ORPHAN RECEPTORS IN ORGANOGENESIS

哺乳动物基因组编码大约50个核激素受体超家族成员，分为大致相等数量的常规受体和孤儿受体。类固醇、甲状腺激素和其他配体的常规受体的许多良好表征的功能与维持成人体内平衡有关，但是关于孤儿的新信息揭示了意想不到的和重要的发育功能。我们假设孤儿在发育信号通路中具有核心作用，并且本申请的广泛目标是表征几个孤儿在器官发生和其他发育过程的各个阶段中的功能。有4个单独的项目，每个项目都基于特定孤儿失去表达能力的影响。Orla Conneely将指导一个关于Nor-1在内耳发育以及骨骼和关节发育中的作用的项目。Austin Cooney将研究GCNF在模式形成和中胚层分化中的功能，特别是在早期发育中。Sophia Tsai将指导一个关于COUP-TFII在前列腺发育中的作用的项目，而首席研究员大卫摩尔将指导一个关于SHP的发育作用的项目，特别关注其在糖尿病中的潜在参与。这些项目都依赖于了解孤儿受体及其靶点在野生型和基因敲除或转基因小鼠中的表达模式。因此，他们将在很大程度上依赖于由Ming-Jer Tsai指导的成像和组织学核心，以及由Francesco DeMayo指导的动物核心，该核心将产生敲除和转基因动物。我们相信，在这个计划项目中加入这些努力，将有力地促进朝着建立这些孤儿和控制多器官系统形态发生的保守信号通路之间的关系的总体主题目标取得进展。

Mammalian genomes encode approximately 50 members of the nuclear hormone receptor superfamily, divided into roughly equal numbers of conventional receptors and orphan receptors. Many of the well characterized functions of the conventional receptors for steroids, thyroid hormone and other ligands are associated with maintenance of homeostasis in adults, but emerging information on the orphans have revealed unexpected and important developmental functions. We hypothesize that orphans have central roles in developmental signaling pathways, and the broad goal of this application is to characterize the functions of several orphans in various stages of organogenesis and other developmental processes. There are 4 individual projects, each based on the effects of loss of expression of a particular orphan. Orla Conneely will direct a project on the role of Nor-1 in development of the inner ear and also in bone and joint development. Austin Cooney will study the function of GCNF in pattern formation and mesoderm differentiation, particularly in early development. Sophia Tsai will direct a project on the role of COUP-TFII in prostate development And David Moore, the principal investigator, will direct a project on the developmental role of SHP, with a particular focus on its potential involvement in diabetes. These projects all depend on understanding the patterns of expression of the orphan receptors and their targets in both wild type and knockout or transgenic mice. Thus, they will rely heavily on both an Imaging and Histology core directed by Ming-Jer Tsai, and on an Animal core directed by Francesco DeMayo that will produce both knockout and transgenic animals. We believe that joining these efforts in this Program Project will strongly stimulate progress toward the overall thematic goal of establishing the relationship between these orphans and the conserved signaling pathways that control morphogenesis of multiple organ systems.