Sonic hedgehog:Insulin-Like Growth Factor Interactions in Proliferating Neural Pr

描述(申请人提供)：髓母细胞瘤是最常见的儿童实体恶性肿瘤。这些肿瘤发生在幼儿身上，是由于小脑中的祖细胞分裂而产生的，小脑是出生后发育的大脑区域。目前的髓母细胞瘤手术、颅脑脊髓放射治疗和化疗给幸存者留下了终生的、毁灭性的副作用，包括运动和认知障碍、癫痫发作、精神问题以及因辐射而患上其他肿瘤的风险。这些影响可以归因于治疗方法无法优先针对肿瘤细胞，而不是大脑的其他部分。由于缺乏对引起肿瘤的分子事件和促进肿瘤起始和生长的细胞生物学事件的了解，更具肿瘤细胞特异性的新的髓母细胞瘤治疗方法的开发一直受到阻碍。更深入地了解基因和蛋白质如何调控小脑祖细胞的增殖，以及它们的异常调控如何促进肿瘤的发生，将确定新疗法的靶点，这些疗法可以在不损害仍在发育中的大脑的情况下专门影响肿瘤的生长。在人类和小鼠模型中，调节小脑祖细胞分裂的信号转导通路与髓母细胞瘤有关。分泌配体Sonic hedgehog(Shh)和胰岛素样生长因子(IGF)激活的通路对小脑孕激素细胞的增殖尤为重要，在髓母细胞瘤中它们的活性增加。小鼠小脑祖细胞的原代培养具有与人类髓母细胞瘤相似的遗传特征，它们依赖Shh和IGF信号进行增殖。在培养中，这些细胞的分裂和分化与体内的情况大致相同，这表明它们对于研究信号通路如何在正常脑发育期间和髓母细胞瘤中调节增殖是有用的。在“Sonic hedgehog：胰岛素样生长因子在增殖神经前体中的合作”提案中描述的研究重点是描述这些通路如何汇聚到一个共同的靶点，即胰岛素受体底物1(IRS1)，以最终调控mRNAs到蛋白质的翻译，这是发育和癌症中细胞周期进展的关键过程。这些研究使用原代小脑祖细胞培养和对野生型和IRS1缺失小鼠的分析，以探讨Shh如何调控IRS1，IRS1在发育中的小脑如何发挥作用，以及IRS1下游效应因子mRNA翻译途径组件eIF4E如何调节小脑前体细胞的新蛋白质合成。这些研究的长期目标是确定调节Shh和IGF下游效应物(如IRS1和eIF4E)的功能如何成为治疗髓母细胞瘤和其他可手术途径的癌症的有效治疗方法，如皮肤、前列腺和成人脑肿瘤。髓母细胞瘤是最常见的儿童实体肿瘤，发生于儿童发育中的大脑。目前，这些肿瘤的治疗方法包括手术、放疗和化疗。由于这些治疗方法对仍在发育中的大脑造成的损害，幸存者遭受了毁灭性的终身副作用。这项发表在《Sonic Hedgehog：胰岛素样生长因子在神经前体细胞增殖中的合作》(Sonic Hedgehog：Insulin-Like Growth For Collaboration in Producing Nerical Prepreors)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髓母细胞瘤的形成和生长，以及这些分子是否为对患者伤害较小的未来治疗的潜在靶点。

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.