权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Discovery of Bone Formation Genes through Integrative Genomics

通过整合基因组学发现骨形成基因

基本信息

批准号：
8848036
负责人：
Charles R Farber
金额：
$ 34.74万
依托单位：
UNIVERSITY OF VIRGINIA
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-07-11 至 2017-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8848036
关键词：
Affect Alleles Biological Bone Density Bone Development Calcium Channel Calvaria Candidate Disease Gene Cells Chemicals Cilia Complex Data Fracture Gene Expression Profile Genes Genetic Genomics Heterozygote Homologous Gene Human Immunoprecipitation In Vitro Mechanics Mediating Messenger RNA Mus Osteoblasts Osteocalcin Osteocytes Osteogenesis Pathway Analysis Phenotype Play Post-Transcriptional Regulation Proprotein Convertase 1 Protein Binding Proteins Quantitative Trait Loci RNA-Binding Proteins Regulation Risk Role Series Signal Pathway Signal Transduction Surface System Technology Testing Tissues Transcript Transgenic Organisms base bone bone cell bone mass crosslink gene discovery genetic approach genetic variant in vivo innovation microCT novel osteoblast differentiation polycystic kidney disease 1 protein receptor research study

项目摘要

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.

描述(由申请人提供)：本提案的目的是确定Bicaudal-C同源基因1(Bicc1)在骨骼中的作用。利用创新的系统遗传学方法，我们在小鼠身上预测Bicc1是BMD数量性状基因座(QTL)的基础。Bicc1是一种与RNA结合的蛋白，参与了初级纤毛的调节。在这个建议中，我们证明了具有Bicc1零等位基因杂合子的jcpk小鼠是骨量减少的，并且人类BICC1基因的遗传变异与BMD有关。此外，Bicc1在分化中的成骨细胞中高表达，而Bicc1基因在原代颅骨成骨细胞中的表达下调会影响其分化。我们还发现Bicc1调节PKD2，PKD2被认为是成骨细胞初级纤毛的关键成分。基于这些数据，我们假设Bicc1通过成骨细胞和PKD2依赖的机制影响骨密度。具体目的1通过一系列的体内外相互作用实验来确定Bicc1对成骨细胞分化和骨密度的作用是否通过调节PKD2水平来实现。在特定的目标2中，我们将确定Bicc1是否以成骨细胞特异性的方式调节BMD。这将通过使用cre-loxP技术去除成骨细胞中的Bicc1，并使用MicroCT和组织形态计量学来表征骨量来实现。转录网络分析也将被用来进一步表征Bicc1的功能。建议的研究将极大地促进我们对一种新的BMD基因的理解。

项目成果

期刊论文数量（6）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Systems genetics: a novel approach to dissect the genetic basis of osteoporosis.

DOI：
10.1007/s11914-012-0112-5
发表时间：
2012-09
期刊：
CURRENT OSTEOPOROSIS REPORTS
影响因子：
4.3
作者：
Farber, Charles R.
通讯作者：
Farber, Charles R.

Systems-level analysis of genome-wide association data.

DOI：
10.1534/g3.112.004788
发表时间：
2013-01
期刊：
G3 (Bethesda, Md.)
影响因子：
0
作者：
Farber CR
通讯作者：
Farber CR

RhoA determines lineage fate of mesenchymal stem cells by modulating CTGF-VEGF complex in extracellular matrix.

DOI：
10.1038/ncomms11455
发表时间：
2016-04-29
期刊：
Nature communications
影响因子：
16.6
作者：
Li C;Zhen G;Chai Y;Xie L;Crane JL;Farber E;Farber CR;Luo X;Gao P;Cao X;Wan M
通讯作者：
Wan M

Contemporary Approaches for Identifying Rare Bone Disease Causing Genes.