Discovery of Bone Formation Genes through Integrative Genomics

描述（由申请方提供）：本提案的目的是确定Bicaudal-C同系物1（Bicc 1）在骨中的作用。在小鼠中使用创新的系统遗传学方法，我们预测Bicc 1是BMD数量性状位点（QTL）的基础。Bicc 1是一种RNA结合蛋白，参与初级纤毛的调节。在这个建议中，我们证明了jcpk小鼠，这是一个Bicc 1无效等位基因杂合，骨质减少和人类BICC 1基因的遗传变异与BMD。此外，Bicc 1在分化成骨细胞中高度表达，并且Bicc 1在原代颅骨成骨细胞中的敲低损害分化。我们还表明，Bicc 1调节Pkd 2，这被认为是成骨细胞上的初级纤毛的关键组成部分。基于这些数据，我们假设Bicc 1通过成骨细胞和Pkd 2依赖性机制影响BMD。在特定目标1中，将使用一系列体外和体内相互作用实验来确定Bicc 1对成骨细胞分化和BMD的作用是否通过调节Pkd 2水平。在特定目标2中，我们将确定Bicc 1是否以成骨细胞特异性方式调节BMD。这将通过使用cre-loxP技术消融成骨细胞中的Bicc 1并使用microCT和组织形态计量学表征骨量来实现。转录网络分析也将用于进一步表征Bicc 1功能。这些研究将大大促进我们对一种新的BMD基因的理解。

DESCRIPTION (provided by applicant): The aim of this proposal is to define the role of Bicaudal-C homolog 1 (Bicc1) in bone. Using an innovative systems genetics approach in the mouse we predicted that Bicc1 was the basis of a BMD quantitative trait locus (QTL). Bicc1 is an RNA-binding protein that has been implicated in the regulation of primary cilia. In this proposal, we demonstrate that jcpk mice, which are heterozygous for a Bicc1 null allele, are osteopenic and that genetic variants in human BICC1 gene are associated with BMD. Moreover, Bicc1 is highly expressed in differentiating osteoblasts and Bicc1 knockdown in primary calvarial osteoblasts impairs differentiation. We also show that Bicc1 regulates Pkd2, which is thought to be a critical component of the primary cilia on osteoblasts. Based on these data we hypothesize that Bicc1 influences BMD through an osteoblast and Pkd2 dependent mechanism. In Specific Aim 1 a series of in vitro and in vivo interaction experiments will be used to determine if the actions of Bicc1 on osteoblast differentiation and BMD are via the regulation of Pkd2 levels. In Specific Aim 2 we will determine if Bicc1 regulates BMD in an osteoblast-specific manner. This will be accomplished by ablating Bicc1 in osteoblasts using the cre-loxP technology and characterizing bone mass using microCT and histomorphometry. Transcriptional network analysis will also be used to further characterize Bicc1 function. The proposed studies will significantly advance our understanding of a novel BMD gene.