MULTIPLICITY OF COL11A1 FUNCTION DURING DEVELOPMENT; STRUCTURE AND SIGNALING

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 细胞外基质分子在脊椎动物的眼睛和骨骼等复杂结构的发育中起着决定性的作用。编码细胞外基质蛋白的基因突变证明了单个分子成分在斯蒂克勒综合征和马歇尔综合征中的重要性，在这种综合征中，COL11A1的突变通过与常规信号通路的相互作用来控制细胞分化。或者，COL11A1本身也可以作为信号分子。BMP、Wnt和PTHrP信号通路的突变导致的表型与COL11A1的突变有相似之处。为解决这一假设而提出的实验方法将结合三个层次的分析--用于分析脊椎动物发育的斑马鱼模型系统，使用细胞培养在细胞水平上分析信号通路，以及使用生化和生物物理技术进行分子结构和相互作用研究，以研究发育和分化过程中复杂事件的分子机制。这些研究的结果将使我们更深入地了解细胞-基质相互作用的分子和细胞机制，以及这种相互作用如何影响信号事件。此外，我们预计将增加对单个分子如何在脊椎动物有机体内的各种环境中用于多种目的的理解，以及在器官发生过程中常见的多种独特结果的基本分子事件。随着理解的增加，我们预计设计新的诊断方法和治疗策略的能力将得到提高，以应对影响眼睛和骨骼发育的突变带来的挑战。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Extracellular matrix molecules play determining roles in development of complex structures such as the vertebrate eye and skeleton. Mutations in genes that encode proteins of the extracellular matrix demonstrate the importance of individual molecular constituents in the case of Stickler and Marshall syndromes in which a mutation in the Col11a1 acts to control cellular differentiation by interaction with regulartory signaling pathways. Alternatively, Col11a1 could act as a signaling molecule itself. Similarities exist between the phenotypes resulting from mutations in the BMP, Wnt, and PTHrP signaling pathways and mutations in Col11a1. The experimental approach proposed to address this hypothesis will combine three levels of analysis--a zebrafish model system for the analysis of vertebrate development, analysis of signaling pathways at the cellular level using cell culture, and molecular structure and interaction studies using biochemical and biophysical techniques to investigate molecular mechanisms of complex events during development and differentiation. The results of these studies will provide a more thorough understanding of the molecular and cellular mechanism of cell-matrix interactions and how such interactions influence signaling events. Moreover, we anticipate an increased understanding of how single molecules may be used for multiple purposes in a variety of contexts within a vertebrate organism, as well as the fundamental molecular events that are common to multiple unique outcomes during organogenesis. With an increase in understanding, we anticipate an improved ability to design new diagnostic approaches and therapeutic strategies to address the challenges introduced by mutations that affect eye and skeletal development.