Hedgehog, Patched, and Gli in Medulloblastoma

髓母细胞瘤中的 Hedgehog、Patched 和 Gli

• 批准号: 6546951
• 负责人: HOWARD L WEINER
• 金额: $ 6.84万
• 依托单位: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-09-27 至 2007-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6546951
• 关键词: biological signal transduction; carcinogenesis; cell cycle; cell migration; cell proliferation; cerebellum; gene expression; granule cell; immunocytochemistry; in situ hybridization; laboratory mouse; medulloblastoma; mutant; protein protein interaction; transcription factor

DESCRIPTION (provided by applicant): Brain tumors are the number one cause of cancer death in children and medulloblastoma is the most common malignant brain tumor. The signaling pathway involving the secreted factor Sonic Hedgehog (Shh) and the downstream genes Patched (Ptc) and Gli play critical roles in brain development, particularly that of the cerebellum. Shh, released by Purkinje cells, relieves Ptc-mediated repression of cell growth and promotes proliferation of granule cell precursors. Granule cells undergo proliferation in the external granule layer (EGL) of the cerebellum during development, then exit the cell cycle and migrate inwardly along radial glia fibers to the internal granule layer (IGL). Medulloblastoma is thought to arise from a granule cell precursor. Recent studies have demonstrated that mutations in components of the Shh pathway are associated with medulloblastoma in humans. Furthermore, approximately 15% of mice heterozygous for a Ptc mutation develop medulloblastoma at 6-12 months of age. We have shown that mis-expression of Shh in the mouse embryonic and postnatal cerebellum produces tumors. Our overall aim is to explore the mechanism by which activation of the Sonic Hedgehog pathway leads to medulloblastoma formation. We will further develop and characterize a mouse model of medulloblastoma in which Shh is mis-expressed in the embryonic cerebellum using a retroviral vector introduced into the embryonic brain by ultrasound-guided injection. The involvement of Ptc, and Gli1 will be determined by the following approaches: 1) we will characterize how activation of the Shh-signaling pathway maintains some early EGL granule neurons in a proliferative, undifferentiated state and induces medulloblastoma formation in wild type mice, 2) we will test whether activation of the Shh-signaling pathway in mice heterozygous for a null mutation in Ptc results in a synergistic effect, with accelerated and/or a higher frequency of tumorigenesis, and 3) we will test whether Gli1 is required downstream of Shh for tumor formation and whether heterozygosity for Gli3 enhances tumor formation by injecting Shh-retrovirus into Gli1-/- and Gli3+/- mutants. This system provides a unique opportunity to investigate an in vivo animal model of childhood medulloblastoma, and to determine the roles of Ptc and Gli in tumorigenesis.

描述(申请人提供)：脑瘤是儿童癌症死亡的头号原因，髓母细胞瘤是最常见的恶性脑肿瘤。涉及分泌因子Sonic Hedgehog(Shh)及其下游基因Patched(PTC)和Gli的信号通路在脑发育，特别是小脑发育中起着关键作用。Shh由Purkinje细胞释放，解除PTC对细胞生长的抑制，促进颗粒细胞前体细胞的增殖。在发育过程中，颗粒细胞在小脑的外颗粒层(EGL)经历增殖，然后退出细胞周期，沿着放射状胶质纤维向内颗粒层(IGL)迁移。髓母细胞瘤被认为起源于颗粒细胞前体。最近的研究表明，Shh通路组件的突变与人类髓母细胞瘤有关。此外，大约15%的PTC突变杂合子小鼠在6-12个月大时发展为髓母细胞瘤。我们已经证明Shh在小鼠胚胎和出生后的小脑中的错误表达会产生肿瘤。我们的总体目标是探索Sonic Hedgehog通路激活导致髓母细胞瘤形成的机制。我们将进一步发展和鉴定髓母细胞瘤的小鼠模型，在该模型中Shh在胚胎小脑中错误表达，使用逆转录病毒载体通过超声引导注射到胚胎大脑中。PTC和Gli1的参与将通过下列方法确定：1)我们将鉴定Shh-信号通路的激活如何维持一些早期的EGL颗粒神经元处于增殖的、未分化的状态并诱导野生型小鼠髓母细胞瘤的形成；2)我们将测试在PTC中存在杂合突变的小鼠中Shh-信号通路的激活是否能导致协同作用，从而加速和/或更高频率的肿瘤发生；以及3)我们将测试是否在Shh下游需要Gli1来促进肿瘤的形成，以及Gli3的杂合性是否通过将Shh逆转录病毒注射到Gli1-/-和Gli3+/突变体中来增强肿瘤的形成。 该系统提供了一个独特的机会来研究儿童髓母细胞瘤的体内动物模型，并确定PTC和Gli在肿瘤发生中的作用。