Molecular Quiescence and Cardiomyocyte Maturation

分子静止和心肌细胞成熟

基本信息

  • 批准号:
    10371079
  • 负责人:
  • 金额:
    $ 42.25万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2020
  • 资助国家:
    美国
  • 起止时间:
    2020-04-05 至 2024-03-31
  • 项目状态:
    已结题

项目摘要

Stem cell approaches to treat heart failure will require production of mature human cardiomyocytes (CMs) to improve systolic heart function. However, CMs derived from embryonic or induced pluripotent stem cells (iPSCs) remain functionally immature using current approaches. When delivered to adult large animal models, these immature CMs result in potentially life-threatening ventricular arrhythmias. Successful translation of cell therapies for cardiovascular disease will thus likely require defining molecular pathways to mature human stem cell-derived CMs. Cellular quiescence is a temporary non-proliferating state that can last for the lifetime of the organism. Cellular quiescence can be a diverse state with varying depth of quiescence and other molecular conditions that fit within the overall quiescence concept. Based on new preliminary data shown here, we seek to investigate whether cellular quiescence is required for CM maturation from human iPSCs. During development, CMs undergo a shift from a proliferative state as a fetus, to a more mature but quiescent state after birth. This shift is accompanied by a change in energy metabolism, with fetal CMs deriving energy primarily through glycolysis, and adult CMs deriving energy primarily through fatty acid oxidation. The mechanistic target of rapamycin (mTOR) signaling pathway plays a key role in nutrient sensing and growth, and regulation of mTOR affects the metabolic shift from glycolysis to lipid metabolism. Cell cycle arrest with transient mTOR inhibition may lead to cellular quiescence. We hypothesize that regulation of the mTOR pathway is a key driver in CM maturation via driving cells to quiescence. The following Aims will test mechanistic hypotheses to understand how the mTOR signaling pathway and the E2F family of transcription factors can enhance CM maturation and test whether mTOR pathway manipulation in 3D systems also enhances CM maturation. Specific Aim 1: To define the role of 4E-BP1 activation in Torin1-induced maturation of iPSC-derived CMs. We will modulate 4E-BP1 at different stages of CM maturation and determine whether this mechanism explains Torin1-induced CM maturation. We will evaluate electrophysiological properties, contractility, metabolism, and gene and protein expression to characterize CM phenotype and maturation. Specific Aim 2: To define how quiescence depth by E2F affects maturation of iPSC-derived cardiomyocytes. We will perform cell cycle analysis on differentiating or maturing CMs with or without cell cycle inhibitors. We will evaluate whether overexpression of E2F1/2/3a or deletion of E2F3a-8 prevents CM maturation. Specific Aim 3: To explore the role of transient inhibition of mTOR in the maturation of iPSC-derived CMs in a 3D environment. Because mTOR signaling can differ in 2D versus 3D environments, we seek to test whether mTOR inhibition increases contractility and enhances excitation-contraction coupling in CMs in 3D.
干细胞治疗心力衰竭需要成熟的人类心肌细胞

项目成果

期刊论文数量(0)
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科研奖励数量(0)
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专利数量(0)

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RICHARD T LEE其他文献

RICHARD T LEE的其他文献

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{{ truncateString('RICHARD T LEE', 18)}}的其他基金

Myocardial Physiology of Growth Differentiation Factor Signaling
生长分化因子信号传导的心肌生理学
  • 批准号:
    10711086
  • 财政年份:
    2023
  • 资助金额:
    $ 42.25万
  • 项目类别:
Molecular Mechanisms of Arrestin-Domain Containing Proteins in Metabolism
含有抑制蛋白结构域的蛋白质在代谢中的分子机制
  • 批准号:
    10320336
  • 财政年份:
    2021
  • 资助金额:
    $ 42.25万
  • 项目类别:
Molecular Mechanisms of Arrestin-Domain Containing Proteins in Metabolism
含有抑制蛋白结构域的蛋白质在代谢中的分子机制
  • 批准号:
    10095220
  • 财政年份:
    2021
  • 资助金额:
    $ 42.25万
  • 项目类别:
Molecular Mechanisms of Arrestin-Domain Containing Proteins in Metabolism
含有抑制蛋白结构域的蛋白质在代谢中的分子机制
  • 批准号:
    10540314
  • 财政年份:
    2021
  • 资助金额:
    $ 42.25万
  • 项目类别:
In vivo Structure-Function relationships of GDF11 and GDF8
GDF11 和 GDF8 的体内结构-功能关系
  • 批准号:
    10246575
  • 财政年份:
    2020
  • 资助金额:
    $ 42.25万
  • 项目类别:
Molecular Quiescence and Cardiomyocyte Maturation
分子静止和心肌细胞成熟
  • 批准号:
    10589890
  • 财政年份:
    2020
  • 资助金额:
    $ 42.25万
  • 项目类别:
Myocardial Effects of Caloric Restriction in Primates
灵长类动物热量限制对心肌的影响
  • 批准号:
    9507133
  • 财政年份:
    2018
  • 资助金额:
    $ 42.25万
  • 项目类别:
Complement Activation and Initiation of Heart Regeneration
补体激活和心脏再生启动
  • 批准号:
    10116444
  • 财政年份:
    2018
  • 资助金额:
    $ 42.25万
  • 项目类别:
Myocardial Effects of Caloric Restriction in Primates
灵长类动物热量限制对心肌的影响
  • 批准号:
    9764223
  • 财政年份:
    2018
  • 资助金额:
    $ 42.25万
  • 项目类别:
Reprogramming Non-myocytes to Cardiomyocytes in vivo
在体内将非心肌细胞重编程为心肌细胞
  • 批准号:
    9493517
  • 财政年份:
    2016
  • 资助金额:
    $ 42.25万
  • 项目类别:

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