Skeletal Phenotyping of KOMP Mice

KOMP 小鼠的骨骼表型

基本信息

批准号：
8699141
负责人：
Cheryl Lynne Ackert-Bicknell
金额：
$ 65.74万
依托单位：
UNIVERSITY OF CONNECTICUT SCH OF MED/DNT
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-08-01 至 2018-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8699141
关键词：
Affect Age Animals Architecture Bar Codes Biology Bone Growth Breeding Cartilage Cell Proliferation Collaborations Communities Complex Computers Cryopreservation Cryoultramicrotomy Custom DEXA Data Data Set Data Sources Databases Dentition Deposition Digital X-Ray Discipline Disease Distal Dose Drug Targeting Dyes Effectiveness Elements Environment Environmental Risk Factor Epiphysial cartilage Evolution Exhibits Female Femur Fluorescence Foundations Funding Funding Agency Genes Genetic Genomics Genotype Goals Grant Growth Harvest Health Healthcare Histology Hormones Human Human Genetics Image Image Analysis Individual Informatics International Investments Knock-out Knockout Mice Label Leg Limb structure Link Maine Mandible Maps Measurement Measures Medical Medicine Methods Modeling Mus Mutant Strains Mice Notification Osteocytes Osteoid Osteoporosis Other Genetics Participant Peer Review Phenotype Physiological Play Procedures Process Production Program Evaluation Research Research Personnel Resources Role S-Phase Fraction Sampling Seasonal Variations Shipping Ships Signal Transduction Site Skeleton Solid Structure Surface System The Jackson Laboratory Time Tissue Harvesting Tissues United States National Institutes of Health Ursidae Family Vertebral column Writing X-Ray Computed Tomography base bone computerized data processing cost craniofacial cranium density design digital fluorescence imaging information gathering knockout gene long bone lumbar vertebra bone structure male member mineralization morphometry multidisciplinary novel osteogenic programs public health relevance screening skeletal skeletal disorder skeletal tissue spine bone structure vertebra body web-accessible web-enabled

项目摘要

DESCRIPTION (provided by applicant): Diseases of the skeleton have a complex genetic mechanism that reflects the summated effect of multiple genes that are further modified by hormones and the environment of the individual. Murine models that reflect the interaction of genetic and environmental factors will play a major role in interpreting human genetic studies because the genetic background of the mouse can be tightly controlled. One major example is the gene knock out phenotyping program (KOMP). It is designed to perform a systemic examination of KO mice but the proposed skeletal assessment will not be helpful to the bone community because it is limited to a full body digital X-ray and DEXA. This grant will show that it is financially and operationally feasible to append a robust skeletal evaluation program to the ongoing KOMP program. A three-site multi-investigator workflow has been established. Dr. Ackert-Bicknell at The Jackson Laboratory in Maine will receive breeder mice from the KO lines that have been animated, breed, genotyped and examined at that site. She will inject mineralization dyes and harvest the spine, limbs and skull for shipment to UCONN Farmington. At UCONN, Dr. Adams will perform a highly automated microCT of the distal femur, vertebral body and skull to identify KO lines with abnormal skeletal architecture. The selected KO lines will be assessed by Dr. Rowe's staff for dynamic and cellular histomorphometry of trabecular, cortical bone, and cartilage growth plate utilizing a computer automated cryohistological approach that has been adapted for mineralized tissues. Once the digital file set for the histological examination is completed, it is ported the Dr. Shin's group at UCONN Storrs where a custom image analysis program measures the fluorescent signals to compute the histomorphometry in terms that are familiar to the bone biologist. When the analysis is complete, the results, underlying images and relevant background phenotyping will be uploaded to a web-enabled database so that the result is available to the skeletal biology community. A mechanism for external peer review of information to be presented to the public has been established. As the database grows, it will become an invaluable resource by allowing an investigator to query for a physiological phenotype and retrieve all the KO genes that have been mapped to query process at the level of dynamic and cellular histology. The assembled teams have a track record for multidisciplinary and multisite interaction to coordinate daily activities and interpretation of KO data sets. Because of the prior investment in developing the highly automated microCT and histological/image analysis procedures, and the ability to use KO mice directly from a KOMP production line, the cost to perform the screen is probably 1/5 of the cost if performed on an ad hoc basis. This is a one-time opportunity to leverage the existing investment of NIH in the KOMP program to produce information that will be essential for personalized skeletal medicine to have a solid phenotypic foundation.

描述（由申请人提供）：骨骼的疾病具有复杂的遗传机制，反映了多个基因的汇总作用，这些基因被激素和个体的环境进一步改变。反映遗传因素和环境因素相互作用的鼠模型将在解释人类遗传研究中起主要作用，因为可以严格控制小鼠的遗传背景。一个主要例子是基因敲除表型程序（KOMP）。它旨在对KO小鼠进行全身检查，但拟议的骨骼评估对骨骼社区无济于事，因为它仅限于全身数字X射线和DEXA。这笔赠款将表明它在经济上和操作上是可行的，可以将强大的骨骼评估程序添加到正在进行的KOMP计划中。已经建立了三个站点的多入侵器工作流程。缅因州杰克逊实验室的Ackert-Bicknell博士将从该地点的动画，繁殖，基因分型和检查的KO系列接收育种小鼠。她将注入矿化染料，并收获脊柱，四肢和头骨，以运往UConn Farmington。在UConn，Adams博士将对远端股骨，椎体和头骨进行高度自动化的微观，以识别具有异常骨骼结构的KO线。 Rowe博士的工作人员将评估所选的KO系，用于小梁，皮质骨和软骨生长板的动态和细胞组织形态法，利用计算机自动冷冻组织学方法已适应矿化组织。一旦完成组织学检查的数字文件，它将在UConn Storrs的Shin's Group上移植，其中自定义图像分析程序测量荧光信号以计算骨骼生物学家熟悉的组织形态计量学。分析完成后，结果，基本图像和相关背景表型将上传到支持Web的数据库，以便骨骼生物学社区可以使用结果。已经建立了向公众提出信息的外部同行审查的机制。随着数据库的增长，它将通过允许研究者查询生理表型并检索已映射到动态和细胞组织学水平的查询过程的所有KO基因来成为宝贵的资源。组装的团队具有多学科和多站点互动的往绩记录，以协调日常活动和对KO数据集的解释。由于先前在开发高度自动化的微观和组织学/图像分析程序以及直接从KOMP生产线上使用KO小鼠的能力的投资，因此，执行屏幕的成本可能是成本的1/5，如果在临时工作中执行。这是一个一次性的机会，可以利用NIH在KOMP计划中的现有投资来生成对个性化骨骼医学至关重要的信息，以拥有坚实的表型基础。