Image-derived Spatiotemporal Models of Cellular Organization and Perturbation

 描述（由申请人提供）：本研究旨在开发和测试方法，这些方法将能够对以下组织的亚细胞组织进行自动化、信息丰富的研究： 蛋白 和其他生物分子。 我们建议开发的计算基础破译的时空形态学途径不同的亚细胞结构在重要的亚细胞过程自动从显微镜图像。 我们将利用我们在上一个项目期间的进展，在该项目期间，我们建立了细胞组织系统，用于构建细胞组织的图像衍生模型，为池和网状结构建立新的建模能力，用于捕获不同细胞成分之间的关系，并了解细胞组织的各个方面在细胞周期等过程中如何变化。 鉴于内质网在许多细胞过程中的重要性（以及包括血液学疾病、颅-颅-缝-缝发育不良、乳糜微粒潴留病等在内的疾病），我们期望我们提出的建模方法提供重要的机制线索，这些结构的“正常”（非病理学）形态学途径以及它们在疾病中可能如何受到干扰。 为了提供有价值的图像来推动建模能力的发展，并同时识别用于治疗ER缺陷疾病的候选先导化合物，我们将对表达atlastin的正常和突变等位基因的细胞进行广泛的化合物筛选研究（这在ER结构中起着关键作用）。 我们开发的计算方法将集成到我们的开源CellOrganizer系统（http：//www.example.com）中。CellOrganizer.org 除了上面提到的应用之外，我们预计我们开发的计算框架将对广泛的成像分析有价值，包括药物筛选，RNAi筛选，细胞学和病理学。

 DESCRIPTION (provided by applicant): This research is aimed at developing and testing methods that will enable automated, information--‐rich studies of the subcellular organization of proteins and other biomolecules. We propose to develop the computational foundation for deciphering the spatiotemporal morphological pathways of different subcellular structures during important subcellular processes automatically from microscopy images. We will leverage our progress in the previous project period, in which we established the Cell Organizer system for building image-‐derived models of cell organization, to build new modeling capabilities for cisternal and reticular structures, for capturing the relationships between different cellular components, and for learning how aspects of cell organization change during processes such as the cell cycle. Given the importance of the endoplasmic reticulum in numerous cellular processes (as well as diseases including hematological disorders, cranio--‐ lenticulo--‐sutural dysplasia, chylomicro retention disease, etc.), we expect the modeling approaches we propose to provide important mechanistic clues as to the "normal" (non-- athological) morphological pathways of these structures and how they may be perturbed in disease. To provide valuable images to drive the development of modeling capabilities, and to simultaneously identify candidate lead compounds for treatment of diseases with ER defects, we will conduct extensive compound screening studies on cells expressing normal and mutant alleles of atlastin (which plays a critical role in ER structure). The computational methods we develop will be integrated into our open source CellOrganizer system (http://CellOrganizer.org). In addition to the applications mentioned above, we anticipate the computational frameworks we develop will be valuable for a wide range of imaging assays including drug screens, RNAi screens, cytology, and pathology.