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

Identification of Gender Specific BMD Candidate Gene in Chromosome 1

1 号染色体中性别特异性 BMD 候选基因的鉴定

基本信息

批准号：
8136857
负责人：
Bouchra Edderkaoui
金额：
$ 7.39万
依托单位：
LOMA LINDA VETERANS ASSN RESEARCH & EDUC
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：
2011-08-01 至 2013-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8136857
关键词：
Adult Age Alleles Animal Model Animals Attention Bone Density Bone Development C57BL/6 Mouse Candidate Disease Gene Chromosomes Chromosomes, Human, Pair 1 Computers Congenic Mice Congenic Strain Data Diagnosis Disease Distal Drug Delivery Systems Estrogen Receptors Evaluation Exercise Exhibits Expressed Sequence Tags Female Femur Fracture Future Gender Gene Expression Genes Genetic Goals Growth Health Heritability Human Inbred Strains Mice Individual Knockout Mice Lead Location Measurement Mechanics Mus Names Osteogenesis Osteoporosis Pathway interactions Patients Peripheral Phenotype Prevalence Process Property Puberty Public Health Quantitative Trait Loci Recombinant Inbred Strain Regulation Risk Sex Characteristics Single Nucleotide Polymorphism Site Skeletal Development Specificity Structure Testing Time Training Transgenic Organisms Variant Woman base bone bone strength cell type congenic genetic analysis improved male men mouse model novel osteoporosis with pathological fracture prepuberty response sex sexual dimorphism skeletal tomography trait

项目摘要

DESCRIPTION (provided by applicant): Osteoporosis is a disease characterized by low bone mineral density (BMD), the strongest predictor of fracture risk. Statistical genetic analyses in humans and animal models have clearly shown that multiple genes contribute to variation in bone traits and that BMD inheritance is gender and site-specific. Accordingly, gender specific BMD quantitative trait loci (QTL) have been identified in several chromosomes both in humans and animal models. However, no gender specific BMD QTL gene has been identified so far. Based on our recent findings that femurs from C57BL/6J (B6)-Castaneous (CAST) congenic mice carrying CAST alleles at D1mit115-D1mit152 (178-185 Mb, named BMD1-4 QTL) exhibit significantly greater peak BMD in the female but not male mice compared to corresponding sex-matched B6 mice, we have proposed the hypothesis that this region of chromosome 1 in CAST mice contains a gene that exerts gender-specific effect on BMD. By using additional subcongenic lines of B6.CAST-1 mice, we have narrowed down the size of the female specific BMD1-4 locus to 2.6 MB, a region small enough to proceed with the gene identification process. Our goal in this application is to investigate the mechanism by which the gene underlying BMD1-4 QTL regulates peak BMD in female mice and to screen the BMD1-4 locus to identify the candidate gene that imparts gender specificity. Towards this goal, we have proposed the following three specific aims. In specific aim 1, we will evaluate the skeletal phenotype of subcongenic lines of mice carrying BMD1-4 QTL gene and corresponding control mice at week 3 (prepubertal), 5 (pubertal), 8 (post pubertal) and 16 (adult). We will determine whether bone resortpion or formation is the main mechanism that contributes to the higher BMD in the female congenic mice with the anticipation that this information will assist in the selection of candidate genes for evaluation. In specific aim 2, we will evaluate the expression levels of the candidate genes underlying BMD1-4 locus in the bones of both male and female congenic and control B6 mice at a time when the phenotype starts to manifest. We will consider the gene/s that shows differential expression between male and female or between congenic and B6 mice as potential candidates. In specific aim 3, we will investigate the response of BMD1-4 gene to mechanical loading and determine if the response is gender-dependent. The successful identification of BMD1- 4 QTL gene that imparts gender specificity would lead to improved understanding of how skeletal growth is regulated and could provide novel drug targets for diagnosis and treatment of osteoporosis for each gender.

描述（由申请人提供）：骨质疏松症是一种以低骨矿物质密度（BMD）为特征的疾病，是骨折风险的最强预测因素。在人类和动物模型中的统计遗传分析清楚地表明，多个基因导致骨性状的变化，并且BMD遗传具有性别和位点特异性。因此，性别特异性BMD数量性状基因座（QTL）已被确定在几个染色体在人类和动物模型。然而，迄今为止尚未鉴定出性别特异性BMD QTL基因。基于我们最近的发现，来自C57 BL/6 J（B6）-Castaneous（CAST）同源小鼠的股骨在D1 mit 115-D1 mit 152处携带CAST等位基因，（178-185 Mb，命名为BMD 1 -4 QTL）与相应的性别匹配的B6小鼠相比，在雌性小鼠中而不是雄性小鼠中表现出显著更高的峰值BMD，我们提出了一个假设，即CAST小鼠1号染色体的这一区域含有一个对BMD产生性别特异性影响的基因。通过使用额外的B6.CAST-1小鼠的亚同源系，我们已经将雌性特异性BMD 1 -4基因座的大小缩小到2.6 MB，该区域足够小以进行基因鉴定过程。我们的目的是研究BMD 1 -4 QTL基因调控雌性小鼠峰值BMD的机制，并筛选BMD 1 -4位点以鉴定赋予性别特异性的候选基因。为此，我们提出了以下三个具体目标。在具体目标1中，我们将在第3周（青春期前）、第5周（青春期）、第8周（青春期后）和第16周（成年）评估携带BMD 1 -4 QTL基因的小鼠亚同源系和相应对照小鼠的骨骼表型。我们将确定骨吸收或骨形成是否是导致雌性同类小鼠BMD较高的主要机制，并预期这些信息将有助于选择候选基因进行评估。在具体目标2中，我们将在表型开始显现时评估雄性和雌性同类系小鼠和对照B6小鼠骨中BMD 1 -4基因座潜在候选基因的表达水平。我们将考虑在雄性和雌性之间或在同源小鼠和B6小鼠之间显示差异表达的基因作为潜在的候选者。在具体目标3中，我们将研究BMD 1 -4基因对机械负荷的响应，并确定该响应是否具有性别依赖性。BMD 1 - 4 QTL基因的成功鉴定赋予性别特异性，将导致更好地了解骨骼生长是如何调节的，并可能为每个性别的骨质疏松症的诊断和治疗提供新的药物靶点。