Computational systems analysis of cardiac mechanical-energetic coupling in heart disease

心脏病中心脏机械-能量耦合的计算系统分析

基本信息

  • 批准号:
    10094080
  • 负责人:
  • 金额:
    $ 44.24万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2019
  • 资助国家:
    美国
  • 起止时间:
    2019-02-01 至 2023-01-31
  • 项目状态:
    已结题

项目摘要

Abstract The energetic status of the myocardium is compromised in decompensated hypertrophy in the failing heart, with the chemical energy (in the form of the ATP hydrolysis potential) available for the heart to do work diminished compared to normal. The consequences of the observed changes in energetic state on mechanical function are not known. In previous studies we have developed computer models that explain how the depletion of cytoplasmic metabolite pools in the myocardium affects energetic state in heart failure; and a metabolic state-dependent computer model for myocardial mechanics that predicts how these observed changes in energetic status affect mechanical function in vivo. Using these models to interpret data from humans and animal models of cardiac decompensation and heart failure, we predict that metabolic/energetic dysfunction directly causes contractile dysfunction of the myocardium in heart failure. In this project we will test the following hypotheses associated with that prediction: (1.) The primary causes of metabolic/energetic dysfunction in the TAC rat model of heart failure are reduction in mitochondrial capacity for oxidative phosphorylation and pathological depletion of cytoplasmic adenine nucleotides and other key metabolic pools. (2.) Diminished cytosolic ATP and increased inorganic phosphate (associated with impaired energy metabolism) impairs the mechanical function of the heart. (3.) By blocking purine degradation pathways that may be overactive in the chronically stressed and/or periodically ischemic myocardium, we can increase/restore the nucleotide pool and protect the heart against mechanical dysfunction and failure. The three specific aims are built around testing and refining these three hypotheses. Metabolic and functional data from experiments on rat models of hypertrophy and failure will be interpreted based on multi- scale computer models integrating cardiac energetic and mechanics with whole-body cardiovascular function. Hypotheses will be tested and refined based on the ability/inability of the models to simultaneously explain the metabolic and mechanical data from the animal models. This approach expedites the cycle of hypothesis testing (via quantitative comparison of model predictions to experimental observations), hypothesis refinement (redesign and reformulation of models in light of mismatches between predictions and data), and model-guided experimental design. Successful testing of the third hypothesis has the potential to point to whole new classes of pharmacological targets associated with purine nucleotide dephosphorylation, deamination, degradation, and transport.
摘要 在衰竭心脏的失代偿性肥大中,心肌的能量状态受到损害, 与化学能(以ATP水解电位的形式)可供心脏做功 与正常相比有所减少。观察到的能量状态变化对机械性能的影响 功能未知。在以前的研究中,我们开发了计算机模型,解释了 心肌细胞质代谢物库的消耗影响心力衰竭的能量状态; 代谢状态依赖的心肌力学计算机模型,预测这些观察到的 能量状态的变化影响体内的机械功能。使用这些模型来解释数据, 人类和动物模型的心脏代偿失调和心力衰竭,我们预测,代谢/能量 功能障碍直接导致心力衰竭中心肌的收缩功能障碍。在这个项目中,我们将测试 与该预测相关的以下假设: (1.)心脏衰竭的TAC大鼠模型中代谢/能量功能障碍的主要原因是 线粒体氧化磷酸化能力降低和细胞质病理性耗竭 腺嘌呤核苷酸和其他关键代谢池。 (2.)胞浆ATP减少和无机磷酸盐增加(与能量受损相关 代谢)损害心脏的机械功能。 (3.)通过阻断嘌呤降解途径,可能是过度活跃的慢性应激和/或 周期性缺血心肌,我们可以增加/恢复核苷酸库,保护心脏免受 机械功能障碍和故障。 这三个具体目标是围绕测试和完善这三个假设而建立的。代谢和 来自肥大和衰竭的大鼠模型的实验的功能数据将基于多个- 将心脏能量和力学与全身心血管功能相结合的比例计算机模型。 假设将根据模型同时解释 代谢和机械数据从动物模型。这种方法加快了假设的循环 测试(通过模型预测与实验观察的定量比较),假设细化 (根据预测和数据之间的不匹配重新设计和重新制定模型), 实验设计第三个假设的成功验证有可能指向全新的类别 与嘌呤核苷酸去磷酸化,脱氨基,降解, 和交通。

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 }}

DANIEL A BEARD其他文献

DANIEL A BEARD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('DANIEL A BEARD', 18)}}的其他基金

Systems and Integrative Biology Training Program
系统和综合生物学培训计划
  • 批准号:
    10714106
  • 财政年份:
    2023
  • 资助金额:
    $ 44.24万
  • 项目类别:
Disentangling the Mechanisms of Coronary Blood Flow Regulation through Multi-scale Modeling
通过多尺度建模阐明冠状动脉血流调节机制
  • 批准号:
    10592338
  • 财政年份:
    2022
  • 资助金额:
    $ 44.24万
  • 项目类别:
Computational systems analysis of cardiac mechanical-energetic coupling in heart disease
心脏病中心脏机械-能量耦合的计算系统分析
  • 批准号:
    10376181
  • 财政年份:
    2019
  • 资助金额:
    $ 44.24万
  • 项目类别:
Multi-scale systems analysis of blood pressure control and hypertension
血压控制和高血压的多尺度系统分析
  • 批准号:
    10117280
  • 财政年份:
    2018
  • 资助金额:
    $ 44.24万
  • 项目类别:
Multi-scale modeling to predict and refine genotype-to-phenotype relationships in mammals
用于预测和完善哺乳动物基因型与表型关系的多尺度建模
  • 批准号:
    9789879
  • 财政年份:
    2018
  • 资助金额:
    $ 44.24万
  • 项目类别:
Coronary Blood Flow: Integrated Theory and Experiments
冠状动脉血流:理论与实验相结合
  • 批准号:
    8803070
  • 财政年份:
    2013
  • 资助金额:
    $ 44.24万
  • 项目类别:
Coronary Blood Flow: Integrated Theory and Experiments
冠状动脉血流:理论与实验相结合
  • 批准号:
    9457478
  • 财政年份:
    2013
  • 资助金额:
    $ 44.24万
  • 项目类别:
Coronary Blood Flow: Integrated Theory and Experiments
冠状动脉血流:理论与实验相结合
  • 批准号:
    8731967
  • 财政年份:
    2013
  • 资助金额:
    $ 44.24万
  • 项目类别:
Mechanisms of Metabolic Dysfunction in Type 2 Diabetes
2 型糖尿病代谢功能障碍的机制
  • 批准号:
    9033896
  • 财政年份:
    2012
  • 资助金额:
    $ 44.24万
  • 项目类别:
Mechanisms of Metabolic Dysfunction in Type 2 Diabetes
2 型糖尿病代谢功能障碍的机制
  • 批准号:
    8271621
  • 财政年份:
    2012
  • 资助金额:
    $ 44.24万
  • 项目类别:

相似国自然基金

鼠伤寒沙门菌5'-nucleotidase在致病过程中的作用机制研究
  • 批准号:
  • 批准年份:
    2023
  • 资助金额:
    50 万元
  • 项目类别:

相似海外基金

The Molecular function of ecto 5' nucleotidase in fusion-negative rhabdomyosarcoma
融合阴性横纹肌肉瘤中5端核苷酸酶的分子功能
  • 批准号:
    10462430
  • 财政年份:
    2022
  • 资助金额:
    $ 44.24万
  • 项目类别:
The Molecular function of ecto 5' nucleotidase in fusion-negative rhabdomyosarcoma
融合阴性横纹肌肉瘤中5端核苷酸酶的分子功能
  • 批准号:
    10615694
  • 财政年份:
    2022
  • 资助金额:
    $ 44.24万
  • 项目类别:
Combinaisons d’immunothérapies et implication de l'ecto-5'-nucleotidase et de l’infiltration lymphocytaire dans le cancer de la prostate
免疫疗法的组合及其对 5-核酸酶和前列腺癌浸润淋巴细胞的影响
  • 批准号:
    311752
  • 财政年份:
    2013
  • 资助金额:
    $ 44.24万
  • 项目类别:
    Studentship Programs
RELEASE TIME TO STUDY THE PATHWAY OF 5'-NUCLEOTIDASE IN DICTYOSTELIUM
释放时间来研究盘基菌中 5-核苷酸酶的通路
  • 批准号:
    7381680
  • 财政年份:
    2006
  • 资助金额:
    $ 44.24万
  • 项目类别:
TAGGING GENES AND EXPRESSION OF 5' NUCLEOTIDASE IN DICTYOSTELIUM DISCOIDEUM
盘基网柄菌中标记基因和 5 核苷酸酶的表达
  • 批准号:
    7381669
  • 财政年份:
    2006
  • 资助金额:
    $ 44.24万
  • 项目类别:
TAGGING GENES AND EXPRESSION OF 5' NUCLEOTIDASE IN DICTYOSTELIUM DISCOIDEUM
盘基网柄菌中标记基因和 5 核苷酸酶的表达
  • 批准号:
    7170907
  • 财政年份:
    2005
  • 资助金额:
    $ 44.24万
  • 项目类别:
Functional role of CD73/ecto-5'-nucleotidase-derived extracellular adenosine in vascular inflammation (B06)
CD73/ecto-5-核苷酸酶衍生的细胞外腺苷在血管炎症中的功能作用 (B06)
  • 批准号:
    5352038
  • 财政年份:
    2002
  • 资助金额:
    $ 44.24万
  • 项目类别:
    Collaborative Research Centres
MOLECULAR BASIS OF PYRIMIDINE 5'-NUCLEOTIDASE (P5N) DEFICIENCY AND FUNCTIONAL ANALYSIS OF P5N
嘧啶 5-核苷酸酶 (P5N) 缺陷的分子基础及 P5N 的功能分析
  • 批准号:
    14571001
  • 财政年份:
    2002
  • 资助金额:
    $ 44.24万
  • 项目类别:
    Grant-in-Aid for Scientific Research (C)
Acquirement of the Ischemic Cardioprotection and ecto-5'-nucleotidase : Investigation of the Receptor Activation and Subsequent Signal Transduction
缺血性心脏保护和 ecto-5-核苷酸酶的获得:受体激活和随后信号转导的研究
  • 批准号:
    12470153
  • 财政年份:
    2000
  • 资助金额:
    $ 44.24万
  • 项目类别:
    Grant-in-Aid for Scientific Research (B)
The Role of 5'Nucleotidase-expressing Cells in the Regulation of Morphogenesis in Dictyostellium
5核苷酸酶表达细胞在网网柄菌形态发生调控中的作用
  • 批准号:
    9816664
  • 财政年份:
    1999
  • 资助金额:
    $ 44.24万
  • 项目类别:
    Continuing Grant
{{ showInfoDetail.title }}

作者:{{ showInfoDetail.author }}

知道了