MOUSE SKELETON PHENOTYPING

本子项目是利用由NIH/NCRR资助的中心赠款提供的资源的众多研究子项目之一。子项目和研究者（PI）可能已经从另一个NIH来源获得了主要资金，因此可以在其他CRISP条目中表示。列出的机构是中心的，不一定是研究者的机构。犹他大学埃克尔斯人类遗传学研究所的Mario Capecchi博士的实验室正在研究小鼠中特定的、诱导的基因异常的表型表达，这种模型已被证明可以深入了解人类先天性疾病的个体发生。传统的小鼠骨骼结构分析需要牺牲研究动物，并在解剖显微镜下进行骨骼准备和物理检查的劳动密集型过程。为了进行有意义的统计分析，通常需要数十甚至数百个标本，这意味着要投入大量的时间和金钱。综合生物医学计算中心与Capecchi实验室合作的目标是开发一种更快、无创的骨骼分析方案，该方案使用三维微型ct的半自动图像处理，而不是手工测量已准备好的骨骼标本。我们正在开发一套用于定量形态测量的图像分割、测量和可视化工具，使我们能够实验新的指标，例如骨骼形状分析，这在准备好的骨骼标本中是不可能的。此外，我们期望我们的工具将允许对长度、密度和体积进行更精确和可重复的测量，从而深入了解以前被描述为多效性（部分渗透）或被认为是次要影响的遗传改变。在短期内，综合生物医学计算中心的目标是发表两个具体的研究项目。第一个项目是验证我们基于非侵入性ct的骨骼分析方案，对照Capecchi实验室研究人员使用制备标本和人工骨骼测量获得的结果（Boulet和Capecchi, 2002； Davies和Capecchi， 1994）。在这项研究中，我们将使用我们的图像处理和可视化工具对骨长度和骨骼进行标量测量。在Boulet-Capecchi的研究中（Boulet和Capecchi， 2002），爪各骨的长度将与肱骨的长度进行比较。我们的假设是，我们可以以更高的精度（更小的标准偏差）再现物理测量，甚至可以测量物理研究固有的测量噪声中丢失的额外变化。我们的第二个研究项目将应用我们的方法来计算统计形状模型，以分割鼠标骨骼。老鼠骨骼是一个非常具有挑战性的数据集，因为它们的表面由许多复杂和不规则的特征组成。我们已经开发了一种计算形状对应点的新技术，这是形状分析管道中的重要步骤，我们相信它比将表面参数化为球体的传统方法更适合这些表面。参考文献“Hoxd11基因的复制导致小鼠轴向和尾向骨骼的改变”，Anne Boulet和Mario Capecchi。《发育生物学》，2002，“定向破坏hoxd-11的小鼠轴向同源性和附肢骨骼缺损”，刘志强，李志强。发展，120,2187-2198,1994。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The laboratory of Dr. Mario Capecchi at the University of Utah's Eccles Institute of Human Genetics is investigating the phenotypic expression of specific, induced genetic abnormalities in mice, a model that has been shown to provide insight into the ontogeny of congenital human disease. Conventional analysis of mouse skeletal structure requires sacrificing the research animal and a labor-intensive process of skeleton preparation and physical inspection under a dissecting microscope. Many tens or even hundreds of specimens are often required for a meaningful statistical analysis, which represents an enormous investment of time and money. The goal of the Center for Integrative Biomediacal Computing collaboration with the Capecchi lab is to develop a faster, non-invasive protocol for skeletal analysis that uses semi- automated image processing of three-dimensional micro-CT rather than hand measurements of prepared skeletal specimens. We are developing a set of image segmentation, measurement and visualization tools for quantitative morphometry that allow us to experiment with new metrics such as the analysis of bone shape that would not be possible with prepared skeletal specimens. Furthermore, we expect that our tools will allow for more precise and repeatable measurements for length, density and volume, and therefore give insight into genetic alterations that have previously been described as pleiotropic (partially penetrant) or that have been written off as minor effects. In the short term, the Center for Integrative Biomediacal Computing is targeting two specific research projects for publication. The first project is to validate our non-invasive CT-based protocol for skeletal analysis against the results obtained using prepared specimens and manual bone measurements by researchers in the Capecchi lab (Boulet and Capecchi, 2002; Davies and Capecchi, 1994). In this study, we will use scalar measurements of bone length and bone taken with our image processing and visualization tools. As in the Boulet-Capecchi study (Boulet and Capecchi, 2002), the length of the various bones of the paw will be compared to the length of the humerus. Our hypothesis is that we can reproduce the physical measurements to a greater accuracy (smaller standard deviation) and perhaps even measure additional variation that was lost in the measurement noise inherent to the physical study. Our second research project will apply our methods for computing statistical shape models to the segmented mouse bones. The mouse bones are a very challenging data set because their surfaces are composed of many complex and irregular features. We have developed a new technique for computing shape correspondence points, an essential step in the shape analysis pipeline, that we believe are more suited for these surfaces than conventional methods which parameterize surfaces as spheres. REFERENCES "Duplication of the Hoxd11 Gene Causes Alterations in the Axial and Appendicular Skeleton of the Mouse", Anne Boulet and Mario Capecchi. Developmental Biology, 249, 96-102, 2002 "Axial homeosis and appendicular skeleton defects in mice with a targeted disruption of hoxd-11", Allan Peter Davies and Mario Capecchi. Development, 120, 2187-2198, 1994.