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

Hedgehog:YAP:IGF2/mTOR 轴在小脑前体分裂和髓母细胞瘤中的作用

• 批准号: 8656459
• 负责人: Anna Marie Kenney
• 金额: $ 24.77万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-30 至 2017-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8656459
• 关键词: Hedgehog; YAP; IGF2; mTOR; axis

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.

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。这些肿瘤在幼儿中由小脑的祖细胞分裂产生，小脑是出生后发育的大脑区域。目前治疗成神经管细胞瘤的手术、颅脊髓放射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、精神问题以及因放射引起的其他肿瘤的风险。这些影响可以归因于治疗无法优先针对肿瘤细胞而不影响大脑的其余部分。由于缺乏对导致肿瘤的分子事件和促进其发生和生长的细胞生物学事件的理解，新的髓母细胞瘤治疗方法的发展受到了阻碍，这些治疗方法更具肿瘤细胞特异性。更深入地了解基因和蛋白质如何调节小脑祖细胞的增殖，以及它们的调节失调如何促进肿瘤发生，将确定新疗法的目标，这些新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。在人和小鼠模型中，调节小脑祖细胞分裂的信号转导通路与成神经管细胞瘤有关。由分泌配体Sonic hedgehog （Shh）和胰岛素样生长因子（IGF）激活的通路对小脑祖细胞增殖特别重要，并且它们的活性在成神经管细胞瘤中增加。增殖小鼠小脑祖细胞的原代培养具有与人类成神经管细胞瘤相似的遗传特征，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在体内一样多，这表明它们对于研究正常大脑发育和成神经管细胞瘤期间信号通路如何调节增殖是有用的。“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表征这些途径如何聚集在一个共同的靶标胰岛素受体底物1 （IRS1）上，最终调节mrna转化为蛋白质，这是发育和癌症中细胞周期进展的重要过程。这些研究使用初级小脑祖细胞培养和野生型和IRS1缺失小鼠的分析来研究Shh如何调节IRS1， IRS1如何在发育中的小脑中发挥作用，以及mRNA翻译途径组分eIF4E （IRS1的下游效应物）如何调节小脑祖细胞中新蛋白的合成。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IRS1和eIF4E）的功能，可能是治疗成神经管细胞瘤和其他这些途径有效的癌症（如皮肤、前列腺和成人脑肿瘤）的有用治疗方法。髓母细胞瘤是最常见的儿童实体肿瘤，发生于幼儿发育中的大脑。目前这些肿瘤的治疗方法有手术、放疗和化疗。由于这些治疗对仍在发育的大脑造成的损害，幸存者遭受了毁灭性的终身副作用。在《Sonic hedgehog：胰岛素样生长因子在增殖神经前体中的合作》（Sonic hedgehog:Insulin-like growth factor cooperation in prolifesneuroprecursor）中提出的研究将揭示未成熟神经元中调节细胞分裂的分子如何促进成神经管细胞瘤的形成和生长，以及这些分子是否可能成为未来治疗的潜在目标，从而减少对患者的伤害。