A Long Path to Power: combining bioengineering, stem cells and cell biology to uncover the mysteries of axonal biology

对于博士项目，我们将基于我们最近发表的先前结果以及在旋转过程中对内质网线粒体结构进行的成像优化，重点关注以下问题：轴突长度如何影响神经元的整体代谢和功能？- ER组织如何随轴突长度变化？随着轴突的延长，er -线粒体组织是如何进化的？-神经元细胞类型如何影响长度依赖性内质网和线粒体的变化？我们最近的工作发现，在人类神经细胞中，依赖于强度的调节机制调节神经元线粒体和翻译谱来维持轴突的生长。这是一项基本的新发现，通过将干细胞建模、实时成像和芯片建模与生物工程设备相结合，使之成为可能。我们现在感兴趣的是探索导致这些长度依赖性适应的分子途径，但我们缺少一个关键的参与者：内质网。事实上，内质网是所有细胞器中最大的（特别是当它跨越整个轴突时），它负责轴突稳态中的几个关键功能，并通过内质网-线粒体接触点调节线粒体动力学。我们也知道内质网动力学沿轴突变化，不同的细胞类型有不同的机制来控制内质网-线粒体相互作用。通过这个项目，我们将详细探索这些动态，并揭示特定亚型神经元和不同轴突长度如何影响内质网。Serio博士将担任主要主管，并提供神经细胞生物学，生物工程和成像方面的专业知识；他将提供干细胞分化和线粒体生物学方面的专业知识。

For the PhD project we will build upon previous results from our recent publications aswell as from the optimisation of the imaging for ER mitochondria structures performedduring the rotation to focus on the following questions: - How does axonal length affectthe overall metabolism and function of the neurons? - How does ER organisationchange with axonal length? - How does ER-mitochondria organisation evolve as theaxons elongate? - How does the neuronal cell type affect the length dependent ER andmitochondria changes? Our recent work lead to the discovery that in human neuronslength-dependent regulatory mechanisms adapt neuronal mitochondrial andtranslational profiles to sustain the growing axons. This is a fundamental newdiscovery made possible by the combination of stem cell modelling, live imaging andon chip modelling with bioengineered devices. We are now interested in exploring themolecular pathways that lead to these length-dependent adaptations, but we aremissing a key player: the ER. In fact, the ER is the largest of all organelles (particularlyas it span the whole axon), it is responsible for several key function in axonalhomeostasis, and regulates mitochondrial dynamics via ER-mitochondrial contactpoints. We also know that ER dynamics vary along the axons and that different celltypes have different mechanism to control ER-mitochondrial interactions. With thisproject we will explore in details these dynamics, and uncover how specific subtypes ofneurons and different axonal length affect the ER. Dr. Serio will be primary supervisorand provide expertise in neuronal cell biology, bioengineering and imaging; Dr. Devinewill provide expertise in stem cell differentiation and mitochondrial biology.