Hedgehog, Patched, and Gli in Medulloblastoma

髓母细胞瘤中的 Hedgehog、Patched 和 Gli

• 批准号: 7022971
• 负责人: HOWARD L WEINER
• 金额: $ 13.69万
• 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/7022971
• 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; sonic hedgehog gene /protein; 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（由申请人提供）：脑肿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）和下游基因Patched（Ptc）和Gli的信号通路在大脑发育中起关键作用，特别是小脑的发育。 由浦肯野细胞释放的Shh缓解了Ptc介导的细胞生长抑制，并促进颗粒细胞前体的增殖。 颗粒细胞在发育过程中在小脑的外部颗粒层（EGL）中经历增殖，然后退出细胞周期并沿着放射状胶质纤维向内迁移到内部颗粒层（IGL）。 髓母细胞瘤被认为是由颗粒细胞前体产生的。 最近的研究表明，突变的Shh通路的组成部分与人类髓母细胞瘤。 此外，大约15%的Ptc突变杂合子小鼠在6-12月龄时发生髓母细胞瘤。 我们已经证明，Shh在小鼠胚胎和出生后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。 我们将进一步开发和表征髓母细胞瘤小鼠模型，其中Shh在胚胎小脑中错误表达，使用通过超声引导注射引入胚胎大脑的逆转录病毒载体。 Ptc和Gli 1的参与将通过以下方法确定：1）我们将表征Shh信号传导途径的激活如何在野生型小鼠中维持一些早期EGL颗粒神经元处于增殖、未分化状态并诱导成神经管细胞瘤形成，2）我们将测试Ptc无效突变杂合小鼠中Shh信号传导途径的激活是否导致协同效应，具有加速的和/或更高的肿瘤发生频率，以及3）我们将通过将Shh-逆转录病毒注射到Gli 1-/-和Gli 3 +/-突变体中来测试Gli 1是否是肿瘤形成所需的Shh下游，以及Gli 3的杂合性是否增强肿瘤形成。 该系统提供了一个独特的机会，调查在体内的儿童髓母细胞瘤的动物模型，并确定Ptc和Gli在肿瘤发生中的作用。