CT IMAGING IN TRANSGENIC MOUSE MODELS FOR HUMAN TUMORS

人类肿瘤转基因小鼠模型中的 CT 成像

基本信息

批准号：
8172259
负责人：
ROSS T WHITAKER
金额：
$ 11.59万
依托单位：
UNIVERSITY OF UTAH
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-09-15 至 2011-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8172259
关键词：
26S proteasome Address Adolescent Age Age-Years Biochemical Bortezomib Brain Neoplasms Cerebellum Child Childhood Brain Neoplasm Clinical Computer Retrieval of Information on Scientific Projects Database Development Down-Regulation Funding Genetically Engineered Mouse Goals Grant Histology Human Image Impaired cognition Institution Laboratories Metastatic Neoplasm to the Leptomeninges Modeling Morbidity - disease rate Mus Neurons Operative Surgical Procedures Patients Penetrance Perinatal Population Pre-Clinical Model Progression-Free Survivals Proteasome Inhibitor Proteins Radiation Regimen Research Research Personnel Resources Role Shapes Signal Transduction Source Stem cells Survival Rate TP53 gene Therapeutic Effect Transgenic Mice Transgenic Organisms United States National Institutes of Health Velcade Wild Type Mouse chemotherapy interest irradiation medulloblastoma mortality mouse model mutant restoration smoothened signaling pathway sonic hedgehog receptor tumor

项目摘要

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.

该子项目是利用该技术的众多研究子项目之一资源由 NIH/NCRR 资助的中心拨款提供。子项目和研究者 (PI) 可能已从 NIH 的另一个来源获得主要资金，因此可以在其他 CRISP 条目中表示。列出的机构是中心，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，具有广泛的科学意义，因为肿瘤本质上是小脑围产期神经元干细胞的过度生长。三分之二的髓母细胞瘤被定性为经典组织学亚型。然而，无论组织学亚型如何，几乎所有髓母细胞瘤儿童都在假设存在软脑膜转移的情况下接受手术、化疗和颅脊髓照射（CSI）治疗。 CSI 对于三岁以下的儿童来说尤其成问题，CSI 会导致严重的认知障碍。不幸的是，在年轻人群中，手术加化疗（但不是 CSI）的经典组织学髓母细胞瘤无进展生存率仅为 34%。这种低无进展生存率清楚地表明年轻患者需要更好的放射治疗。针对关键信号转导分子的疗法有一天可能会克服当前治疗方案的死亡率和治疗相关的发病率。生理上准确的转基因临床前模型可以在此类新疗法的开发中发挥重要作用。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。该模型依赖于同时有条件地删除 Sonic Hedgehog (Shh) 的 Patched1 (Ptc1) 受体以及幼年小脑中的 p53 基因的一个副本。这些 Pax7Cre,Patched1 小鼠在 90 天龄时出现外显率 100% 的脑肿瘤。该模型中的肿瘤与最常见的临床表现相似：经典的组织学、均匀的局部侵袭和频繁的软脑膜转移。 Keller实验室表明，26S蛋白酶体抑制剂bortezomib（velcade，PS-341）在髓母细胞瘤中具有显着的抗肿瘤活性，同时伴有Ptc1蛋白的恢复和hedgehog信号通路的下调。该项目的目标是进一步明确硼替佐米在髓母细胞瘤中的治疗效果和机制。该策略是研究发育中的野生型小鼠的小脑形状，并与经过治疗和未经治疗的易患肿瘤的突变体进行比较。