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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

基本信息

批准号：
8471652
负责人：
ROBERT Daniel BLANK
金额：
$ 29.54万
依托单位：
MEDICAL COLLEGE OF WISCONSIN
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-07-15 至 2015-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8471652
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

项目摘要

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（由申请人提供）：预防骨折是一项重要的医疗保健挑战，因为脆性骨折已经很常见，并且随着美国人口的持续老龄化，这种情况将变得更加常见。脆性骨折的易感性差异很大，遗传因素约占这种变化的 50%。骨折风险取决于成年早期达到的峰值骨量和骨骼形态以及此后骨质流失的速度和程度。小鼠为研究骨骼遗传学提供了有价值的动物模型。几个研究小组已经确定了有助于小鼠骨骼强度的基因位点。我们绘制了 HcB-13 x HcB-14 和 HcB-8 x HcB 23 重组同源小鼠杂交中的生物力学性能数量性状位点 (QTL)，QTL 位于染色体 1、2、3、4、6、10 和 X 上。我们假设这些 QTL 在分离为完全同源后将在骨骼上保留明显的影响含有最终源自 C3H/DiSnA 背景上 HcB 系列共同 C57BL/10ScSnA 祖先的单个供体片段的菌株。我们进一步假设历史重组事件将有助于我们鉴定 QTL 背后的基因，就像 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 衍生供体片段的同源菌株，以具有最稳健的映射 QTL 的染色体为目标。其次，我们将在 N5F2 上对初期同源基因进行表型分析，并在 N10F2 上对新建立的同源基因进行表型分析。因此，将评估 C3H/DiSnA 背景下供体片段基因型对表型的影响。第三，我们将确定亲本菌株 HcB/8、HcB/13、HcB/14、HcB/23 和早期同源菌株的遗传精细结构，并努力鉴定相关基因。从定位的 QTL 到识别的基因通常需要几个干预步骤，对此同源菌株特别有价值。首先是确认该基因座在分离后仍保留其作用。接下来是利用交叉来细分负责基因的候选区间。 HcB 菌株经历了重组事件，这将在现阶段的分析中证明是有用的。这些努力最终对一组有限的候选基因进行了功能分析。同源菌株在研究个体 QTL 之间的上位相互作用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的相互作用将有可能设计出更好的措施来预防骨折，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。公共卫生相关性：我们绘制了导致小鼠骨强度和相关特性差异的基因图谱。我们将通过标准同源育种程序分离包含这些基因的染色体片段。我们将确认在育种计划之后骨骼效应仍然存在。我们将进行额外的基因实验来识别相关基因。

项目成果

期刊论文数量（17）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Diffuse osteosclerosis as a presentation of recurrent breast cancer: role of endothelin 1.

弥漫性骨硬化是乳腺癌复发的表现：内皮素的作用 1。

DOI：
10.1007/s00198-019-04998-5
发表时间：
2019
期刊：
Osteoporosis international : a journal established as result of cooperation between the European Foundation for Osteoporosis and the National Osteoporosis Foundation of the USA
影响因子：
0
作者：
Zarnecki,KG;Kristianto,J;Charlson,J;Wilson,B;Blank,RD;Shaker,JL
通讯作者：
Shaker,JL

Bone and Muscle Pleiotropy: The Genetics of Associated Traits.

DOI：
10.1007/s12018-014-9159-4
发表时间：
2014-06-01
期刊：
Clinical reviews in bone and mineral metabolism
影响因子：
1.8
作者：
Blank RD
通讯作者：
Blank RD

Comprehensive skeletal phenotyping and linkage mapping in an intercross of recombinant congenic mouse strains HcB-8 and HcB-23.

重组同源小鼠品系 HcB-8 和 HcB-23 杂交中的全面骨骼表型分析和连锁图谱。

DOI：
10.1159/000324774
发表时间：
2011
期刊：
Cells, tissues, organs
影响因子：
0
作者：
Saless,Neema;Litscher,SuzanneJ;Houlihan,MeghanJ;Han,InKyu;Wilson,Derek;Demant,Peter;Blank,RobertD
通讯作者：
Blank,RobertD

Dual-Energy X-ray Absorptiometry Image Resolution and TBS Precision.

双能 X 射线吸收法图像分辨率和 TBS 精度。