Understanding the role of pyruvate metabolism-dependent signaling networks in the differentiation of neural stem cells

了解丙酮酸代谢依赖性信号网络在神经干细胞分化中的作用

基本信息

  • 批准号:
    RGPIN-2021-03352
  • 负责人:
  • 金额:
    $ 2.19万
  • 依托单位:
  • 依托单位国家:
    加拿大
  • 项目类别:
    Discovery Grants Program - Individual
  • 财政年份:
    2022
  • 资助国家:
    加拿大
  • 起止时间:
    2022-01-01 至 2023-12-31
  • 项目状态:
    已结题

项目摘要

Our cells need energy to function properly. There are two major pathways that can be used to generate energy in the form of ATP. Oxidative phosphorylation (OXPHOS), uses oxygen to drive the formation ATP. In the absence of oxygen, a pathway called glycolysis can break down glucose and generate ATP independently through a process called lactate fermentation. While OXPHOS can generate far more ATP than glycolysis, paradoxically, many highly active cells prefer to use glycolysis for energy production even when oxygen is available. This allows cells to use metabolic intermediates from the glycolytic pathway to synthesize cellular building blocks or modify proteins to change the way they transmit signaling messages. Therefore, cells need to `decide' when to sacrifice their ATP production to generate more metabolic precursors. Pyruvate lies at the bifurcation point between glycolysis and OXPHOS. Whether pyruvate feeds into the into the mitochondria to support OXPHOS or gets converted to lactate to maintain ongoing glycolysis is governed by the action of three main enzymes: the mitochondrial pyruvate carrier (MPC), pyruvate dehydrogenase (PDH), and lactate dehydrogenase (LDH). Although pyruvate fate represents a critical determination point in cellular energy production, the role of the pyruvate metabolic networks in regulating cellular communication and signaling mechanisms is not well understood. The brain utilizes 20% of the body's glucose and oxygen despite comprising only 2% of the body's mass. The brain is composed of a complex network of neurons and supporting cells, each with their own unique functions. These distinct cell types all arise from the differentiation of neural stem cells (NSCs), however, the metabolic preferences and metabolism-related signaling mechanisms that regulate NSC differentiation are unclear. Using cutting-edge techniques to generate `brains in a dish' we will study the metabolic changes that occur during NSC differentiation. We will also employ a small animal model using zebrafish, which represents an ideal model to study NSC differentiation because they contain populations of regenerative NSCs throughout their lifespan. Finally, we will use genetic engineering technologies to manipulate the MPC-PDH-LDH axis and to determine how changes in pyruvate metabolism impact neural differentiation into specific cell types. This research program represents a new emerging area of research focused on exploring the concept of metabolism as being a central regulator of multi-lineage NSC differentiation. Knowledge generated from this program will significantly advance the field of neuroscience and greatly enhance our understanding about the role of metabolism in regulating the neural stem cell niche and lineage-specific differentiation.
我们的细胞需要能量才能正常运作。有两条主要途径可以用来以三磷酸腺苷的形式产生能量。氧化磷酸化(OXPHOS),使用氧气来驱动ATP的形成。在没有氧气的情况下,一种称为糖酵解的途径可以通过一种称为乳酸发酵的过程独立地分解葡萄糖并生成三磷酸腺苷。虽然OXPHOS可以产生比糖酵解多得多的ATP,但矛盾的是,许多高活性细胞更喜欢利用糖酵解来产生能量,即使在氧气可用的情况下也是如此。这使得细胞可以使用糖酵解途径中的代谢中间产物来合成细胞构建块或修改蛋白质来改变它们传递信号信息的方式。因此,细胞需要“决定”何时牺牲它们的ATP生产,以产生更多的代谢前体。丙酮酸位于糖酵解和氧磷酸盐之间的分叉点。丙酮酸是进入线粒体以支持OXPHOS,还是转化为乳酸以维持正在进行的糖酵解,取决于三种主要酶的作用:线粒体丙酮酸载体(MPC)、丙酮酸脱氢酶(PDH)和乳酸脱氢酶(LDH)。虽然丙酮酸的命运是细胞能量产生的关键决定点,但丙酮酸代谢网络在调节细胞通讯和信号机制中的作用还不是很清楚。尽管大脑只占身体质量的2%,但它利用了身体20%的葡萄糖和氧气。大脑由神经元和支持细胞组成的复杂网络组成,每个细胞都有自己独特的功能。这些不同的细胞类型都起源于神经干细胞的分化,然而,调控神经干细胞分化的代谢偏好和代谢相关的信号机制尚不清楚。我们将使用尖端技术产生“盘中脑”,研究在NSC分化过程中发生的代谢变化。我们还将使用斑马鱼的小动物模型,这是研究神经干细胞分化的理想模型,因为它们在整个生命周期中包含大量再生的神经干细胞。最后,我们将使用基因工程技术来操纵MPC-PDH-LDH轴,并确定丙酮酸代谢的变化如何影响神经分化为特定类型的细胞。这项研究计划代表了一个新的新兴研究领域,专注于探索代谢作为多谱系神经干细胞分化的中心调节因子的概念。该项目所产生的知识将极大地推动神经科学领域的发展,并极大地增强我们对新陈代谢在调节神经干细胞生态位和谱系特异性分化中的作用的理解。

项目成果

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Sharif, Tanveer其他文献

Ras transformation results in cleavage of reticulon protein Nogo-B that is associated with impairment of IFN response
  • DOI:
    10.1080/15384101.2015.1044187
  • 发表时间:
    2015-07-18
  • 期刊:
  • 影响因子:
    4.3
  • 作者:
    Ahn, Dae-Gyun;Sharif, Tanveer;Lee, Patrick W. K.
  • 通讯作者:
    Lee, Patrick W. K.
Delphinidin-3-O-glucoside and delphinidin-3-O-rutinoside mediate the redox-sensitive caspase 3-related pro-apoptotic effect of blackcurrant juice on leukaemia Jurkat cells
  • DOI:
    10.1016/j.jff.2015.06.043
  • 发表时间:
    2015-08-01
  • 期刊:
  • 影响因子:
    5.6
  • 作者:
    Leon-Gonzalez, Antonio J.;Sharif, Tanveer;Schini-Kerth, Valerie B.
  • 通讯作者:
    Schini-Kerth, Valerie B.
Red wine polyphenols cause growth inhibition and apoptosis in acute lymphoblastic leukaemia cells by inducing a redox-sensitive up-regulation of p73 and down-regulation of UHRF1
  • DOI:
    10.1016/j.ejca.2009.12.029
  • 发表时间:
    2010-03-01
  • 期刊:
  • 影响因子:
    8.4
  • 作者:
    Sharif, Tanveer;Auger, Cyril;Schini-Kerth, Valerie B.
  • 通讯作者:
    Schini-Kerth, Valerie B.
Autophagic homeostasis is required for the pluripotency of cancer stem cells
  • DOI:
    10.1080/15548627.2016.1260808
  • 发表时间:
    2017-01-01
  • 期刊:
  • 影响因子:
    13.3
  • 作者:
    Sharif, Tanveer;Martell, Emma;Gujar, Shashi A.
  • 通讯作者:
    Gujar, Shashi A.
Metabolism-based targeting of MYC via MPC-SOD2 axis-mediated oxidation promotes cellular differentiation in group 3 medulloblastoma.
  • DOI:
    10.1038/s41467-023-38049-9
  • 发表时间:
    2023-05-02
  • 期刊:
  • 影响因子:
    16.6
  • 作者:
    Martell, Emma;Kuzmychova, Helgi;Kaul, Esha;Senthil, Harshal;Chowdhury, Subir Roy;Morrison, Ludivine Coudiere;Fresnoza, Agnes;Zagozewski, Jamie;Venugopal, Chitra;Anderson, Chris M.;Singh, Sheila K.;Banerji, Versha;Werbowetski-Ogilvie, Tamra E.;Sharif, Tanveer
  • 通讯作者:
    Sharif, Tanveer

Sharif, Tanveer的其他文献

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{{ truncateString('Sharif, Tanveer', 18)}}的其他基金

Understanding the role of pyruvate metabolism-dependent signaling networks in the differentiation of neural stem cells
了解丙酮酸代谢依赖性信号网络在神经干细胞分化中的作用
  • 批准号:
    RGPIN-2021-03352
  • 财政年份:
    2021
  • 资助金额:
    $ 2.19万
  • 项目类别:
    Discovery Grants Program - Individual
Understanding the role of pyruvate metabolism-dependent signaling networks in the differentiation of neural stem cells
了解丙酮酸代谢依赖性信号网络在神经干细胞分化中的作用
  • 批准号:
    DGECR-2021-00369
  • 财政年份:
    2021
  • 资助金额:
    $ 2.19万
  • 项目类别:
    Discovery Launch Supplement

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Understanding the role of pyruvate metabolism-dependent signaling networks in the differentiation of neural stem cells
了解丙酮酸代谢依赖性信号网络在神经干细胞分化中的作用
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