Congenic Mouse Strains Harboring Bone Strength Quantitative Trait Loci

具有骨强度定量性状位点的同类小鼠品系

• 批准号: 8274338
• 负责人: ROBERT Daniel BLANK
• 金额: $ 31.09万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-15 至 2013-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8274338
• 关键词: Accounting; Adverse effects; Affect; Age; Aging; Animal Model; Animals; Backcrossings; Biology; Biomechanics; Body Size; Breeding; Candidate Disease Gene; Chromosome Mapping; Chromosomes; Chromosomes, Human, Pair 1; Chromosomes, Human, Pair 4; Cloning; Congenic Mice; Congenic Strain; Data; Development; Event; Failure; Female; Fracture; Future; Genes; Genetic; Genetic Epistasis; Genetic Recombination; Genotype; Hand; Health; Healthcare; Homologous Gene; Human; Individual; Lead; Left; Maps; Measures; Modeling; Morphology; Mouse Strains; Mus; NR4A1 gene; Performance; Pharmaceutical Preparations; Phenotype; Population; Predisposition; Property; Quantitative Trait Loci; Recombinants; Risk; Series; Skeleton; Staging; Structure; Testing; Variant; Work; base; bone; bone geometry; bone loss; bone mass; bone strength; congenic; congenic breeding; design; falls; gene cloning; male; mineralization; offspring; prevent; programs; research study; skeletal; young adult

DESCRIPTION (provided by applicant): Preventing fractures is an important health care challenge, as fragility fractures are already common and will become more so as the US population continues to age. Susceptibility to fragility fractures varies widely with genetic factors accounting for ~50% of this variation. Fracture risk is determined by peak bone mass and skeletal morphology achieved in young adulthood and the rate and extent of bone loss thereafter. Mice provide a valuable animal model for studying skeletal genetics. Several groups have identified genetic loci that contribute to bone strength in the mouse. We have mapped biomechanical performance quantitative trait loci (QTLs) in intercrosses of HcB- 13 x HcB-14 and HcB-8 x HcB 23 recombinant congenic mice, with QTLs located on chromosomes 1, 2, 3, 4, 6, 10, and X. We hypothesize that these QTLs will retain demonstrable effects on the skeleton following isolation as fully congenic strains harboring individual donor segments ultimately derived from HcB series' common C57BL/10ScSnA ancestor on a C3H/DiSnA background. We further hypothesize that historical recombination events will facilitate our efforts to identify the genes underlying the QTLs, as has been the case on chromosome 4. The project includes 3 specific aims. First, we will construct 4 congenic strains harboring C57BL/10ScSnA-derived donor segments, targeting chromosomes with the most robust mapped QTLs. Second, we will phenotype incipient congenics at N5F2 and newly established congenics at N10F2. The donor segment genotype's effect on phenotype in the context of the C3H/DiSnA background will thus be assessed. Third, we will determine the genetic fine structure of the parental strains HcB/8, HcB/13, HcB/14, HcB/23, and the incipient congenics and work toward identifying the responsible genes. Proceeding from a mapped QTL to an identified gene usually requires several intervening steps, for which congenic strains are particularly valuable. The first is to confirm that the locus retains its effect when isolated. The next is to exploit crossovers to subdivide the candidate interval for the responsible gene(s). The HcB strains have undergone recombination events that will prove useful at this stage of analysis. These efforts culminate in functional analyses of a restricted set of candidate genes. The congenic strains will also prove valuable in studying epistatic interactions between the individual QTLs. Identifying genes that affect bone biomechanical performance and understanding their interactions will offer the potential to design better measures to prevent fracture, regardless of whether these are related to aging, extreme loading conditions, other illnesses, or adverse effects from medications. PUBLIC HEALTH RELEVANCE: We have mapped genes that contribute to differences in bone strength and related properties in mice. We will isolate the chromosome segments that contain these genes by a standard congenic breeding program. We will confirm that the bone effects persist following the breeding program. We will perform additional genetic experiments to identify the responsible genes.

描述(申请人提供)：预防骨折是一个重要的卫生保健挑战，因为脆性骨折已经很常见，并将随着美国人口的继续老龄化而变得更加常见。脆性骨折的易感性差异很大，遗传因素约占这种差异的50%。骨折风险由青壮年达到的峰值骨量和骨骼形态以及此后骨丢失的速度和程度决定。小鼠为研究骨骼遗传学提供了一个有价值的动物模型。几个研究小组已经确定了影响小鼠骨骼强度的遗传基因。我们定位了hcb-13 x hcb-14和hcb-8 x hcb 23重组同源小鼠的生物力学性能数量性状基因座(QTL)，QTL位于1，2，3，4，6，10和X染色体上。我们推测，这些QTL在分离后将保留对骨骼的明显影响，因为这些QTL完全同源菌株含有单个供体片段，最终来自HcB系列共同的C57BL/10ScSnA祖先。我们进一步假设，历史重组事件将有助于我们努力识别QTL的潜在基因，就像在4号染色体上的情况一样。该项目包括3个具体目标。首先，我们将构建4个含有C57BL/10ScSnA供体片段的同源菌株，定位于具有最健壮的QTL的染色体。其次，我们将在N5F2对早期遗传进行表型，在N10F2对新建立的遗传进行表型。因此，将在C3H/DiSnA背景的背景下评估供体片段基因对表型的影响。第三，我们将测定亲本株HCB/8、HCB/13、HCB/14、HCB/23的遗传精细结构和早期基因，并致力于确定相关基因。从定位的QTL到确定的基因通常需要几个中间步骤，对这些步骤来说，同源菌株特别有价值。第一个是确认该基因座在被隔离时仍保持其作用。下一步是利用交叉来细分负责基因的候选区间(S)。六氯联苯毒株经历了重组事件，这将在这个分析阶段被证明是有用的。这些努力的最终结果是对一组有限的候选基因进行功能分析。同源品系在研究单个QTL之间的上位性互作方面也将被证明是有价值的。识别影响骨骼生物力学性能的基因并了解它们之间的相互作用，将为设计更好的预防骨折的措施提供可能性，无论这些措施是否与衰老、极端负荷条件、其他疾病或药物的不良反应有关。与公共健康相关：我们已经定位了导致小鼠骨骼强度和相关特性差异的基因。我们将通过标准的同源基因育种程序分离包含这些基因的染色体片段。我们将在繁殖计划后确认骨骼效应是否持续存在。我们将进行额外的基因实验，以确定相关基因。