Comparative analysis of PCP signaling architecture

PCP信令架构对比分析

• 批准号: 8607574
• 负责人: Jeffrey D. Axelrod
• 金额: $ 32.88万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-02-06 至 2016-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8607574
• 关键词: Abdomen; Accounting; Address; Affect; Apical; Architecture; Binding; Biological; Cell Polarity; Cells; Characteristics; Complex; Conflict (Psychology); Congenital Heart Defects; Defect; Development; Diagnostic; Disease; Drosophila genus; Epidermis; Epithelial; Epithelium; Eye; Genes; Goals; Hair; Hybrids; Individual; Leg; Methods; Modeling; Neoplasm Metastasis; Neural Tube Defects; Output; Pathogenesis; Pathway interactions; Pattern; Physiological; Polycystic Kidney Diseases; Pulmonary Hypertension; Relative (related person); Research Personnel; Series; Signal Transduction; Signaling Molecule; Specific qualifier value; Structure; System; Techniques; Therapeutic; Tissues; Wing; Work; cancer cell; comparative; deafness; design; fly; mathematical methods; mathematical model; migration; network architecture; novel; polarized cell; research study; tool

DESCRIPTION (provided by applicant): The Planar Cell Polarity (PCP) system polarizes cells in some epithelial sheets along an axis orthogonal to their apical-basal axis, and is necessary for numerous physiological functions. Studies in the fruit fly, Drosophila, have led to the concept of a modular system controlling PCP. The PCP genes can be grouped together into functional modules, each representing a genetically and biochemically related unit. However, conflicting models describing the relationships between the principal ("global," "core" and "effector") PCP modules have been proposed, suggesting either a series or parallel relationship upstream of the various tissue specific effector modules. Notably, the connectivity between the PCP modules, and between the PCP modules and their targets is controversial. Targets of PCP signaling may be discrete systems that act within single cells to build polarized structures, or may be multicellular units that themselves constitute modules in which signals within and between cells contribute to patterning. The components of the PCP signaling system, and the effector systems with which they interact, function together to produce emergent patterns. Manipulation of individual PCP signaling molecules in specified groups of cells not only perturbs the polarization of the targeted cells at a subcellular level, but also perturbs patterns of polarity at the multicellular level, often affecting nearby cells in characteristic ways. These kinds of experiments should, in principle, allow us to infer the architecture of the governing control systems, but the relationships between molecular interactions and tissue-level pattern are sufficiently complex that they defy intuitive understanding. Mathematical modeling has been an important tool to address this problem. Here, we propose to combine novel, hybrid models, amenable to analysis, with biological experimentation to better understand the PCP signaling network architecture and whether a single or multiple architectures function in different contexts. Specifically, we propose to first probe the global and core modules and network architecture in two tissues, wing and abdomen, in which the output is hair polarization, but in which mutually exclusive model architectures have been proposed. Next, we will probe the corresponding modules and network architecture in a third system, the bristles, in which the effector is a more complex multicellular system that may be more divergent in how it responds to PCP input. We believe that this work will result in an enhanced understanding of PCP, which will be important in understanding the many vertebrate developmental defects and diseases to which PCP contributes. The work will also produce broadly applicable mathematical tools as well as mathematical model components that can be integrated with existing developmental models.

描述（由申请人提供）：平面细胞极性（PCP）系统使一些上皮片中的细胞沿着与其顶底轴正交的轴极化，并且对于许多生理功能是必需的。对果蝇的研究提出了控制 PCP 的模块化系统的概念。 PCP 基因可以分为功能模块，每个模块代表一个遗传和生化相关的单元。然而，已经提出了描述主要（“全局”、“核心”和“效应器”）PCP模块之间关系的相互矛盾的模型，表明各种组织特异性效应器模块上游存在串联或并行关系。值得注意的是，PCP 模块之间以及 PCP 模块与其目标之间的连接性存在争议。 PCP信号传导的目标可以是在单细胞内作用以构建极化结构的离散系统，也可以是本身构成模块的多细胞单元，其中细胞内和细胞间的信号有助于模式化。 PCP 信号系统的组件以及与其相互作用的效应器系统共同发挥作用，产生紧急模式。操纵特定细胞群中的单个 PCP 信号分子不仅会在亚细胞水平上扰乱目标细胞的极化，还会扰乱多细胞水平上的极性模式，通常会以特有的方式影响附近的细胞。原则上，这类实验应该让我们能够推断出控制系统的架构，但是分子相互作用和组织水平模式之间的关系非常复杂，以至于无法直观理解。数学建模已成为解决这一问题的重要工具。在这里，我们建议将易于分析的新颖混合模型与生物实验相结合，以更好地理解 PCP 信号网络架构以及单个或多个架构是否在不同环境中发挥作用。具体来说，我们建议首先探测机翼和腹部这两个组织中的全局和核心模块以及网络架构，其中输出是毛发极化，但其中提出了相互排斥的模型架构。接下来，我们将探讨第三个系统（鬃毛）中的相应模块和网络架构，其中效应器是一个更复杂的多细胞系统，其对 PCP 输入的响应方式可能更加不同。我们相信这项工作将加深对五氯苯酚的了解，这对于了解五氯苯酚造成的许多脊椎动物发育缺陷和疾病非常重要。这项工作还将产生广泛适用的数学工具以及可以与现有发展模型集成的数学模型组件。