MOLECULAR CONTROL OF THE GROWTH OF THE MEDULLOBLASTOMA

髓母细胞瘤生长的分子控制

• 批准号: 6188087
• 负责人: SCOTT Loren POMEROY
• 金额: $ 22.04万
• 依托单位: BOSTON CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-08-01 至 2003-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6188087
• 关键词: animal genetic material tag; apoptosis; athymic mouse; biological signal transduction; cell growth regulation; clinical research; enzyme activity; enzyme induction /repression; gene mutation; genetically modified animals; granule cell; growth factor receptors; human genetic material tag; human subject; medulloblastoma; neoplasm /cancer genetics; neoplasm /cancer pharmacology; neoplastic cell; neoplastic growth; neurotrophic factors; protein tyrosine kinase

DESCRIPTION: Recent discoveries have identified two different molecular signals that appear to be critical regulators of medulloblastoma growth. Mutations of the Patched (Ptc) gene in Gorlin's syndrome, an inherited disorder associated with medulloblastoma, and in about 20 percent of sporadic tumors has implicated the Sonic hedgehog (Shh)/Ptc pathway as a proliferative stimulus. Favorable prognosis has been tightly linked to the expression of the neurotrophin-3 (NT-3) receptor TrkC. TrkC appears to be more than a passive marker for favorable prognosis, for medulloblastomas undergo apoptosis when grown in the presence of nT-3 in vitro and are growth inhibited in nude mice when the receptor is overexpressed in tumor xenografts. These findings support a model of medulloblastoma oncogenesis in which the Shh/Ptc and neurotrophin signaling pathways collaborate to promote and modulate the growth of these tumors that arise from cerebellar granule cell precursors. In this model, they hypothesize that deregulated signaling of the Shh/Ptc pathway, either by gain of Shh function or by inactivating mutations of ptc, promotes tumor proliferation. By either mechanism, loss of Ptc transcription suppression promotes expression of molecules downstream of Ptc that induce excessive granule cell proliferation. They hypothesize that NT-3 inhibits the growth of medulloblastomas either by inducing apoptosis or differentiation of the tumor cells. This model predicts that highly malignant medulloblastomas have a constitutive Shh/Ptc proliferative signal with little or no Nt-3 induced cell death or differentiation, and that the progression of tumors induced by Shh/Ptc signaling will be inhibited by NT-3 especially when there is a high level of endogenous trkC expression. The experiments of this proposal test this model. In Specific Aim 1, they ask whether deregulation of the Shh/Ptc signaling pathway is a general feature of medulloblastomas. The experiments of Specific Aim 2 determine whether excessive Shh signaling is sufficient to induce the growth of medulloblastomas and whether the biological effects of Shh overexpression can be modified by TrkC activation. In Specific Aim 3, they determine whether TrkC activation inhibits the growth of medulloblastomas that arise in Ptc +/- mice, by breeding compound mutant mice deficient in both Ptc and TrkC signaling. In Specific Aim 4, they will determine in a nude mouse/xenograft model whether exogenous NT-3 can induce the regression of medulloblastomas in vivo. By testing whether Shh/Ptc and NT-3/TrkC collaborate to regulate the growth of the tumors, these experiments ultimately aim to define critical determinants of medulloblastoma growth, which have until now been poorly understood.

描述：最近的发现已经确定了两个不同的分子 似乎是髓母细胞瘤生长的关键调节剂的信号。 Gorlin综合征中修补基因（PTC）基因的突变，一种遗传 与髓母细胞瘤相关的疾病，约20％ 零星肿瘤已将声音刺猬（SHH）/PTC途径牵涉到 增殖性刺激。 有利的预后紧密相连 神经营养蛋白3（NT-3）受体TRKC的表达。 trkc 似乎不仅仅是一个被动预后的被动标记，因为 髓母细胞瘤在NT-3存在下生长时会凋亡 体外并在受体为时在裸鼠中抑制生长 过表达肿瘤异种移植物。 这些发现支持 髓母细胞瘤的肿瘤发生，其中SHH/PTC和神经营养素 信号通路协作以促进和调节 这些肿瘤来自小脑颗粒细胞前体。 在 他们假设这种模型说SHH/PTC的信号传导 途径，无论是通过SHH功能的增长还是通过灭活突变 PTC，促进肿瘤增殖。 通过这两种机制，PTC的损失 转录抑制促进下游分子的表达 诱导过度颗粒细胞增殖的PTC。 他们 假设NT-3抑制了髓母细胞瘤的生长 诱导肿瘤细胞的细胞凋亡或分化。 这个模型 预测高度恶性的髓母细胞瘤具有组成型 SHH/PTC增殖信号很少或没有NT-3诱导细胞死亡 或分化，以及由 NT-3将抑制SHH/PTC信号传导，尤其是在有一个 高水平的内源性TRKC表达。 实验的实验 建议测试此模型。 在特定的目标1中，他们问是否 SHH/PTC信号通路的放松管制是 髓母细胞瘤。 特定目标2的实验确定是否 过多的SHH信号足以诱导 髓母细胞瘤以及SHH的生物学作用是否 可以通过TRKC激活来修改过表达。 在特定的目标3中 他们确定TRKC激活是否抑制了 PTC +/-小鼠中出现的髓母细胞瘤，通过繁殖化合物突变体 PTC和TRKC信号不足的小鼠。 在特定的目标4中，他们 将在裸鼠/异种移植模型中确定外源性NT-3是否 可以诱导体内髓母细胞瘤的回归。 通过测试 SHH/PTC和NT-3/TRKC是否合作以规范 肿瘤，这些实验最终旨在定义关键决定因素 髓母细胞瘤的生长，到目前为止尚未了解。

项目成果

Analysis of the SDHD gene, the susceptibility gene for familial paraganglioma syndrome (PGL1), in pheochromocytomas.

嗜铬细胞瘤中 SDHD 基因（家族性副神经节瘤综合征 (PGL1) 的易感基因）的分析。

• DOI: 10.1210/jcem.86.6.7547
• 发表时间: 2001
• 期刊: The Journal of clinical endocrinology and metabolism.
• 作者: Aguiar,RC;Cox,G;Pomeroy,SL;Dahia,PL
• 通讯作者: Dahia,PL

Magnetic resonance imaging of patched heterozygous and xenografted mouse brain tumors.

修补杂合和异种移植小鼠脑肿瘤的磁共振成像。

• DOI: 10.1023/a:1023339902812
• 发表时间: 2003
• 期刊: Journal of neuro-oncology
• 影响因子: 3.9
• 作者: Nelson,AaronL;Algon,SibelA;Munasinghe,Jeeva;Graves,Ondrea;Goumnerova,Liliana;Burstein,Deborah;Pomeroy,ScottL;Kim,JohnYH
• 通讯作者: Kim,JohnYH