Computational Modeling of Scar Formation After Myocardial Infarction
心肌梗塞后疤痕形成的计算模型
基本信息
- 批准号:9131778
- 负责人:
- 金额:$ 36.84万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2014
- 资助国家:美国
- 起止时间:2014-09-01 至 2018-12-31
- 项目状态:已结题
- 来源:
- 关键词:AmericanAnisotropyBiologyCardiacCell modelCellsChemicalsCicatrixCollagenCollagen FiberComputer SimulationCoupledCytoskeletonDataDepositionDevelopmentElementsEnvironmentEventEvolutionExperimental ModelsFiberFibroblastsGoalsHeartHeart failureIn VitroIndividualInfarctionInjection of therapeutic agentLeadLeft ventricular structureMeasurementMeasuresMechanicsModelingMyocardial InfarctionMyocardiumOperative Surgical ProceduresPatientsPatternPeriodicityPolymersRegulationResearch PersonnelRestRiskRoleRuptureSignal TransductionStimulusStretchingStructureTestingTherapeutic InterventionTimeTissuesWorkWound Healingbasedensitydesignexperimental studyhealingheart functionimprovedin vivoinnovationinsightmechanical propertiesmigrationmulti-scale modelingnew therapeutic targetnovelnovel therapeutic interventionnovel therapeuticspredictive modelingpublic health relevanceresponserestraintscreeningtherapy designtool
项目摘要
DESCRIPTION (provided by applicant): Over a million Americans suffer a heart attack (myocardial infarction) each year. For the majority who survive the initial event, the risks of serious complications such as infarct rupture and heart failure depend on the structure and mechanical properties of the scar tissue that replaces damaged heart muscle over the first few weeks. That scar tissue is produced by cardiac fibroblasts, and we recently showed that scar structure and mechanical properties are strongly influenced by mechanical stretch during healing. The biology of how fibroblasts respond to individual signals such as mechanical stretch has been studied extensively; yet we still understand relatively little about how fibroblasts integrate and respond to the multiple signals present in a healing wound. We therefore developed an agent-based model (ABM) of scar formation that represents individual fibroblasts - each migrating, aligning, depositing and remodeling collagen, dividing, dying, and responding to individual chemical, structural, and mechanical signals according to experimental measurements - and predicts the resulting evolution of tissue-level collagen content and fiber alignment in scars healing under different patterns of stretch. Here, we propose to couple this ABM with a finite-element model (FEM) of the infarct left ventricle to produce a coupled model that can predict the dynamic interplay between evolving scar structure, scar mechanics, and heart function after infarction and in response to therapies that alter infarct mechanics (Aim 1). Then, we will use a combination of experiments and modeling to better understand the cellular mechanisms by which mechanical stretch regulates collagen content and alignment in healing myocardial infarcts. Specifically, we will test the hypotheses that mechanical regulation of collagen degradation significantly influences collagen content and alignment during mechanical unloading (Aim 2) and that scar compaction significantly influences collagen fiber density but not in-plane fiber alignment across a range of loading conditions (Aim 3). The proposed studies are potentially significant both because they will generate the first validated, predictive model of infarct healing across a range of mechanical conditions - enabling computational screening and design of novel therapies - and because they will provide important new insight into the cellular mechanisms by which mechanical environment regulates scar formation, which could lead to the identification of new therapeutic approaches to modulating infarct healing.
描述(由申请人提供):每年有超过一百万的美国人患有心脏病发作(心肌梗死)。对于大多数在最初事件中幸存下来的人来说,严重并发症(如梗死破裂和心力衰竭)的风险取决于在最初几周内取代受损心肌的疤痕组织的结构和机械特性。瘢痕组织是由心脏成纤维细胞产生的,我们最近发现瘢痕结构和机械性能在愈合过程中受到机械拉伸的强烈影响。成纤维细胞如何响应单个信号(如机械拉伸)的生物学已经得到了广泛的研究;然而,我们对成纤维细胞如何整合和响应愈合伤口中存在的多种信号仍然知之甚少。因此,我们开发了一个基于代理的模型(ABM)的疤痕形成,代表个别成纤维细胞-每个迁移,对齐,沉积和重塑胶原蛋白,分裂,死亡,并根据实验测量响应个别化学,结构和机械信号-并预测组织水平的胶原蛋白含量和纤维对齐在不同的拉伸模式下愈合疤痕的演变。在这里,我们建议耦合此ABM与梗死左心室的有限元模型(FEM),以产生耦合模型,该模型可以预测梗死后的瘢痕结构,瘢痕力学和心脏功能之间的动态相互作用,并响应于改变梗死力学的治疗(目标1)。然后,我们将使用实验和建模相结合,以更好地了解机械拉伸调节胶原蛋白含量和对齐愈合心肌梗死的细胞机制。具体而言,我们将测试以下假设:胶原降解的机械调节显著影响机械卸载期间的胶原含量和排列(目标2),瘢痕压实显著影响胶原纤维密度,但在一系列加载条件下不影响平面内纤维排列(目标3)。拟议的研究具有潜在的重要意义,因为它们将在一系列机械条件下生成第一个经过验证的梗死愈合预测模型-使计算筛选和设计新疗法成为可能-并且因为它们将为机械环境调节瘢痕形成的细胞机制提供重要的新见解,这可能导致识别调节梗塞愈合的新治疗方法。
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 }}
JEFFREY W HOLMES其他文献
JEFFREY W HOLMES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('JEFFREY W HOLMES', 18)}}的其他基金
Systems Pharmacology Model for Spatial Control of Cardiac Fibrosis
心脏纤维化空间控制的系统药理学模型
- 批准号:
9363220 - 财政年份:2017
- 资助金额:
$ 36.84万 - 项目类别:
2017 Summer Biomechanics, Bioengineering and Biotransport Conference
2017夏季生物力学、生物工程与生物转运会议
- 批准号:
9330598 - 财政年份:2017
- 资助金额:
$ 36.84万 - 项目类别:
Multiscale Models of Cardiac Growth, Remodeling, and Myocardial Infarction
心脏生长、重塑和心肌梗死的多尺度模型
- 批准号:
9144435 - 财政年份:2015
- 资助金额:
$ 36.84万 - 项目类别:
Computational Modeling of Scar Formation After Myocardial Infarction
心肌梗塞后疤痕形成的计算模型
- 批准号:
8916817 - 财政年份:2014
- 资助金额:
$ 36.84万 - 项目类别:
Computational Modeling of Scar Formation After Myocardial Infarction
心肌梗塞后疤痕形成的计算模型
- 批准号:
8629133 - 财政年份:2014
- 资助金额:
$ 36.84万 - 项目类别:
Anisotropic Reinforcement to Improve Post-Infarction LV Function
各向异性强化可改善梗塞后左心室功能
- 批准号:
8403788 - 财政年份:2012
- 资助金额:
$ 36.84万 - 项目类别:
Anisotropic Reinforcement to Improve Post-Infarction LV Function
各向异性强化可改善梗塞后左心室功能
- 批准号:
8223807 - 财政年份:2012
- 资助金额:
$ 36.84万 - 项目类别:
PARAMETERIZATION OF CARDIAC WALL MOTION: REUNITING ENGINEERING & CARDIOLOGY
心壁运动的参数化:重新结合工程
- 批准号:
8169343 - 财政年份:2010
- 资助金额:
$ 36.84万 - 项目类别:
PARAMETERIZATION OF CARDIAC WALL MOTION: REUNITING ENGINEERING & CARDIOLOGY
心壁运动的参数化:重新结合工程
- 批准号:
7955232 - 财政年份:2009
- 资助金额:
$ 36.84万 - 项目类别:
MODEL-BASED DEVELOPMENT OF NEW DIAGNOSTIC MEASURES
基于模型的新诊断措施开发
- 批准号:
7955292 - 财政年份:2009
- 资助金额:
$ 36.84万 - 项目类别:
相似海外基金
Exploration of Anisotropy and Inhomogeneity of Ocean Boundary Layer Turbulence
海洋边界层湍流的各向异性和不均匀性探索
- 批准号:
2344156 - 财政年份:2024
- 资助金额:
$ 36.84万 - 项目类别:
Standard Grant
CAREER: Anisotropy-Directed Synthesis of Optically Active 1D van der Waals Nanocrystals and Development of Multiscale Solid State Chemistry Educational Activities
职业:光学活性一维范德华纳米晶体的各向异性定向合成和多尺度固态化学教育活动的发展
- 批准号:
2340918 - 财政年份:2024
- 资助金额:
$ 36.84万 - 项目类别:
Continuing Grant
Seismic Tomography Models for Alaska: Validation, Iteration, and Complex Anisotropy
阿拉斯加地震层析成像模型:验证、迭代和复杂各向异性
- 批准号:
2342129 - 财政年份:2024
- 资助金额:
$ 36.84万 - 项目类别:
Continuing Grant
CEDAR: Evaluating Ion Temperature Anisotropy in the Weakly Collisional F-region Ionosphere
CEDAR:评估弱碰撞 F 区电离层中的离子温度各向异性
- 批准号:
2330254 - 财政年份:2023
- 资助金额:
$ 36.84万 - 项目类别:
Standard Grant
A novel fluorescence anisotropy imaging for imaging nano-scale LLPS in living cells
一种用于活细胞中纳米级 LLPS 成像的新型荧光各向异性成像
- 批准号:
23K17398 - 财政年份:2023
- 资助金额:
$ 36.84万 - 项目类别:
Grant-in-Aid for Challenging Research (Pioneering)
Lower mantle seismic anisotropy and heterogeneities - insight from the thermoelastic properties of CaSiO3 perovskite
下地幔地震各向异性和异质性——从 CaSiO3 钙钛矿热弹性性质的洞察
- 批准号:
2240506 - 财政年份:2023
- 资助金额:
$ 36.84万 - 项目类别:
Continuing Grant
Origin of intracellular anisotropy investigated by FCS utilizing spatial information
利用空间信息的 FCS 研究细胞内各向异性的起源
- 批准号:
23K05776 - 财政年份:2023
- 资助金额:
$ 36.84万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
Advanced Research into Crystallographic Anisotropy & Nucleation Effects in single crystals (ARCANE)
晶体各向异性的高级研究
- 批准号:
EP/X025454/1 - 财政年份:2023
- 资助金额:
$ 36.84万 - 项目类别:
Research Grant
Synchrotron deformation experiments of olivine under the deep upper mantle conditions: Transient creep, plastic anisotropy, and the role of grain-boundary sliding.
上地幔深部条件下橄榄石的同步加速变形实验:瞬态蠕变、塑性各向异性和晶界滑动的作用。
- 批准号:
2322719 - 财政年份:2023
- 资助金额:
$ 36.84万 - 项目类别:
Continuing Grant
Global optimization of anisotropy in antiferromagnets
反铁磁体各向异性的全局优化
- 批准号:
2740295 - 财政年份:2022
- 资助金额:
$ 36.84万 - 项目类别:
Studentship