Dual filament control of myocardial power and hemodynamics
Dual filament control of myocardial power and hemodynamics
批准号:
10472655
负责人:
Kenneth S Campbell
金额:
$46.71万
依托单位国家:
美国
项目类别:
财政年份:
2020
资助国家:
美国
项目状态:
已结题
起止时间:
2020-08-25 至 2024-07-31
关键词:
ActinsAreaAtomic Force MicroscopyBindingBiochemicalBiophysical ProcessBiophysicsBloodBlood CirculationCardiacCardiac MyocytesCardiomyopathiesCardiovascular systemCell physiologyCellsClinicalComputer ModelsCoupledCouplingCyclic AMP-Dependent Protein KinasesDataFilamentGenerationsGeneticHeartHeart failureHumanInterventionLinkMeasuresMechanicsMediatingMicrofilamentsModelingModificationMolecularMusMutationMyocardialMyosin ATPaseOrganOutputPatientsPerformancePhosphorylationPhysiologyPropertyPumpRegulationResearchSarcomeresSignal PathwaySpeedSystemTestingThickThick FilamentThin FilamentThinnessTimeTranscendTransgenic MiceTransgenic OrganismsTranslatingTranslationsVentricularVentricular FunctionWorkbaseblood pumpcombinatorialexperimental studyheart functionhemodynamicsinnovationkinetic modelmulti-scale modelingmyosin-binding protein Cnovelpredictive modelingpressurerecruitsimulationtherapeutic targettool
中文摘要
摘要
心室做功的能力(即,发电)对于将血液
循环系统。心室功率由肌丝的发电能力决定
在心肌细胞内。然而,调节肌丝功率的亚细胞过程是
不完全理解。该提案的总体目标是利用生物化学、生物物理和
转基因工具,以辨别(i)细丝和(ii)厚的基于免疫调节的机制,
(iii)将这些控制机制整合到一个计算模型中,
修改影响血流动力学。这两个机制假设是(目的1)功能的改变,
细丝调节单位的刚性调节跨桥的协同募集,反过来,
决定功率和(目的2)磷酸化肌球蛋白结合蛋白- C(MyBP-C)本身增加
肌原纤维功率输出由三种不同的生物物理机制。在(目标3)中,
将产生肌节功率输出,由此可以
操纵和评估对合作性和权力的功能影响。目标3超越了
肌节,并使用多尺度建模来预测肌丝靶点的策略操作将如何
影响心室功能和血流动力学,这将在假设驱动的实验中进行实验测试。
方式多尺度建模将提供一个新的平台,以询问生物物理修改,
最大的功能效应,从而阐明高价值的治疗靶点,以优化心室
在遗传性和适应性心肌病患者中的表现。
英文摘要
Abstract
The capacity of the ventricles to perform work (i.e., generate power) is essential for moving blood throughout
the circulatory systems. Ventricular power is determined by the power generating capacity of the myofilaments
within the cardiac myocyte. However, the sub-cellular processes that regulate myofilament power are
incompletely understood. The overall objective of this proposal is to use biochemical, biophysical, and
transgenic tools to discern (i) thin filament and (ii) thick filament-based mechanisms that regulate power and
(iii) integrate these control mechanisms into a computational model that can predict how sarcomere-level
modifications impact hemodynamics. The two mechanistic hypotheses are (Aim 1) alterations in the functional
rigidity of thin filament regulatory units modulate cooperative recruitment of cross-bridges, which, in turn,
determines power and (Aim 2) phosphorylation of myosin binding protein- C (MyBP-C) per se increases
myofibrillar power output by three distinct biophysical mechanisms. In (Aim 3), a multi-state kinetic model of
sarcomeric power output will be generated whereby thin and thick filament dynamic properties can be
manipulated and evaluated for functional impacts to cooperativity and power. Aim 3 goes beyond the
sarcomere and uses multiscale modeling to predict how strategic manipulation of myofilament targets will
impact ventricular function and hemodynamics, which will be experimentally tested in a hypothesis-driven
manner. Multi-scale modeling will provide a new platform to interrogate biophysical modifications that produce
the largest functional effects and, thus, illuminate high-value therapeutic targets to optimize ventricular
performance in patients with genetic and adaptive cardiomyopathies.
期刊论文(0)
专著(0)
科研奖励(0)
会议论文
Carol Act Supplement to Data-driven optimization of therapy for heart failure
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批准号:10851206
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项目类别:
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资助金额:$12.86万
-
财政年份:2022
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负责人:Kenneth S Campbell
-
依托单位:
Data-driven optimization of therapy for heart failure
-
批准号:10467277
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项目类别:
-
资助金额:$57.93万
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财政年份:2022
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负责人:Kenneth S Campbell
-
依托单位:
Data-driven optimization of therapy for heart failure
-
批准号:10615143
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项目类别:
-
资助金额:$56.6万
-
财政年份:2022
-
负责人:Kenneth S Campbell
-
依托单位:
Dual filament control of myocardial power and hemodynamics
-
批准号:10245290
-
项目类别:
-
资助金额:$46.71万
-
财政年份:2020
-
负责人:Kenneth S Campbell
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依托单位:
Length-dependent activation in human myocardium
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批准号:10468226
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项目类别:
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资助金额:$67.56万
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财政年份:2020
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负责人:Kenneth S Campbell
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依托单位:
Dual filament control of myocardial power and hemodynamics
-
批准号:10672422
-
项目类别:
-
资助金额:$46.71万
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财政年份:2020
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负责人:Kenneth S Campbell
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依托单位:
Length-dependent activation in human myocardium
-
批准号:10678926
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项目类别:
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资助金额:$65.06万
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财政年份:2020
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负责人:Kenneth S Campbell
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依托单位:
Length-dependent activation in human myocardium
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批准号:10259881
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项目类别:
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资助金额:$69.46万
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财政年份:2020
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负责人:Kenneth S Campbell
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依托单位:
Multiscale modeling of inherited cardiomyopathies and therapeutic interventions
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批准号:9980457
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项目类别:
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资助金额:$64.48万
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财政年份:2017
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依托单位:
Multiscale modeling of inherited cardiomyopathies and therapeutic interventions
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批准号:10223922
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项目类别:
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资助金额:$57.63万
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财政年份:2017
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依托单位:
Graduate Training in Integrative Physiology
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批准号:10201642
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项目类别:
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资助金额:$19.06万
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财政年份:2017
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负责人:Kenneth S Campbell
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依托单位:
Multiscale modeling of inherited cardiomyopathies and therapeutic interventions
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批准号:10448074
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项目类别:
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资助金额:$0.34万
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财政年份:2017
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负责人:Kenneth S Campbell
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依托单位:
Myocardial Stiffness in Diastolic Heart Failure
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批准号:7899934
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项目类别:
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资助金额:$32.96万
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财政年份:2008
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负责人:Kenneth S Campbell
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依托单位:
Myocardial Stiffness in Diastolic Heart Failure
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批准号:8267690
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项目类别:
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资助金额:$32.63万
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财政年份:2008
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负责人:Kenneth S Campbell
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依托单位:
Myocardial Stiffness in Diastolic Heart Failure
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批准号:7669387
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项目类别:
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资助金额:$32.96万
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财政年份:2008
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负责人:Kenneth S Campbell
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依托单位:
Myocardial Stiffness in Diastolic Heart Failure
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批准号:8131616
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项目类别:
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资助金额:$32.96万
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财政年份:2008
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负责人:Kenneth S Campbell
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依托单位:
Myocardial Stiffness in Aging Associated Diastolic Heart Failure
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批准号:7282035
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项目类别:
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资助金额:$5.83万
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财政年份:2006
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负责人:Kenneth S Campbell
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依托单位:
Myocardial Stiffness in Aging Associated Diastolic Heart Failure
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批准号:7082271
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项目类别:
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资助金额:$6.01万
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财政年份:2006
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负责人:Kenneth S Campbell
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