MULTIPLICITY OF COL11A1 FUNCTION DURING DEVELOPMENT; STRUCTURE AND SIGNALING

这个子项目是许多利用资源的研究子项目之一 由NIH/NCRR资助的中心拨款提供。子项目的主要支持 而子项目的主要调查员可能是由其他来源提供的， 包括其它NIH来源。 列出的子项目总成本可能 代表子项目使用的中心基础设施的估计数量， 而不是由NCRR赠款提供给子项目或子项目工作人员的直接资金。 细胞外基质分子在脊椎动物眼睛和骨骼等复杂结构的发育中起决定性作用。编码细胞外基质蛋白的基因突变证明了个体分子组分在Stickler和马歇尔综合征中的重要性，其中Col 11 a1的突变通过与常规信号传导途径的相互作用来控制细胞分化。 或者，Col 11 a1本身可以作为信号分子。 BMP、Wnt和PTHrP信号通路突变与Col 11 a1突变导致的表型之间存在相似性。提出解决这一假设的实验方法将结合联合收割机三个层次的分析-斑马鱼模型系统的分析脊椎动物的发展，在细胞水平上使用细胞培养的信号通路的分析，和分子结构和相互作用的研究，利用生物化学和生物物理技术，以调查在发展和分化过程中的复杂事件的分子机制。 这些研究的结果将提供一个更透彻的了解细胞-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，我们预计将增加了解单个分子如何在脊椎动物生物体内的各种情况下用于多种目的，以及器官发生过程中多种独特结果所共有的基本分子事件。 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所带来的挑战。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. 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.