Phenotyping Skeletal QTLs in a DO Mouse Population

描述(由申请人提供)：基因组革命通过针对个人独特的基因星座量身定做干预措施，有望取得重大的医学进步。这一希望建立在了解每个基因对人类健康的贡献以及它与环境的相互作用的基础上。这些基本信息必须来自复制人类生物学的模型生物。小鼠遗传学领域对这一挑战作出了回应，发展了具有遗传定义和高度多态(多样性超种，DO)的小鼠品系，用于数量性状连锁(QTL)研究，能够直接识别表型极端的遗传单位。骨骼生物学领域还没有利用这一进展，部分原因是用于骨/软骨表型的负担得起的工具相对不敏感， 以及建立小鼠克隆和进行QTL研究所需的昂贵和耗时的工作。鉴于生物医学研究的预算不断缩水，骨骼生物界如果想要参与个性化药物的承诺，就必须重新设计进行QTL研究的方式。这笔赠款为骨骼医学提供了一条参与确定导致骨质疏松症或退行性关节炎等复杂医学疾病的基因座的途径。它有两个目标。第一种是一种组织学方法，用于评估骨和关节软骨的动态和细胞组织形态，这与基于计算机的QTL研究相兼容。该方法具有较低的成本和较高的吞吐量，并且图像的定量与观察者无关。第二个是将骨骼QTL研究附加到正在进行的、为另一个与骨骼问题兼容的生物学问题而设计的资助项目中的能力。在目标1中，在两个DO研究中，将使用一种成熟的计算机驱动的骨组织形态学方法来评估骨骼状态。(1)9月龄经产雌性小鼠。与以前所有使用处女的QTL研究不同，这项研究可能会确定在哺乳竞争后恢复骨矿物质所需的基因。(2)6月龄、12月龄和18月龄雄性和雌性小鼠。骨骼的老化研究特别困难，与NIA支持的冲击核心设备的合作使这一机会成为可能。在这两种情况下，进行研究的主要固定成本都包括在内。在目标2中，将改进组织学/成像方法和图像分析算法，以提供基于计算机的关节软骨健康的组织形态计量学评估，该组织形态计量学评估与用于骨骼研究的相同切片相兼容。该方法将使用来自5个不同近交系小鼠的现有切片进行验证，然后将其应用于两个DO研究。我们的数字组织学技术可以与多用途DO研究相结合，以一种基于网络的数据就绪的形式识别与极端骨骼变异有关的遗传位点，这一证明应该使骨骼生物学研究界能够参与个性化医学革命。

DESCRIPTION (provided by applicant): The genomic revolution promises major medical advances by tailoring interventions to an individual's unique genetic constellation. This hope is predicated on understanding the contribution to human health of each gene and its interaction with the environment. This essential information will have to come from model organisms that replicate human biology. The mouse genetics community has responded to this challenge by developing genetically defined and highly polymorphic (diversity outbreed, DO) mouse lines for quantitative trait linkage (QTL) studies capable of directly identifying the genetic unit underlyin a phenotypic extreme. The skeletal biology field is not yet taking advantage of this advance in part because of the relative insensitivity of affordable tools used for bone/cartilage phenotyping, and the expensive and time consuming effort required to establish the mouse colonies and to perform a QTL study. Given the shrinking budget for biomedical research, the skeletal biology community has to reinvent how it conducts a QTL study if it wants to participate in promise of personalized medicine. This grant proposes one avenue for skeletal medicine to participate in identifying genetic loci that contribute to complex medical diseases such as osteoporosis or degenerative arthritis. It has two objectives. The first is a histological approach for assessing dynamic and cellular histomorphology of bone and articular cartilage that is compatible with a computer-based QTL study. The method is relatively low cost and high through put and the quantitation of the images is observer independent. The second is ability to append a skeletal QTL study to an ongoing and funded project designed for another biological question that is compatible with the skeletal question. In Aim 1, a well-developed computer driven bone histomorphogical method will be used to assess the skeleton status in two DO studies. (1) In 9 month old multiparous female mice. Unlike all previous QTL studies that use virgin females, this study may identify genes that are needed to recover bone mineral after lactation is competed. (2) In male and female mice at 6, 12 and 18 months of age. Aging studies of the skeleton have been particularly difficult to perform and partnering with a NIA supported Shock core facility makes this opportunity possible. In both cases, the major fixed costs for conducting the study are covered. In Aim 2, the histological/imaging methods and image analysis algorithms will be refined to provide a computer based histomorphometric assessment of articular cartilage health that is compatible with the same sections used for the bone studies. The method will be validated using existing sections from 5 different inbred mouse lines before it is applied to the two DO studies. The demonstration that our digital histological technology can be coupled with multipurpose DO study to identify genetic loci linked to extreme skeletal variation in a format that is web-based data-ready should empower the skeletal biology research community to participate in the personalized medicine revolution.