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遗传星座进行干预，有望实现重大的医学进步。这一希望的前提是了解每个基因对人类健康的贡献及其与环境的相互作用。这些基本信息必须来自复制人类生物学的模式生物。小鼠遗传学界已经通过开发遗传上确定的和高度多态性的（多样性远交种，DO）小鼠品系来应对这一挑战，用于能够直接鉴定表型极端中的遗传单位的数量性状连锁（QTL）研究。骨骼生物学领域尚未利用这一进展，部分原因是用于骨/软骨表型分析的负担得起的工具相对不敏感， 以及建立小鼠集落和进行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减，骨骼生物学界如果想参与个性化医疗的承诺，就必须重新设计进行QTL研究的方式。 这项资助为骨骼医学提供了一条途径，使其能够参与鉴定导致骨质疏松症或退行性关节炎等复杂医学疾病的遗传位点。它有两个目标。第一种是用于评估骨和关节软骨的动态和细胞组织形态学的组织学方法，其与基于计算机的QTL研究兼容。该方法成本相对较低，吞吐量高，图像的定量与观察者无关。第二个是能够附加一个骨骼QTL研究，以一个正在进行的和资助的项目，旨在为另一个生物学问题，是兼容的骨骼问题。在目标1中，将使用成熟的计算机驱动骨组织形态学方法评估两项DO研究中的骨骼状态。(1)9月龄经产雌性小鼠。与以前所有使用处女女性的QTL研究不同，这项研究可能会确定哺乳期结束后恢复骨矿物质所需的基因。(2)在6、12和18月龄的雄性和雌性小鼠中。骨骼的老化研究特别难以进行，与NIA支持的Shock核心设施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费用都包括在内。在目标2中，将完善组织学/成像方法和图像分析算法，以提供与骨研究所用相同切片兼容的基于计算机的关节软骨健康组织形态学评估。在将该方法应用于两项DO研究之前，将使用5种不同近交系小鼠的现有切片对该方法进行验证。我们的数字组织学技术可以与多用途DO研究相结合，以基于网络的数据就绪的格式识别与极端骨骼变异相关的遗传基因座，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.