GENETIC ANALYSIS OF HIP FRAGILITY

髋关节脆弱性的遗传分析

• 批准号: 7215629
• 负责人: CHARLES H TURNER
• 金额: $ 31.45万
• 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 2009-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7215629
• 关键词: Accounting; Adult; Age; Age-Months; Animal Model; Biomechanics; Bone Density; Chromosome Mapping; Failure; Female; Genes; Genetic; Goals; Growth; Health Care Costs; Hip Fractures; Hip region structure; Human; Hybrids; Inbred Strains Rats; Individual; Link; Measurement; Measures; Morbidity - disease rate; Neck; Osteoporosis; Partner in relationship; Phenotype; Population; Principal Investigator; Property; Quantitative Trait Loci; Range; Rat Strains; Rattus; Skeletal system; Sprague-Dawley Rats; Structure; Testing; Variant; Work; base; bone; bone strength; cost; genetic analysis; interest; mortality; novel; osteoporosis with pathological fracture; progenitor; programs

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）：遗传影响是骨矿物质密度和骨脆弱性的大多数种群差异。考虑到髋部骨折是骨质疏松性骨折中最昂贵的，无论是在医疗保健成本和人为成本方面（即发病率和死亡率），应该对动物模型进行研究，以研究对髋关节脆弱性的遗传影响。我们最近确定了两种大鼠哥本哈根2331（COP）和DA菌株，它们在其股骨颈的生物力学特性上有很大变化。我们建议使用这些大鼠菌株来识别负责髋关节变化的基因。我们将检验三个假设：（1）COP和DA大鼠在六个月大时达到股骨颈强度和骨骼质量。我们的目标是确定股骨颈强度达到峰值时对生物力学特性和骨结构的遗传影响。 Sprague-Dawley大鼠在5-9个月大的窗户内达到峰值骨质量和强度。据推测，COP和DA菌株遵循类似的骨骼生长曲线。我们将测量2至10个月大的大鼠的股生物力学特性，几何形状和微观结构，以确定与峰值相关的年龄； （2）可以确定大鼠的染色体区域，这些染色体区域具有调节股骨颈强度和微观结构的基因。 COP和DA祖细胞大鼠将交配，其F1混合后代在互相交配以创建一个含有500-600个个体的F2种群。这些大鼠将根据股骨颈生物力学，几何和微结构测量进行表型。将进行定量性状基因座（QTL）分析，以识别影响变异表型的遗传基因座。我们预计这些分析将识别几个含有影响股骨颈脆性的基因的QTL。 （3）至少部分通过不同的遗传基因座调节了股骨轴和颈部脆弱性。将进一步表征COP X DA F2种群在股骨中部QTL分析下的骨骼脆弱性，以确定有助于表型变异的遗传基因座。我们预计这些分析将确定某些先前与AIM 2中股骨颈脆性相关的QTL，以及专门影响股骨轴表型的新型QTL。