GENETIC ANALYSIS OF BONE MASS

骨质疏松性骨折已经是一个主要的医疗保健问题， 随着老年人口的稳步增长，预计他们将 在接下来的几十年里急剧增加。峰值骨量 在成年早期取得的成绩是患高血压风险的主要决定因素 骨质疏松性骨折。尽管生活方式和环境因素 在达到峰值骨量起作用时，现在有明确的 遗传因素似乎非常重要的证据。 总而言之，据计算，多达75%的骨矿物质 密度是由基因决定的，这一贡献似乎是 本质上是多基因的。基因研究的下一个关键步骤是 骨质疏松症是将这种多基因性状分解为离散的遗传 各种因素。我们最近采用了一种新的方法来定位基因。 这会影响不断变化的特征，如骨量。是这样的 基因(或QTL)是通过首先对全身进行表征来识别的 22个BXD/TY重组近交系小鼠品系的骨密度， 来源于C57BL/6J和DBA/2J的近交系 祖细胞菌株。全身的应变差异模式 骨密度与遗传标记的大型数据库进行了比较， 之前在R1菌株中进行了基因分型，以产生候选 QTL的染色体图谱定位。我们已经确认了17名 可能影响峰值骨量获取的临时QTL 在雌性小鼠的骨骼生长过程中。这项提案的重点是 验证与达到骨峰值相关的临时QTL 大量生产和开发新的遗传动物模型(同源菌株) 研究已验证的QTL的效应。当小鼠的基因组变成 由于许多人的累积努力，地图绘制得更加密集 组，将更容易识别与BMD相关的TLS的位置 更准确地说。小鼠基因组显示80%的连锁同源性 人类基因组的一部分，使得QTL很可能 在地图结果中鼠标会立即提示地图站点中的 人类基因组。我们提出的绘制风险和保护基因图谱的建议 开发独特的遗传动物模型来分离这些影响 基因，为可能的风险识别提供了一条重要途径 以及人类的保护性基因。这将允许预测 个人风险，而不是统计风险，这反过来可能导致 有效地针对高危人群制定预防为主的治疗策略 人口。此外，寻找对骨量峰值至关重要的基因 发展将提供对生物化学和生物化学的巨大洞察 骨骼建模的细胞学基础和骨骼发育障碍。

Osteoporotic fractures are already a major health care problem, and with a steadily increasing geriatric population, they are projected to increase dramatically in the next few decades. Peak bone mass achieved in early adulthood is a major determinant of risk of osteoporotic fracture. Although lifestyle and environmental factors play a role in the achievement of peak bone mass, there is now clear evidence that genetic factors appear to be of great importance. Altogether, it has been calculated that up to 75% of bone mineral density is genetically determined, a contribution that appears to be polygenic in nature. The next essential step in genetic research on osteoporosis is to dissect this polygenic trait into discrete genetic factors. We have recently employed a new method for mapping genes which influence continuously varying traits such as bone mass. Such genes (or QTLs) were identified by first characterizing whole body BMD in a panel of 22 BXD/Ty recombinant inbred mouse strains, derived from a cross between C57BL/6J and DBA/2J inbred progenitor strains. The pattern of strain differences in whole body BMD was compared with a large data base of genetic markers, previously genotyped in the R1 strains, to generate candidate chromosome map sites for QTLs. We have identified seventeen provisional QTLs that may influence the acquisition of peak bone mass in female mice during skeletal growth. The focus of this proposal is to verify the provisional QTLs pertinent to the attainment of peak bone mass and develop new genetic animal models (congenic strains) for studying the effects of verified QTLs. As the mouse genome becomes ever more densely mapped due to the cumulative efforts of many groups, it will be easier to identify the location of BMD-relevant Tls more precisely. The mouse genome shows 80% linkage homology with portions of the human genome, making it likely that a QTL mapping result in the mouse will immediately suggest a map site in the human genome. Our proposal to map risk and protective genes and develop unique genetic animal models for isolating the effects of those genes, offers an important route to the possible identification of risk and protective genes in humans. This would allow prediction of individual, rather than statistical, risk, which in turn could lead to effective targeting of prevention-based treatment strategies to high-risk populations. Moreover, finding genes essential for peak bone mass development would offer tremendous insight into the biochemical and cellular basis of bone modeling and disorders of skeletal development.