Control of Medulloblastoma Migration & Survival by Unc5c

控制髓母细胞瘤迁移

• 批准号: 7870605
• 负责人: Robert J. Wechsler-Reya
• 金额: $ 9.1万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-06-01 至 2011-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7870605
• 关键词: Address; Animal Model; Apoptosis; Behavior; Cells; Cerebellum; Child; Dependence; Development; Disease; Event; Family; Genes; Growth; Immigration; Ligands; Light; Malignant Neoplasms; Malignant neoplasm of brain; Molecular; Mutant Strains Mice; Mutate; Neoplasm Metastasis; Nervous system structure; Play; Proteins; Public Health; Reporting; Research Personnel; Role; Signal Transduction; Signaling Molecule; Staging; Surface; Testing; Tumor Suppressor Proteins; cell motility; fighting; granule cell; improved; medulloblastoma; migration; mutant; neoplastic cell; netrin receptor; precursor cell; prevent; programs; rapid growth; receptor; tumor; tumor progression

Medulloblastoma is the most common malignant brain tumor in children. Its rapid growth and tendency to spread through the nervous system make it extremely difficult to treat, and more than 40% of the children who develop the disease die from it. Improved treatment of medulloblastoma is likely to come from a deeper understanding of the signals that control normal cerebellar development, and an appreciation of how these signals are dysregulated in tumors. To identify such signals, we have studied an animal model of medulloblastoma - the patched mutant mouse - and identified genes whose expression is altered in tumor cells compared to granule cell precursors (GCPs), the cells from which the tumor is believed to arise. Among the genes whose expression decreased most significantly was UncSc, which encodes a receptor for the netrin family of signaling molecules. UncSc was originally described as a regulator of cell migration, but has recently been shown to play an important role in apoptosis as well. Moreover, UncSc is deleted or mutated in a variety of cancers, and has therefore been suggested to function as a tumor suppressor. We hypothesize that UncSc controls migration and survival of GCPs during normal cerebellar development, and that its loss contributes to the abnormal migration and increased survival observed in medulloblastoma. If this hypothesis is correct, it will have important implications for our understanding of medulloblastoma, and open up new avenues for treatment of the disease. To test our hypothesis, we propose to: 1) Determine whether UncSc regulates inward migration of granule cell precursors and tumor cells 2) Test whether UncSc regulates survival of granule cell precursors and tumor cells 3) Determine whether loss of UncSc is required for medulloblastoma formation Relevance to Public Health: One of the greatest challenges in medulloblastoma treatment is the ability of tumor cells to migrate into regions where they would not normally go, and to survive once they get there. Our observation of altered UncSc expression in medulloblastoma is significant because it can contribute to both of these behaviors. By elucidating the role of UncSc in migration and survival, our studies will shed light on the molecular mechanisms that underlie the aggressive growth and dissemination of medulloblastoma. This, in turn, will pave the way for developing new treatments that can be used to fight this devastating disease.

髓母细胞瘤是儿童最常见的恶性脑肿瘤。它的快速增长和趋势， 通过神经系统传播，使其非常难以治疗，超过40%的儿童 神经管母细胞瘤治疗的改善可能来自于更深层次的 了解控制正常小脑发育的信号，并了解这些信号是如何产生的。 信号在肿瘤中失调。 为了识别这种信号，我们研究了髓母细胞瘤的动物模型--斑贴突变小鼠 - 并确定了与颗粒细胞前体相比，肿瘤细胞中表达发生改变的基因， （GCP），肿瘤被认为是由其产生的细胞。在表达减少的基因中， 最显著的是UncSc，其编码netrin家族信号分子的受体。UncSc 最初被描述为细胞迁移的调节剂，但最近已被证明在细胞迁移中起重要作用。 在凋亡中的作用。此外，UncSc在多种癌症中被缺失或突变，因此， 被认为是一种肿瘤抑制剂。我们假设UncSc控制着迁移， 在正常小脑发育过程中，GCPs的存活，以及它的丧失导致了异常的 在髓母细胞瘤中观察到迁移和存活增加。如果这个假设是正确的， 这对我们理解髓母细胞瘤具有重要意义，并为治疗髓母细胞瘤开辟了新途径。 这种疾病为了验证我们的假设，我们建议： 1)确定UncSc是否调节颗粒细胞前体和肿瘤细胞的向内迁移 2)测试UncSc是否调节颗粒细胞前体和肿瘤细胞的存活 3)确定髓母细胞瘤形成是否需要UncSc的缺失 与公共卫生的相关性： 髓母细胞瘤治疗中的最大挑战之一是肿瘤细胞迁移到肿瘤细胞中的能力。 他们通常不会去的地方，一旦他们到达那里就能生存。我们观察到 髓母细胞瘤中UncSc的表达是重要的，因为它可以促进这两种行为。通过 阐明UncSc在迁移和生存中的作用，我们的研究将阐明UncSc的分子机制。 神经管母细胞瘤侵袭性生长和扩散的机制。反过来，这将 为开发可用于对抗这种毁灭性疾病的新疗法铺平道路。