CT IMAGING IN TRANSGENIC MOUSE MODELS FOR HUMAN TUMORS

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 中心，不一定是研究者的机构。 髓母细胞瘤是最常见的儿童脑肿瘤，并且具有广泛的科学兴趣，因为肿瘤本质上是小脑的围产期神经元干细胞的过度生长。 三分之二的髓母细胞瘤的特点是经典的组织学亚型。然而，无论组织学亚型，几乎所有的儿童髓母细胞瘤的治疗与手术，化疗和颅脊髓照射（CSI）的假设下，软脑膜转移存在。 CSI在三岁以下的儿童中变得特别成问题，CSI导致严重的认知障碍。不幸的是，在这个年轻人群中，手术加化疗（而不是CSI）治疗经典组织学髓母细胞瘤的无进展生存率仅为34%。 这种低的无进展生存率清楚地表明，年轻患者需要更好的放射节省治疗。针对关键信号转导分子的治疗可能有一天会克服目前治疗方案的死亡率和治疗相关的发病率。生理学上准确的转基因临床前模型在这种新疗法的开发中可以发挥重要作用。 该项目通过凯勒实验室开发的基因工程小鼠模型（GEM）来研究髓母细胞瘤的生化基础。 该模型依赖于并发条件删除一个拷贝的Patched 1（Ptc 1）受体的Sonic Hedgehog（Shh）以及p53基因在青少年小脑。 这些Pax 7 Cre，Patched 1小鼠在90天龄时以100%的存活率发展脑肿瘤。 该模型中的肿瘤与最常见的临床表现相似：经典的组织学，均匀的局部浸润和频繁的软脑膜转移。 Keller实验室已经证明，硼替佐米（velcade，PS-341），一种26 S蛋白酶体抑制剂，在髓母细胞瘤中具有显著的抗肿瘤活性，伴随着Ptc 1蛋白的恢复和hedgehog信号通路的下调。本项目的目的是进一步明确硼替佐米在髓母细胞瘤中的治疗作用和机制。 该策略是研究发育中的野生型小鼠小脑的形状，并与治疗和未治疗的肿瘤倾向突变体进行比较。

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. Medulloblastoma is the most common childhood brain tumor and is of broad scientific interest because tumors are essentially overgrowths of perinatal neuronal stem cells of the cerebellum. Two-thirds of medulloblastomas are characterized as the classic-histology subtype. However, irrespective of histological subtype, nearly all children with medulloblastoma are treated with surgery, chemotherapy, and craniospinal irradiation (CSI) under the assumption that leptomeningeal metastases are present. CSI becomes especially problematic in children under three years of age, for whom CSI results in severe cognitive impairment results. Unfortunately, in this young population treatment with surgery plus chemotherapy (but not CSI) has only a 34% progression-free survival rate for classical histology medulloblastoma. This low progression-free survival rate clearly indicates the need for better radiation-sparing treatments in younger patients. Therapies targeted at key signal transduction molecules might one day overcome both mortality and treatment-related morbidity of current regimens. Physiologically accurate, transgenic preclinical models can have an important role in the development of such new therapies. This project addresses the biochemical underpinnings of medulloblastoma through a genetically engineered mouse model (GEM), developed by the Keller laboratory. The model relies on concurrent conditional deletion of one copy of the Patched1 (Ptc1) receptor for Sonic Hedgehog (Shh) as well as the p53 gene in the juvenile cerebellum. These Pax7Cre,Patched1 mice develop brain tumors with 100% penetrance by 90 days of age. Tumors in this model are similar to the most common clinical presentation: classic histology, uniform local invasion, and frequent leptomeningeal metastasis. The Keller laboratory has 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 and downregulation of the hedgehog-signaling pathway. The goal of this project is to further define the therapeutic effect and mechanism of bortezomib in medulloblastoma. The strategy is to study the shape of the cerebellum in the developing wild-type mouse and to make comparisons with treated and untreated tumor-prone mutants.