Molecular Quiescence and Cardiomyocyte Maturation

分子静止和心肌细胞成熟

基本信息

  • 批准号:
    10589890
  • 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.
治疗心力衰竭的干细胞方法需要产生成熟的人类心肌细胞 (CMs)改善心脏收缩功能然而,来自胚胎或诱导多能干细胞的CM 使用目前的方法,多能干细胞(iPSC)在功能上仍然不成熟。当交付给成年大型动物时 这些不成熟的CM导致潜在的危及生命的室性心律失常。成功 因此,将细胞疗法转化为心血管疾病可能需要定义分子途径, 成熟人干细胞衍生的CM。细胞静止是一种暂时的非增殖状态, for the lifetime寿命of the organism有机体.细胞静止可以是具有不同静止深度的不同状态 以及其他符合整体静止概念的分子条件。根据新的初步数据 在这里,我们试图研究细胞静止是否需要从人类CM成熟 iPSCs。在发育过程中,CM经历了从胎儿时的增殖状态到更成熟但 出生后的静止状态这种转变伴随着能量代谢的变化, 主要通过糖酵解获得能量,成年CM主要通过脂肪酸获得能量 氧化雷帕霉素靶蛋白(mTOR)信号通路在营养传感中起着关键作用 和生长,并且mTOR的调节影响从糖酵解到脂质代谢的代谢转变。细胞周期 瞬时mTOR抑制的停滞可能导致细胞静止。我们假设, mTOR途径是CM成熟的关键驱动因素,通过驱动细胞静止。以下目标将测试 理解mTOR信号通路和E2 F家族转录的机制假说 因子可以增强CM成熟,并测试3D系统中的mTOR通路操纵是否也 促进CM成熟。 具体目的1:确定4 E-BP 1活化在Torin 1诱导的iPSC衍生的细胞成熟中的作用。 CM我们将在CM成熟的不同阶段调节4 E-BP 1,并确定这种机制是否 解释了Torin 1诱导的CM成熟。我们将评估电生理特性,收缩性, 代谢以及基因和蛋白质表达来表征CM表型和成熟。 具体目标2:定义E2 F的静止深度如何影响iPSC衍生的细胞的成熟。 心肌细胞我们将对分化或成熟的CM进行细胞周期分析,无论是否有细胞周期 抑制剂的我们将评估E2 F1/2/3a的过表达或E2 F3 a-8的缺失是否可以预防CM 成熟 具体目的3:探索瞬时抑制mTOR在iPSC衍生的细胞成熟中的作用。 3D环境中的CM。由于mTOR信号在2D与3D环境中可能不同,我们试图测试 mTOR抑制是否增加收缩性并增强3D中CM的兴奋-收缩偶联。

项目成果

期刊论文数量(2)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
A Grim link: the association between subclinical atherosclerosis and epigenetic age.
严峻的联系:亚临床动脉粥样硬化与表观遗传年龄之间的关联。
  • DOI:
    10.1093/eurheartj/ehad326
  • 发表时间:
    2023
  • 期刊:
  • 影响因子:
    39.3
  • 作者:
    Velayutham,Nivedhitha;Lee,RichardT
  • 通讯作者:
    Lee,RichardT
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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:
Molecular Quiescence and Cardiomyocyte Maturation
分子静止和心肌细胞成熟
  • 批准号:
    10371079
  • 财政年份:
    2020
  • 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:
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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