Molecular Genetics of Hemicentin

描述(申请人提供)：半乳菌素是一种新型的细胞外基质 (ECM)蛋白质，最先由PI和同事在线虫中发现。 半乳菌素有一个简单的模块化结构：48个串联免疫球蛋白重复 侧翼有独特的末端，在两个人类半乳糖蛋白中高度保守 同源异物。ECM蛋白提供了调节和结构信息， 通过影响细胞将正在生长的细胞组织成复杂的三维组织 增殖、分化、黏附和迁移。然而，我们的 了解信息从互联网上传输的机制 ECM和细胞解释是不完整的。 基于突变表型和蛋白质定位研究，PI建议 半边菌素的功能是将细胞接触的广泛区域提炼成 不同的线状细胞连接，这一功能依赖于 将半乳糖凝集成细小的轨道。半影菌素的合成， 由肌肉细胞分泌，但半胱氨酸的轨迹在远处聚集。这 暗示这些站点有一种机制来招募半边菌素并支持其 可能涉及细胞表面受体和/或其他ECM分子的组装。 为了确定半菌素对组织组织的影响机制， 建议的研究将利用强大的分子和转基因 利用线虫可能的技术来： (1)将半球蛋白分解为介导靶向靶点的功能结构域 组装，在这些地点组装成轨道，以及组织单元的能力 连接，(2)识别特定的细胞表面受体和/或细胞外基质分子 招募半边菌素并支持其组装的次要部位和(3) 半乳菌素蛋白的生化和免疫学特征 组装好的半球蛋白轨迹。 长期目标是确定ECM蛋白如何将信息传递给 单元格，单元格如何解释此信息以指定体系结构 复杂的三维组织以及ECM蛋白中的遗传缺陷如何影响 这一过程。

DESCRIPTION (provided by applicant): Hemicentin is a novel extracellular matrix (ECM) protein first identified in C. elegans by the PI and co-workers. Hemicentin has a simple modular structure: 48 tandem immunoglobulin repeats flanked by unique ends that are highly conserved in two human hemicentin orthologs. ECM proteins provide regulatory and structural information that organizes growing cells into complex 3-dimensional tissues by influencing cell proliferation, differentiation, adhesion and migration. However, our understanding of the mechanisms by which information is transmitted from the ECM and interpreted by cells is not complete. Based on the mutant phenotype and protein localization studies, the PI proposes that the function of hemicentin is to refine broad regions of cell contact into distinct, line-shaped cell junctions and that this function is dependent upon the assembly of hemicentin into fine tracks. Hemicentin is synthesized and secreted by muscle cells but hemicentin tracks assemble at distant sites. This implies that these sites have a mechanism to recruit hemicentin and support its assembly that may involve a cell surface receptor and/or other ECM molecules. To determine the mechanism of hemicentin's influence on tissue organization, the proposed studies will utilize the powerful molecular and transgenic techniques possible with C. elegans to: (1) dissect hemicentin into functional domains that mediate targeting to sites of assembly, assembly into tracks at these sites, and ability to organize cell junctions, (2) identify specific cell surface receptors and/or ECM molecules at secondary sites that recruit hemicentin and support its assembly and (3) biochemically and immunologically characterize the hemicentin protein and assembled hemicentin tracks. The long-term goal is to determine how ECM proteins transmit information to cells, how this information is interpreted by cells to specify the architecture of complex 3-dimensional tissues and how genetic defects in ECM proteins affect this process.