherapeutic InterventionUnited StatesUnited States National Institutes of HealthVentricularWorkbaseextracellularfluorescence imagingheart functionhuman modelinnovationmouse modelnew therapeutic targetnovel strategiespreservationreceptorreceptor couplingrecruit
项目摘要
PROJECT SUMMARY/ABSTRACT
In ventricular cardiomyocytes, transverse-tubules (T-tubules) concentrate L-type calcium
channels (LTCC) which approximate and form dyads with ryanodine receptors (RyR2) at sarcoplasmic
reticulum membrane. It is not well understood how the dyads form. The overall objective of this
application is to identify the key components of dyad organization in healthy and failing hearts. My
central hypothesis is that the membrane deformation protein BIN1 creates microdomains within T-
tubule microfolds, organizing LTCC clusters and recruiting RyR2 receptors for proper dyad formation,
facilitating synchronized calcium-induced-calcium-release and limiting arrhythmias. Furthermore, BIN1
is known to decrease in acquired heart failure, and heart failure can result when these BIN1-orgnized
microdomains are disrupted. The rationale that underlies the proposed research is that BIN1-based
impaired regulation of dyad structure and function is a reversible aspect of heart failure progression.
The first of three aims is to determine, in physiologically normal cardiomyocytes, whether and
how cardiac BIN1 is responsible for organizing LTCC-RyR2 dyads. Building on preliminary data, in adult
mouse (with or without Bin1 deletion) and human cardiomyocytes, we will use super-resolution
fluorescent imaging to identify LTCC-RyR2 localization at BIN1-induced microdomains, and test the role
of actin cytoskeleton in LTCC-RyR2 complex formation and function. The second aim is to determine
how BIN1 dependent microdomains are disrupted in heart failure. Building on preliminary data, we will
use human and mouse models of heart failure to quantify BIN1 splicing and isoform expression, T-
tubule folds, and LTCC-RyR2 complex formation and function, as well as the rescue ability of
exogenous BIN1. We will also study whether the mechanism of reduced Bin1 transcription and aberrant
splicing in heart failure is due to -adrenergic sympathetic dysregulation. The third aim is to determine
whether -adrenergic blockade can rescue BIN1-microdomains and limit arrhythmias and heart failure
development. Building on preliminary data, we will investigate whether Bin1 deleted mice develop
arrhythmia and heart failure when stressed, which can be rescued by -adrenergic blockade.
Our contribution here is expected to be a detailed understanding of how BIN1-induced LTCC-
RyR2 microdomains are organized and regulated in both normal and diseased hearts. This contribution
is significant because it will identify a new approach to ameliorate heart failure progression by
preserving the BIN1 microdomains that are critical to normal heart function. The proposed research is
innovative, in our opinion, because it introduces the relatively unknown BIN1 as a determinant of T-
tubule microdomains thus helping regulate cardiac dyads and calcium transients.
项目总结/文摘
项目成果
期刊论文数量(4)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(1)
Cardiac T-Tubule cBIN1-Microdomain, a Diagnostic Marker and Therapeutic Target of Heart Failure.
- DOI:10.3390/ijms22052299
- 发表时间:2021-02-25
- 期刊:
- 影响因子:5.6
- 作者:Li J;Richmond B;Hong T
- 通讯作者:Hong T
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TingTing Hong其他文献
TingTing Hong的其他文献
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{{ truncateString('TingTing Hong', 18)}}的其他基金
Correcting Cardiac Microdomains Reverses Non-Ischemic Cardiomyopathy
纠正心脏微区可逆转非缺血性心肌病
- 批准号:
10720077 - 财政年份:2023
- 资助金额:
$ 38.13万 - 项目类别:
Regulation of Cav1.2 Trafficking by GJA1-20k and cBIN1
GJA1-20k 和 cBIN1 对 Cav1.2 贩运的监管
- 批准号:
10475207 - 财政年份:2021
- 资助金额:
$ 38.13万 - 项目类别:
Advancing cBIN1 Therapy to Large Preclinical Animals
将 cBIN1 疗法推广至大型临床前动物
- 批准号:
10317539 - 财政年份:2021
- 资助金额:
$ 38.13万 - 项目类别:
Advancing cBIN1 Therapy to Large Preclinical Animals
将 cBIN1 疗法推广至大型临床前动物
- 批准号:
10456878 - 财政年份:2021
- 资助金额:
$ 38.13万 - 项目类别:
Regulation of Cav1.2 Trafficking by GJA1-20k and cBIN1
GJA1-20k 和 cBIN1 对 Cav1.2 贩运的监管
- 批准号:
10317525 - 财政年份:2021
- 资助金额:
$ 38.13万 - 项目类别:
Regulation of Cav1.2 Trafficking by GJA1-20k and cBIN1
GJA1-20k 和 cBIN1 对 Cav1.2 贩运的监管
- 批准号:
10658983 - 财政年份:2021
- 资助金额:
$ 38.13万 - 项目类别:
Regulation of Ion Channels at BIN1-induced T-tubule Microdomains
BIN1 诱导的 T 管微区离子通道的调节
- 批准号:
9159395 - 财政年份:2016
- 资助金额:
$ 38.13万 - 项目类别:
Regulation of Ion Channels at BIN1-induced T-tubule Microdomains
BIN1 诱导的 T 管微区离子通道的调节
- 批准号:
9921467 - 财政年份:2016
- 资助金额:
$ 38.13万 - 项目类别:
BIN1 is a mediator and marker of cardiac reserve in heart failure.
BIN1 是心力衰竭心脏储备的调节因子和标志物。
- 批准号:
8880264 - 财政年份:2012
- 资助金额:
$ 38.13万 - 项目类别:
BIN1 is a mediator and marker of cardiac reserve in heart failure.
BIN1 是心力衰竭心脏储备的调节因子和标志物。
- 批准号:
8300530 - 财政年份:2012
- 资助金额:
$ 38.13万 - 项目类别:
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