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:
- 金额:$ 11.59万
- 依托单位:
- 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:
- 关键词:26S proteasomeAddressAdolescentAgeAge-YearsBiochemicalBortezomibBrain NeoplasmsCerebellumChildChildhood Brain NeoplasmClinicalComputer Retrieval of Information on Scientific Projects DatabaseDevelopmentDown-RegulationFundingGenetically Engineered MouseGoalsGrantHistologyHumanImageImpaired cognitionInstitutionLaboratoriesMetastatic Neoplasm to the LeptomeningesModelingMorbidity - disease rateMusNeuronsOperative Surgical ProceduresPatientsPenetrancePerinatalPopulationPre-Clinical ModelProgression-Free SurvivalsProteasome InhibitorProteinsRadiationRegimenResearchResearch PersonnelResourcesRoleShapesSignal TransductionSourceStem cellsSurvival RateTP53 geneTherapeutic EffectTransgenic MiceTransgenic OrganismsUnited States National Institutes of HealthVelcadeWild Type Mousechemotherapyinterestirradiationmedulloblastomamortalitymouse modelmutantrestorationsmoothened signaling pathwaysonic hedgehog receptortumor
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.
这个子项目是许多研究子项目中利用
资源由NIH/NCRR资助的中心拨款提供。子项目和
调查员(PI)可能从NIH的另一个来源获得了主要资金,
并因此可以在其他清晰的条目中表示。列出的机构是
该中心不一定是调查人员的机构。
髓母细胞瘤是最常见的儿童脑肿瘤,由于肿瘤本质上是围产期小脑神经干细胞的过度生长,因此具有广泛的科学价值。三分之二的髓母细胞瘤是典型的组织学亚型。然而,不管组织学亚型如何,几乎所有的儿童髓母细胞瘤都是在假定存在软脑膜转移的情况下接受手术、化疗和颅脑放射治疗(CSI)。CSI在三岁以下的儿童中尤其成问题,对他们来说,CSI会导致严重的认知障碍。不幸的是,在这个年轻的人群中,手术加化疗(而不是CSI)治疗的经典组织学髓母细胞瘤的无进展存活率只有34%。这种低的无进展存活率清楚地表明,需要对年轻患者进行更好的放射保守治疗。针对关键信号转导分子的治疗有朝一日可能会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。该模型依赖于同时条件删除Sonic Hedgehog(Shh)的Patched1(Ptc1)受体的一个副本以及幼年小脑中的p53基因。这些Pax7Cre,Patched1小鼠在出生90天时出现100%外显性的脑瘤。这个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,以及频繁的软脑膜转移。Keller实验室已经证明26S蛋白酶体抑制剂Bortezomib(VELCADE,PS-341)在髓母细胞瘤中具有显著的抗肿瘤活性,伴随着Ptc1蛋白的恢复和Hedgehog信号通路的下调。本项目的目标是进一步明确硼替佐米治疗髓母细胞瘤的疗效和作用机制。该策略是研究发育中的野生型小鼠的小脑形状,并与治疗和未治疗的易患肿瘤的突变体进行比较。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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{{ truncateString('ROSS T WHITAKER', 18)}}的其他基金
STATISTICAL AND BIOMECHANICAL ANALYSIS OF HIP DYSPLESIA
髋关节发育不良的统计和生物力学分析
- 批准号:
8363716 - 财政年份:2011
- 资助金额:
$ 11.59万 - 项目类别:
IMAGE AND SURFACE PROCESSING FOR BRAIN STRUCTURE ANALYSIS
用于脑结构分析的图像和表面处理
- 批准号:
7669312 - 财政年份:2008
- 资助金额:
$ 11.59万 - 项目类别:
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