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）系统沿着轴正交与顶端基轴轴沿某些上皮板的细胞偏振细胞，对于众多生理功能是必要的。果蝇的果蝇研究导致了控制PCP的模块化系统的概念。 PCP基因可以分为功能模块，每个模块代表遗传学和生物化学相关的单位。但是，已经提出了描述主（“全局”，“核心”和“效应子”）PCP模块之间关系的相互冲突模型，这表明了各种组织特异性效应器模块上游的串联或平行关系。值得注意的是，PCP模块之间以及PCP模块及其目标之间的连通性是有争议的。 PCP信号传导的靶标可能是在单个单元内作用以构建极化结构的离散系统，或者可能是多细胞单元，其本身构成模块，其中细胞内部和细胞之间有助于图案的信号。 PCP信号系统的组件及其相互作用的效应系统共同起作用以产生新兴模式。在特定细胞组中对单个PCP信号分子的操纵不仅会使靶细胞水平上的靶细胞极化，而且在多细胞水平上也存在极性模式，通常以特征性的方式影响附近的细胞。这些类型的实验原则上应该允许我们推断控制系统的结构，但是分子相互作用与组织层面模式之间的关系非常复杂，以致它们不违反直观的理解。数学建模一直是解决此问题的重要工具。在这里，我们建议将新颖的混合模型与分析相结合，并将其与生物学实验相结合，以更好地了解PCP信号网络架构以及单个或多个体系结构在不同情况下是否起作用。具体而言，我们建议在两个组织（翼和腹部）中首先探测全局和核心模块和网络体系结构，其中输出是头发极化，但已经提出了相互排斥的模型体系结构。接下来，我们将在第三个系统（即刷毛）中探测相应的模块和网络体系结构，其中效应器是一个更复杂的多细胞系统，在对PCP输入的响应方式上可能更加不同。我们认为，这项工作将导致对PCP的了解，这对于理解PCP贡献的许多脊椎动物发育缺陷和疾病非常重要。这项工作还将生成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。