IMAGE BASED SMALL ANIMAL PHENOTYPING

基于图像的小动物表型分析

• 批准号: 8363710
• 负责人: ROSS T WHITAKER
• 金额: $ 8.88万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-08-01 至 2012-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8363710
• 关键词: 26S proteasome; Address; Alleles; Animals; Biochemical; Biological Markers; Biological Process; Biomedical Computing; Birth; Bortezomib; Cell Differentiation process; Cerebellum; Childhood; Childhood Brain Neoplasm; Complex; Development; Disease Progression; Down-Regulation; External Granular Layer; Funding; Genes; Genetically Engineered Mouse; Grant; Image; Imagery; Laboratories; Life; Methods; Mus; National Center for Research Resources; Neurons; Pattern; Perinatal; Pharmaceutical Preparations; Phase; Phenotype; Principal Investigator; Proteasome Inhibitor; Proteins; Publications; Research; Research Infrastructure; Resources; Shapes; Source; Stem cells; Treatment Efficacy; United States National Institutes of Health; Variant; Velcade; Work; base; cost; design; interest; medulloblastoma; mouse model; positional cloning; restoration; smoothened signaling pathway; tumor; tumor growth

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Background: Medulloblastoma is the most common childhood brain tumor and is of scientific interest because tumors are essentially overgrowths of perinatal neuronal stem cells in the external granular layer of the cerebellum. Medulloblastomas arise in the cerebellum early in childhood, coincident with the development of the cerebellum, which occurs after birth by the proliferation and differentiation of the cells in the external granular layer (EGL) of the cerebellum. This project addresses the biochemical underpinnings of medulloblastoma through a genetically engineered mouse model (GEM), developed by the Keller laboratory. Rationale: In their recent publication, the Keller laboratory has uncovered a new mechanism of disease progression for medulloblastoma, as well as a clinically-available drug that halts and reverses tumor growth. They have shown that bortezomib (velcade, PS-341), a 26S proteasome inhibitor, had significant anti-tumor activity in medulloblastoma, which was accompanied by restoration of Ptc1 protein (from the second, non-mutated allele) and downregulation of the hedgehog signaling pathway. This work represents an ongoing strategy of reverse genetics in the mouse as a way of determining the contribution of a single gene to a complex biological process, such as developmental patterning. Questions: This DBP poses several important challenges for the CIBC: (1) Establishing a pipeline for segmenting the cerebellum of the mice; (2) Addressing the more general problem of complex shape with relatively high-curvature features that present variations important to the analysis; and (3) Performing a significant amount of 3D visualization. Design & Methods: The project design consists of three essentials aims: (1) Quantify macroscopic, morphological changes in the 21-day preneoplastic (pretumor) phase for the medulloblastomaprone mice; (2) Characterize tumor shape and invasiveness of established medulloblastomas as they develop in the first six weeks of life; and (3) Develop a shape-based biomarker to quantify the therapeutic efficacy and mechanisms of bortezomib on medulloblastomas.

该子项目是利用资源的众多研究子项目之一 由 NIH/NCRR 资助的中心拨款提供。子项目的主要支持 并且子项目的首席研究员可能是由其他来源提供的， 包括其他 NIH 来源。 子项目可能列出的总成本 代表子项目使用的中心基础设施的估计数量， NCRR 赠款不直接向子项目或子项目工作人员提供资金。 背景： 髓母细胞瘤是最常见的儿童脑肿瘤，具有科学意义 因为肿瘤本质上是围产期神经元干细胞的过度生长 小脑的外部颗粒层。髓母细胞瘤早期出现在小脑 在童年时期，与出生后小脑的发育同时发生 通过外颗粒层（EGL）细胞的增殖和分化 小脑。该项目解决了髓母细胞瘤的生化基础 通过凯勒实验室开发的基因工程小鼠模型（GEM）。 理由： 凯勒实验室在最近的出版物中发现了一种新的机制 髓母细胞瘤的疾病进展，以及阻止疾病进展的临床药物 并逆转肿瘤生长。他们证明硼替佐米（velcade，PS-341）是一种 26S 蛋白酶体抑制剂，对髓母细胞瘤具有显着的抗肿瘤活性， 伴随着 Ptc1 蛋白的恢复（来自第二个非突变等位基因）和 下调hedgehog信号通路。这项工作代表了一项正在进行的 小鼠反向遗传学策略作为确定基因贡献的一种方法 从单个基因到复杂的生物过程，例如发育模式。 问题： 该 DBP 给 CIBC 带来了几个重要的挑战： (1) 建立一条管道 分割小鼠的小脑； (2) 解决更普遍的问题 具有相对高曲率特征的复杂形状，呈现出重要的变化 进行分析； (3) 执行大量 3D 可视化。 设计与方法： 项目设计包含三个基本目标：（1）量化宏观， 21天肿瘤前（肿瘤前期）阶段的形态变化 易发生髓母细胞瘤的小鼠； (2) 表征肿瘤的形态和侵袭性 在生命的前六周内形成髓母细胞瘤；和（3） 开发基于形状的生物标志物来量化治疗功效和机制 硼替佐米治疗髓母细胞瘤。