Decode Mitochondrial Morphology Dynamics to Predict Cell Fate Decisions

项目总结/摘要 摘要 线粒体不仅提供了阅读这些线条所需的90%的能量，而且它们还 负责肠道细胞的正确分化。最近认识到线粒体 在干细胞命运决定中发挥积极作用，使它们从被动的发电厂变成了主动的发电中心。 细胞信号我们无法自动追踪线粒体并将其与细胞的命运联系起来， 这一细胞器在干细胞命运决定和肠道疾病（如克罗恩病）中的相关性日益增加， 疾病和结直肠癌。线粒体对于体积成像来说总是太小和太快， 跟踪.我们的初步数据表明，最近开发的晶格光片显微镜和 我们内部开发的计算图像处理管道可以成功地进行四维跟踪 整个细胞线粒体网络。在这里，我们建议1）将我们的原型扩展为一个通用工具， 可以跟踪多种细胞类型和网络形态中的线粒体，以2）阐明 线粒体网络形态和细胞命运，以及3）创建一个预测模型，将线粒体网络形态和细胞命运联系起来。 线粒体网络形态与其潜在的信号驱动因素和导致的命运决定有关， 不同的形态。我们建议使用肠上皮类器官和肠上皮细胞的分化， 将干细胞转化为潘氏细胞作为一个模型系统，用于一个靶向的命运决定。这项建议会 打开了一扇线粒体生物学的新窗口，这将转化为大量与线粒体相关的 癌症等疾病和癫痫、帕金森病和阿尔茨海默病等神经系统疾病 疾病

Project Summary/Abstract ABSTRACT Mitochondria not only provide 90% of the energy required for reading these very lines but they are also responsible for the correct differentiation of the cells lining your gut. The recent recognition that mitochondria play an active role in stem cell fate decisions has moved them from passive power plants to active centers of cell signaling. Our inability to automatically track mitochondria and link them to the fate of a cell is in stark contrast to the increasing relevance of this organelle in stem cell fate decisions and intestinal diseases such as Crohn’s disease and colorectal cancer. Mitochondria have always been too small and too fast for volumetric imaging and tracking. Our preliminary data show that a combination of recently developed lattice light-sheet microscopy and our in-house developed computational image processing pipeline can succeed in the four-dimensional tracking of the entire cellular mitochondrial network. Here we propose to 1) expand our prototype into a general tool that can track mitochondria in multiple cell types and network morphologies, to 2) elucidate the coupling between mitochondrial network morphology and cellular fate, and to 3) create a predictive model that links the mitochondrial network morphology to its underlying signaling drivers and to the fate decisions that are caused by different morphologies. We propose to use intestinal epithelial organoids and the differentiation of intestinal stem cells to paneth cells as a model system for a mitochondria-directed fate determination. This proposal will open a new window into mitochondrial biology that will translate to a large number of mitochondria-related diseases such as cancer and neurological disorders such as epilepsy, Parkinson’s disease, and Alzheimer’s disease.