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

我们的细胞需要能量才能正常工作。有两种主要的途径可以用来产生ATP形式的能量。氧化磷酸化（OXPHOS）利用氧气驱动ATP的形成。在缺氧的情况下，一种叫做糖酵解的途径可以通过乳酸发酵的过程独立地分解葡萄糖并产生ATP。虽然OXPHOS可以比糖酵解产生更多的ATP，但矛盾的是，即使在有氧气的情况下，许多高活性细胞也更倾向于使用糖酵解来产生能量。这使得细胞可以利用糖酵解途径中的代谢中间体合成细胞构件或修改蛋白质以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ATP的产生，以产生更多的代谢前体。丙酮酸位于糖酵解和氧化磷酸化的分歧点上。丙酮酸是否进入线粒体以支持OXPHOS或转化为乳酸以维持糖酵解是由三种主要酶的作用决定的：线粒体丙酮酸载体（MPC），丙酮酸脱氢酶（PDH）和乳酸脱氢酶（LDH）。尽管丙酮酸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尚不清楚。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。大脑是由神经元和支持细胞组成的复杂网络，每个细胞都有自己独特的功能。这些不同的细胞类型都来自神经干细胞（NSCs）的分化，然而，调节NSC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在培养皿中生成大脑，研究NSC分化过程中发生的代谢变化。我们还将使用斑马鱼作为小动物模型，这是研究NSC分化的理想模型，因为斑马鱼在其整个生命周期中都含有再生的NSCs群体。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的细胞类型。这个研究项目代表了一个新兴的研究领域，专注于探索代谢作为多谱系NSC分化的中心调节器的概念。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。

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.