GENETIC ANALYSIS OF HIP FRAGILITY

髋关节脆弱性的遗传分析

• 批准号: 6878034
• 负责人: CHARLES H TURNER
• 金额: $ 31.5万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-04-04 至 2008-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6878034
• 关键词: animal breeding; biomechanics; bone density; chromosomes; femur; gene expression; genetic polymorphism; genetic susceptibility; genotype; hip fractures; laboratory rat; phenotype; quantitative trait loci; tensile strength

DESCRIPTION (provided by applicant): Genetic influences account for the majority of the population variance in bone mineral density and bone fragility. Considering that hip fracture is the most expensive of osteoporotic fractures, both in terms of health care cost and in human costs (i.e., morbidity and mortality), there should be considerable interest in an animal model for studying genetic influences on hip fragility. We recently identified two strains of rats, Copenhagen 2331 (COP) and DA, which have considerable variation in the biomechanical properties of their femoral necks. We propose to use these rat strains to identify genes responsible for the variation in hip fragility. We will test three hypotheses: (1) COP and DA rats reach peak femoral neck strength and bone mass at six months of age. Our goal is to determine genetic influences on the biomechanical properties and bone structure at an age when femoral neck strength is at its peak. Sprague-Dawley rats achieve peak bone mass and strength within a window of 5-9 months of age. Presumably, COP and DA strains follow similar skeletal growth curves. We will measure femoral biomechanical properties, geometry and microstructure in rats ranging from 2 to 10 months of age to determine the age associated with peak values; (2) chromosomal regions harboring genes that regulate femoral neck strength and microstructure can be determined for rats. COP and DA progenitor rats will be mated and their F1 hybrid offspring intercrossed to create an F2 population containing 500-600 individuals. These rats will be phenotyped based upon femoral neck biomechanical, geometrical and microstructural measurements. Quantitative trait loci (QTL) analyses will be performed to identify the genetic loci influencing variation phenotypes. We anticipate that these analyses will identify several QTLs containing genes that influence femoral neck fragility; and (3) femoral shaft and neck fragility are regulated, at least in part, by different genetic loci. The COP x DA F2 population will be further characterized for bone fragility at the femoral midshaft QTL analyses will be performed to identify the genetic loci contributing to the variation in the phenotypes. We anticipate that these analyses will identify some QTLs previously linked to femoral neck fragility in Aim 2, as well as novel QTLs specifically influencing femoral shaft phenotypes.

描述（由申请人提供）：遗传影响占骨矿物质密度和骨脆弱性人群差异的大部分。考虑到髋部骨折是骨质疏松性骨折中最昂贵的，无论是在医疗费用方面还是在人类成本（即发病率和死亡率）方面，应该对研究遗传对髋部脆弱性影响的动物模型有相当大的兴趣。我们最近鉴定了两种大鼠，哥本哈根2331 （COP）和DA，它们在股骨颈的生物力学特性上有相当大的差异。我们建议使用这些大鼠菌株来鉴定导致髋关节脆性变异的基因。我们将检验三个假设：(1)COP和DA大鼠在6月龄时达到股骨颈强度和骨量的峰值。我们的目标是确定遗传对股骨颈力量达到顶峰时的生物力学特性和骨结构的影响。Sprague-Dawley大鼠在5-9个月大时达到骨量和强度的峰值。据推测，COP和DA菌株遵循相似的骨骼生长曲线。我们将测量2 - 10月龄大鼠的股骨生物力学特性、几何形状和微观结构，以确定与峰值相关的年龄；(2)可以确定大鼠股骨颈强度和微观结构调控基因所在的染色体区域。将COP和DA祖先大鼠进行交配，并将它们的F1杂交后代进行杂交，形成包含500-600只个体的F2群体。这些大鼠将根据股骨颈生物力学、几何和显微结构测量结果进行表型分析。将进行数量性状位点（QTL）分析，以确定影响变异表型的遗传位点。我们预计这些分析将鉴定出几个含有影响股骨颈脆性基因的qtl；(3)股骨干和颈脆性至少在一定程度上受不同基因位点的调控。将对COP x DA F2群体进行股骨中轴骨脆性的进一步表征，并进行QTL分析，以确定导致表型变异的遗传位点。我们预计这些分析将在Aim 2中确定一些先前与股骨颈脆性相关的qtl，以及专门影响股骨干表型的新qtl。