Hedgehog:YAP:IGF2/mTOR axis in cerebellar precursor division and medulloblastoma

描述（由申请方提供）：髓母细胞瘤是最常见的儿科实体恶性肿瘤。这些肿瘤发生在幼儿中，来自小脑中的分裂祖细胞，小脑是出生后发育的大脑区域。目前的髓母细胞瘤手术治疗，颅脊髓放射治疗和化疗给幸存者留下了终身的，毁灭性的副作用，包括运动和认知障碍，癫痫发作，精神问题和其他肿瘤的风险。这些效应可以归因于治疗不能优先靶向肿瘤细胞而不影响大脑的其余部分。由于缺乏对引起肿瘤的分子事件和促进其启动和生长的细胞生物学事件的理解，开发更具肿瘤细胞特异性的新髓母细胞瘤疗法受到阻碍。更深入地了解基因和蛋白质如何调节小脑祖细胞的增殖，以及它们的失调如何促进肿瘤发生，将确定新疗法的靶点，这些疗法可以特异性地影响肿瘤生长，而不会损害仍在发育的大脑。调节小脑祖细胞分裂的信号转导途径与人类和小鼠模型中的髓母细胞瘤有关。由分泌的配体Sonic hedgehog（Shh）和胰岛素样生长因子（IGF）激活的途径对小脑祖细胞增殖特别重要，并且它们的活性在髓母细胞瘤中增加。增殖的小鼠小脑祖细胞的原代培养物具有与人类髓母细胞瘤相似的遗传特征，并且它们依赖于Shh和IGF信号传导进行增殖。在培养中，这些细胞的分裂和分化与体内一样，这表明它们可用于研究信号通路如何在正常脑发育和髓母细胞瘤中调节增殖。在提案“Sonic hedgehog：Insulin-like growth factor cooperation in proliferating neural precursor”中描述的研究重点在于表征这些途径如何汇聚在一个共同的靶点上，胰岛素受体底物1（IRS 1），以最终调节mRNA翻译成蛋白质，这是发育和癌症期间细胞周期进展的一个重要过程。这些研究使用原代小脑祖细胞培养物和野生型和IRS 1缺失小鼠的分析来研究Shh如何调节IRS 1，IRS 1如何在发育中的小脑中发挥作用，以及IRS 1的下游效应子mRNA翻译途径组分eIF 4 E如何调节小脑祖细胞中的新蛋白质合成。这些研究的长期目标是确定如何调节Shh和IGF下游效应物如IRS 1和eIF 4 E的功能可能是治疗成神经管细胞瘤和其他癌症的有用治疗方法，其中这些途径是可操作的，如皮肤、前列腺和成人脑肿瘤。这些肿瘤目前用手术、放疗和化疗来治疗。由于这些治疗对仍在发育的大脑造成的损害，幸存者遭受毁灭性的终身副作用。在“Sonic hedgehog：Insulin-like growth factor cooperation in proliferating neural precursor”中提出的研究将阐明调节未成熟神经元细胞分裂的分子如何促进成神经管细胞瘤的形成和生长，以及这些分子是否是未来治疗的潜在靶点，对患者的危害较小。

DESCRIPTION (provided by applicant): Medulloblastomas are the most common solid pediatric malignant tumors. These tumors arise in young children from dividing progenitor cells in the cerebellum, a brain region which develops after birth. The current treatments for medulloblastoma surgery, cranio-spinal radiation, and chemotherapy leave survivors with life-long, devastating side effects, including movement and cognitive disorders, seizures, psychiatric problems, and risk of other tumors due to radiation. These effects can be attributed to the inability of the treatments to preferentially target the tumor cells and spare the rest of the brain. Development of new medulloblastoma therapies that are more tumor-cell specific has been hampered by a lack of understanding of the molecular events causing the tumors and the cell biological events that promote their initiation and growth. Greater insight into how genes and proteins regulate proliferation in cerebellar progenitor cells, and how their dys-regulation contributes to tumorigenesis, will identify targets for new therapies that can specifically affect tumor growth without damaging the still-developing brain. Signal transduction pathways that regulate cerebellar progenitor cell division have been associated with medulloblastomas in humans and in mouse models. The pathways activated by the secreted ligands Sonic hedgehog (Shh) and insulin-like growth factor (IGF) are particularly important for cerebellar progentior cell proliferation, and their activity is increased in medulloblastomas. Primary cultures of proliferating mouse cerebellar progenitor cells have genetic profiles similar to those of human medulloblastomas, and they depend on Shh and IGF signaling for proliferation. In culture, these cells divide and differentiate much as they do in vivo, indicating that they are useful for studying how signaling pathways regulate proliferation during normal brain development and in medulloblastomas. The studies described in the proposal "Sonic hedgehog:Insulin-like growth factor cooperation in proliferating neural precursors" focus on characterizing how these pathways converge on a common target, insulin receptor substrate 1 (IRS1), to ultimately regulate translation of mRNAs into protein, an essential process for cell cycle progression during development and in cancer. These studies use primary cerebellar progenitor cultures and analysis of wild-type and IRS1-null mice to investigate how Shh regulates IRS1, how IRS1 functions in the developing cerebellum, and how the mRNA translation pathway component eIF4E, a downstream effector of IRS1, regulates new protein synthesis in cerebellar progenitors. The long- term goal of these studies is to determine how modulating the function of Shh and IGF downstream effectors such as IRS1 and eIF4E might be a useful therapeutic approach to treat medulloblastomas and other cancers where these pathways are operative, such as skin, prostate, and adult brain tumors.Medulloblastomas, the most common solid pediatric tumor, arise in the developing brain of young children. These tumors are currently treated with surgery radiation, and chemotherapy. Survivors suffer devastating life-long side effects due to the damage these treatments do to the still-developing brain. The studies proposed in 'Sonic hedgehog:Insulin-like growth factor cooperation in proliferating neural precursors' will shed light on how molecules that regulate cell division in immature neurons contribute to medulloblastoma formation and growth, and whether those molecules are potential targets for future treatments that will be less harmful to patients.