GENETIC ANALYSIS OF VERTEBRAL STRENGTH

椎骨强度的遗传分析

• 批准号: 6497415
• 负责人: CHARLES H TURNER
• 金额: $ 44.16万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-02-08 至 2004-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6497415
• 关键词: alleles; bone density; bone development; computed axial tomography; femur; gene expression; gene interaction; genetic mapping; genetic markers; genetic polymorphism; genotype; growth /development; laboratory mouse; physical property; polymerase chain reaction; quantitative trait loci; vertebrae

While many environmental factors (i.e., diet and exercise) affect bone accumulation during growth, studies in twins have determined that about 70 percent of the variability in bone mineral density is genetically based, yet there is still much work to be done before the genes linked to bone fragility are identified. One useful strategy for uncovering the complex gene interactions contributing to bone fragility employs inbred strains of mice differing in bone mineral density and strength. Individuals within an inbred strain are identical "twins" and their environments can be closely controlled. Two inbred strains of mice with substantially different femoral bone densities are C3H/HeJ or C3H (high bone density) and C57BL/6J or B6 (low bone density). Planned matings between these inbred strains allow the segregation of genetic alleles; alleles important for BMD or bone strength in the progenitors will affect those traits in the offspring. Our preliminary data demonstrate that both B6 and C3H strains contain alleles that promote both high and low vertebral strength. Our results also suggest that midshaft femoral and vertebral strengths are regulated by different genes. As a result, we propose that there is differential genetic regulation of cortical and trabecular bone microstructures during growth and developement. We will test the following hypotheses: 1) vertebral fragility is regulated by different genes compared to bone mineral density of the femur, a phenotype that was previously characterized; 2) B6 and C3H alleles that affect vertebral fragility can be isolated in congenic strains of mice; 3) B6 and C3H alleles affect both cortical and trabecular microstructural organization of the vertebrae and thus vertebral fragility; 4) the genetic differences in vertebral biomechanical properties and microstructural organization become apparent in mice during the rapid growth phase (2-26 wks of age). We will use quantitative trait loci (QTL) analysis of an F2 population from C3H and B6 progenitor strains to determine correlations between genotype (B6 and C3H alleles) and a phenotype determined from biomechanical testing of the lumbar vertebrae. Congenic strains and recombinant inbred strains from the B6C3H-F2 population will be characterized using biomechanical testing and micro-computed tomography (muCT) to evaluate femoral and vertebral microstructure. Finally, the genetic effects on femoral and vertebral microstructure during growth and development will be analyzed for different inbred strains of mice using muCT and biomechanical testing.

虽然许多环境因素（即饮食和运动）会影响生长过程中的骨积累，但对双胞胎的研究已确定，骨矿物质密度的变异约 70% 是基于遗传的，但在确定与骨脆性相关的基因之前，仍有许多工作要做。 揭示导致骨脆性的复杂基因相互作用的一种有用策略是采用骨矿物质密度和强度不同的近交系小鼠。 近交系中的个体是相同的“双胞胎”，它们的环境可以被严密控制。 股骨骨密度显着不同的两种近交系小鼠是 C3H/HeJ 或 C3H（高骨密度）和 C57BL/6J 或 B6（低骨密度）。 这些近交系之间有计划的交配可以实现遗传等位基因的分离。对祖细胞 BMD 或骨强度很重要的等位基因将影响后代的这些特征。 我们的初步数据表明，B6 和 C3H 菌株都含有促进高和低脊椎强度的等位基因。 我们的结果还表明，中段股骨和椎骨的强度受到不同基因的调节。 因此，我们提出在生长和发育过程中皮质骨和小梁骨微结构存在差异的遗传调控。 我们将测试以下假设：1）与股骨的骨矿物质密度相比，椎骨脆性受到不同基因的调节，股骨的骨矿物质密度是先前表征的表型； 2）可以在同系小鼠品系中分离到影响椎体脆性的B6和C3H等位基因； 3) B6和C3H等位基因影响椎骨的皮质和小梁微结构组织，从而影响椎骨脆性； 4）在快速生长期（2-26周龄）的小鼠中，椎骨生物力学特性和微观结构组织的遗传差异变得明显。 我们将对 C3H 和 B6 祖细胞株的 F2 群体进行数量性状位点 (QTL) 分析，以确定基因型（B6 和 C3H 等位基因）与通过腰椎生物力学测试确定的表型之间的相关性。 来自 B6C3H-F2 群体的同源菌株和重组近交菌株将使用生物力学测试和微计算机断层扫描 (muCT) 进行表征，以评估股骨和椎骨微观结构。 最后，利用 muCT 和生物力学测试，分析不同近交系小鼠生长发育过程中股骨和椎骨微观结构的遗传影响。