Decode Mitochondrial Morphology Dynamics to Predict Cell Fate Decisions

解码线粒体形态动力学以预测细胞命运决策

基本信息

批准号：
10473200
负责人：
Johannes Schoeneberg
金额：
$ 142.2万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
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：
2022-09-08 至 2025-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10473200
关键词：
Affect Alzheimer&apos s Disease Biological Models Biology Cell Differentiation process Cells Colorectal Cancer Coupling Crohn&apos s disease Data Digestive System Disorders Disease Epilepsy Four-dimensional Image Inflammatory Bowel Diseases Intestinal Diseases Intestines Lead Light Link Malignant Neoplasms Microscopy Mitochondria Morphology Organelles Organoids Paneth Cells Parkinson Disease Play Power Plants Process Reading Role Signal Transduction Translating cell type image processing intestinal epithelium nervous system disorder novel therapeutics predictive modeling prototype public health relevance stem cell fate stem cells tool

Affect Alzheimer&apos s Disease Biological Models Biology Cell Differentiation process Cells Colorectal Cancer Coupling Crohn&apos s disease Data Digestive System Disorders Disease Epilepsy Four-dimensional Image Inflammatory Bowel Diseases Intestinal Diseases Intestines Lead Light Link Malignant Neoplasms Microscopy Mitochondria Morphology Organelles Organoids Paneth Cells Parkinson Disease Play Power Plants Process Reading Role Signal Transduction Translating cell type image processing intestinal epithelium nervous system disorder novel therapeutics predictive modeling prototype public health relevance stem cell fate stem cells tool

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项目摘要

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.

项目摘要/摘要抽象的线粒体不仅提供了阅读这些行所需的90％的能量，而且还提供负责对肠道内衬的细胞的正确分化。最近认识到线粒体在干细胞命运决策中发挥积极作用，使它们从被动发电厂转移到了活跃的中心细胞信号传导。我们无法自动跟踪线粒体并将其链接到细胞的命运是鲜明的对比度在干细胞命运的决策和肠道疾病（例如克罗恩）中，该细胞器中的相关性越来越多疾病和结直肠癌。线粒体一直太小，太快了，无法进行体积成像和追踪。我们的初步数据表明，最近开发的晶格灯页显微镜和我们内部开发的计算图像处理管道可以在四维跟踪中取得成功整个细胞线粒体网络的。在这里，我们建议1）将原型扩展到一个通用工具中可以跟踪多种细胞类型和网络形态的线粒体，至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，将线粒体网络形态学到其基本信号驱动因素和引起的脂肪决策通过不同的形态。我们建议使用肠上皮器官和肠道分化干细胞将细胞作为线粒体指导命运确定的模型系统。该提议将打开一个新的窗口，进入线粒体生物学，该窗口将转化为大量与线粒体有关癌症和神经系统疾病等疾病，例如癫痫，帕金森氏病和阿尔茨海默氏病疾病。