Somatic Cell Transfer to Model Medulloblastoma in Mice
体细胞转移至小鼠髓母细胞瘤模型
基本信息
- 批准号:7728576
- 负责人:
- 金额:$ 22.55万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2005
- 资助国家:美国
- 起止时间:2005-06-01 至 2014-05-31
- 项目状态:已结题
- 来源:
- 关键词:1-Phosphatidylinositol 3-KinaseAbbreviationsAchievementApoptosisAutomobile DrivingAvian Leukosis VirusBiological ModelsBrain InjuriesCell ProliferationCell Surface ReceptorsCell SurvivalCellsCerebellumCerebrospinal FluidChildCytoplasmic GranulesDevelopmentEctopic ExpressionErinaceidaeGene TransferGenesGenetically Engineered MouseGrowthGrowth FactorHematoxylin and Eosin Staining MethodHepatocyte Growth FactorHumanInsulin-Like Growth Factor IILong Terminal RepeatsMalignant neoplasm of brainModelingMolecular TargetMonoclonal AntibodiesMonoclonal Antibody TherapyMusNeoplasm MetastasisNeurofilament ProteinsNeurological outcomeNeuronsOncogene ProteinsOperative Surgical ProceduresPathogenesisPathway interactionsPatientsPhenotypePlayPreclinical TestingPrognostic FactorProtein Tyrosine KinaseProteinsProto-Oncogene Protein c-metRNA SplicingRadiationResearchRetroviral VectorRetroviridaeRibosomal Protein S6RoleSignal TransductionSignal Transduction PathwaySignaling MoleculeSiteSleeping BeautySomatic CellSpinalStimulusSubgroupSurvival RateSystemTransgenesTransgenic MiceTranslatingTreatment ProtocolsVertebral columnchemotherapydensityenhancing factorhuman diseaseimprovedintraperitonealmedulloblastomameetingsmouse modelneoplastic cellnerve stem cellnestin proteinneurotoxicitypartial responsepostnatalprogramspromoterpublic health relevancereceptorsubcutaneoustherapeutic targettreatment responsetumortumor growthvector
项目摘要
DESCRIPTION (provided by applicant): Medulloblastomas (MBs) are malignant brain tumors that arise by transformation of neural progenitor cells in the cerebellum in children. Aggressive treatment approaches combining surgery, craniospinal radiation, and chemotherapy result in 5-year survival rates exceeding 70%. Treatment- related neurotoxicity has created a critical need to identify signaling molecules that can be targeted therapeutically to maximize tumor growth suppression and minimize collateral brain damage. The overall objective of this research is to use a mouse model of MB, which we developed using the RCAS/tv-a gene transfer system, as a preclinical testing platform for molecular targeted MB therapy. This experimental system uses a retroviral vector (RCAS) derived from avian leukosis virus and a transgenic mouse line that expresses the retrovirus receptor under control of the Nestin gene promoter, which is active in neural progenitor cells during normal cerebellar development. Using this system, we showed that ectopic expression of Sonic Hedgehog (Shh) in the postnatal cerebellum induces MBs in mice. Furthermore, we identified proteins belonging to different functional classes that cooperate with Shh to enhance MB formation. These enhancing factors are (a) Myc oncoproteins, which stimulate proliferation of neural progenitors during normal development, (b) Bcl-2, which potently inhibits apoptosis, (c) insulin-like growth factor-II, which concomitantly stimulates proliferation and blocks apoptosis by activating the phosphatidylinositol 3-kinase (PI3K) signal transduction pathway, and (d) hepatocyte growth factor (HGF), a growth factor with pleiotropic effects on tumor growth. The fact that all of these proteins are highly expressed in human MBs indicates that their tumor-promoting activity in mice accurately reflects the pathogenesis of the human disease. Moreover, these proteins and their downstream signaling molecules can be considered therapeutic targets. Specific aim 1 is to determine whether inhibiting Shh signaling cooperates with blockade of HGF signaling to enhance treatment response in mice bearing Shh?induced MBs. Specific aim 2 is to determine whether MB growth suppression by HGF monoclonal antibody therapy can be enhanced by pharmacologic inhibition of the HGF receptor c- Met or downstream PI3K signaling. Specific aim 3 is to use the RCAS/tv-a system to identify genes that cause Shh-induced MBs to metastasize to the spine. Spinal metastasis is a highly unfavorable prognostic factor for patients with MBs. Achievement of these aims will make it possible to translate the mechanistic discoveries to molecular targeted therapies for children with MB. PUBLIC HEALTH RELEVANCE: Although aggressive treatment regimens in children with medulloblastoma result in favorable survival rates, treatment-related neurotoxicity has created a critical need to identify signaling molecules that can be targeted therapeutically to maximize tumor growth suppression and minimize collateral brain damage. The overall objective of this research is to use a mouse model of medulloblastoma as a preclinical testing platform for molecular targeted therapy. The results can be translated to promoting long-term survival and improving neurological outcome for patients with medulloblastomas.
描述(申请人提供):髓母细胞瘤(MB)是儿童小脑神经祖细胞转化引起的恶性脑肿瘤。结合手术、颅脊髓放射和化疗的积极治疗方法可使5年生存率超过70%。治疗相关的神经毒性已经产生了识别可以在治疗上靶向以最大化肿瘤生长抑制和最小化附带脑损伤的信号传导分子的迫切需要。本研究的总体目标是使用我们使用RCAS/tv-a基因转移系统开发的MB小鼠模型作为分子靶向MB治疗的临床前测试平台。该实验系统使用来自禽白血病病毒的逆转录病毒载体(RCAS)和在巢蛋白基因启动子控制下表达逆转录病毒受体的转基因小鼠系,巢蛋白基因启动子在正常小脑发育期间在神经祖细胞中是活跃的。使用这个系统,我们表明,异位表达的Sonic Hedgehog(Shh)在出生后的小脑诱导小鼠的MB。此外,我们确定了属于不同功能类别的蛋白质与Shh合作,以增强MB的形成。这些增强因子是(a)Myc癌蛋白,其在正常发育期间刺激神经祖细胞的增殖,(B)Bcl-2,其有效地抑制凋亡,(c)胰岛素样生长因子-II,其通过激活磷脂酰肌醇3-激酶(PI 3 K)信号转导途径同时刺激增殖并阻断凋亡,和(d)肝细胞生长因子(HGF),一种对肿瘤生长有多效作用的生长因子。所有这些蛋白质在人类MB中高度表达的事实表明,它们在小鼠中的促肿瘤活性准确地反映了人类疾病的发病机制。此外,这些蛋白质及其下游信号分子可以被认为是治疗靶点。具体目标1是确定抑制Shh信号传导是否与阻断HGF信号传导合作,以增强Shh小鼠的治疗反应?诱导MB。具体目标2是确定HGF单克隆抗体治疗对MB生长的抑制是否可以通过HGF受体c-Met或下游PI 3 K信号传导的药理学抑制来增强。具体目标3是使用RCAS/tv-a系统来鉴定导致Shh诱导的MB转移到脊柱的基因。脊柱转移是MB患者的一个非常不利的预后因素。这些目标的实现将使得有可能将机制发现转化为MB儿童的分子靶向治疗。公共卫生相关性:尽管儿童髓母细胞瘤的积极治疗方案带来了有利的生存率,但治疗相关的神经毒性迫切需要识别可以在治疗上靶向的信号分子,以最大限度地抑制肿瘤生长并最大限度地减少附带脑损伤。本研究的总体目标是使用髓母细胞瘤小鼠模型作为分子靶向治疗的临床前测试平台。该结果可以转化为促进髓母细胞瘤患者的长期生存和改善神经功能结局。
项目成果
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DANIEL WEBSTER FULTS其他文献
DANIEL WEBSTER FULTS的其他文献
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{{ truncateString('DANIEL WEBSTER FULTS', 18)}}的其他基金
Somatic Cell Transfer to Model Medulloblastoma in Mice
体细胞转移至小鼠髓母细胞瘤模型
- 批准号:
7878765 - 财政年份:2005
- 资助金额:
$ 22.55万 - 项目类别:
Somatic Cell Transfer to Model Medulloblastoma in Mice
体细胞转移至小鼠髓母细胞瘤模型
- 批准号:
8076215 - 财政年份:2005
- 资助金额:
$ 22.55万 - 项目类别:
SOMATIC CELL TRANSFER TO MODEL MEDULLOBLASTOMA IN MICE
体细胞转移至小鼠髓母细胞瘤模型
- 批准号:
7068639 - 财政年份:2005
- 资助金额:
$ 22.55万 - 项目类别:
SOMATIC CELL TRANSFER TO MODEL MEDULLOBLASTOMA IN MICE
体细胞转移至小鼠髓母细胞瘤模型
- 批准号:
7423922 - 财政年份:2005
- 资助金额:
$ 22.55万 - 项目类别:
SOMATIC CELL TRANSFER TO MODEL MEDULLOBLASTOMA IN MICE
体细胞转移至小鼠髓母细胞瘤模型
- 批准号:
6965421 - 财政年份:2005
- 资助金额:
$ 22.55万 - 项目类别:
Somatic Cell Transfer to Model Medulloblastoma in Mice
体细胞转移至小鼠髓母细胞瘤模型
- 批准号:
8464013 - 财政年份:2005
- 资助金额:
$ 22.55万 - 项目类别:
SOMATIC CELL TRANSFER TO MODEL MEDULLOBLASTOMA IN MICE
体细胞转移至小鼠髓母细胞瘤模型
- 批准号:
7243512 - 财政年份:2005
- 资助金额:
$ 22.55万 - 项目类别:
Somatic Cell Transfer to Model Medulloblastoma in Mice
体细胞转移至小鼠髓母细胞瘤模型
- 批准号:
8265663 - 财政年份:2005
- 资助金额:
$ 22.55万 - 项目类别:
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