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

• 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
• 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

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.

该副本是利用众多研究子项目之一 由NIH/NCRR资助的中心赠款提供的资源。子弹和 调查员（PI）可能已经从其他NIH来源获得了主要资金， 因此可以在其他清晰的条目中代表。列出的机构是 对于中心，这不一定是调查员的机构。 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描述为经典的基础学亚型。然而，无论组织学亚型如何，几乎所有髓母细胞瘤的儿童均通过手术，化学疗法和颅性脊髓辐射（CSI）治疗，假设存在瘦脑转移酶。 在三岁以下的儿童中，CSI尤其有问题，CSI会导致严重的认知障碍。不幸的是，在这种接受手术的年轻人口治疗中，化学疗法（但不是CSI）对于经典的组织学髓母细胞瘤只有34％的无进展生存率。 这种无进展的生存率清楚地表明需要在年轻患者中进行更好的放射治疗。针对关键信号转导分子的疗法可能有一天可以克服当前方案的死亡率和与治疗相关的发病率。生理上准确的转基因临床前模型可以在此类新疗法的发展中起重要作用。 该项目通过凯勒实验室开发的基因工程小鼠模型（GEM）来解决髓母细胞瘤的生化基础。 该模型依赖于Sonic Hedgehog（SHH）的Patched1（PTC1）受体的一个副本以及少年小脑中的p53基因的同时条件缺失。 这些PAX7CRE修补了1小鼠，出现了90天大的脑肿瘤，100％渗透率。 该模型中的肿瘤类似于最常见的临床表现：经典的组织学，局部局部侵袭和频繁的瘦脑转移。 凯勒实验室表明，硼替佐米（Velcade，PS-341）是26S蛋白酶体抑制剂，在髓母细胞瘤中具有显着的抗肿瘤活性，并伴随着PTC1蛋白的恢复和刺猬签名途径的下调。该项目的目的是进一步定义甲状腺母细胞瘤中硼替佐米的治疗作用和机制。 该策略是研究在发育中的野生型小鼠中小脑的形状，并与经过处理和未经处理的易受肿瘤的突变体进行比较。