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Cellular mechanisms of bioenergetic plasticity

生物能可塑性的细胞机制

基本信息

批准号：
10667640
负责人：
Ghazaleh Ashrafi
金额：
$ 37.77万
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-08-01 至 2027-06-30
项目状态：
未结题

项目摘要

Cellular mechanisms of bioenergetic plasticity The long-term goal of our research program is to understand how cells fine-tune their metabolic programs to meet their ever-changing energetic needs. Many cell types in the body, from muscle fibers to neurons, have evolved unique metabolic programs that are essential for survival and proper function. Even within a single cell, specific processes are energetically coupled to mitochondria or the glycolytic machinery for specialized metabolic support. However, the underlying molecular basis of metabolic plasticity and its relationship to cellular function are poorly understood. Understanding the mechanisms of metabolic regulation is highly relevant to many disease states, including diabetes, myopathies, and Leigh syndrome, where metabolic dysfunction is heavily implicated. In eukaryotic cells, energy, in the form of ATP molecules is primarily produced by glycolysis and mitochondrial oxidative phosphorylation. My laboratory combines optical imaging of biosensors in live cells with genomics and transcriptomic analysis to investigate metabolic regulation in cellular compartments. With these tools, we have been able to discover novel pathways for stimulation of mitochondrial and glycolytic ATP production in active neurons during electrical activity. We now seek to understand how energy metabolism is locally regulated in subcellular compartments, and uncover metabolic specialization of functionally distinct neuronal types. To carry out this work, we plan to utilize our strength in cellular imaging of metabolic function along with new technological advances to: (1) determine how subcellular organization of the glycolytic machinery regulates synaptic vesicle endocytosis, and (2) elucidate molecular mechanisms of metabolic specialization using the available transcriptional profiles of neuronal subtypes. Our study will shed light on both local and global mechanisms of metabolic plasticity at the subcellular level and across cell types. As such, our findings will be broadly relevant to the scientific community studying cellular metabolism and its implications in disease states.

生物能量可塑性的细胞机制我们研究计划的长期目标是了解细胞如何微调其代谢程序，满足他们不断变化的能量需求。身体中的许多细胞类型，从肌肉纤维到神经元，进化出独特的代谢程序，对生存和正常功能至关重要。即使在单个细胞内，特定的过程在能量上与线粒体或糖酵解机制偶联，支持.然而，代谢可塑性的潜在分子基础及其与细胞的关系功能知之甚少。了解代谢调节的机制，许多疾病状态，包括糖尿病、肌病和Leigh综合征，其中代谢功能障碍是严重牵连。在真核细胞中，能量以ATP分子的形式主要通过糖酵解产生和线粒体氧化磷酸化。我的实验室将活细胞中生物传感器的光学成像利用基因组学和转录组学分析来研究细胞区室中的代谢调节。与这些工具，我们已经能够发现新的途径刺激线粒体和糖酵解ATP 在电活动期间活跃的神经元中产生。我们现在试图了解能量代谢在亚细胞区室中进行局部调节，并揭示了功能上的代谢特化。不同的神经元类型。为了开展这项工作，我们计划利用我们在代谢细胞成像方面的优势，沿着新技术的进步发挥作用：（1）确定糖酵解的亚细胞组织如何机械调节突触囊泡内吞作用，（2）阐明代谢的分子机制，使用神经元亚型的可用转录谱进行特化。我们的研究将揭示这两个在亚细胞水平和跨细胞类型的代谢可塑性的局部和全局机制。所以我们的这些发现将广泛地与科学界研究细胞代谢及其对人类健康的影响有关。疾病状态。