Leukotriene-Induced Nestin Expression Promotes Medulloblastoma Tumorigenesis

白三烯诱导的巢蛋白表达促进髓母细胞瘤肿瘤发生

• 批准号: 8989976
• 负责人: Zeng-Jie Yang
• 金额: $ 37.04万
• 依托单位: RESEARCH INST OF FOX CHASE CAN CTR
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-01-01 至 2018-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8989976
• 关键词: Adverse effects; Affect; Arachidonate 5-Lipoxygenase; Cell Proliferation; Cells; Child; Cognitive deficits; Cytoplasmic Granules; Cytoskeletal Proteins; Data; Development; Disease; Endocrine; Endocrine System Diseases; Gene Targeting; Goals; Health; Human; Impairment; In Vitro; Inflammation Mediators; Length; Leukotriene Antagonists; Leukotrienes; Lipids; Malignant neoplasm of brain; Mediating; Modeling; Molecular; Morbidity - disease rate; Mus; Nervous system structure; Neurons; Operative Surgical Procedures; PPAR gamma; Patients; Penetrance; Peroxisome Proliferator-Activated Receptors; Phosphorylation; Play; Process; Proteins; Radiation therapy; Regulation; Reporting; Repression; Research Personnel; Role; SHH gene; Sonic Hedgehog Pathway; Survivors; Testing; Therapeutic; Zinc Fingers; base; chemotherapy; clinically significant; hedgehog signal transduction; improved; inhibitor/antagonist; lipid mediator; medulloblastoma; neoplastic cell; nestin protein; prevent; rapid growth; small hairpin RNA; smoothened signaling pathway; targeted treatment; tumor progression; tumorigenesis

DESCRIPTION (provided by applicant): Medulloblastoma (MB) is the most common malignant brain tumor in children. Its rapid growth and tendency to spread through the nervous system necessitate the use of extreme aggressive and toxic therapies. Even with such therapies, a significant proportion of patients die from this disease, and survivors often suffer severe long-term side effects such as cognitive deficits and endocrine disorders. Improved strategies for treating MB are urgently needed. The goal of this study is to explore the targeted therapeutic approaches for MB. Preliminary studies suggest that a cytoskeletal protein, Nestin is essential for MB cell proliferation. In this proposal, investigators will further determine the mechanisms for Nestin in promoting MB development. In addition, recent studies have revealed that leukotriene, a lipid mediator, is required for Nestin expression in tumor cells and inhibitionof leukotriene synthesis significantly prevents tumor cell proliferation. This study therefore proposes to examine the therapeutic potentials of leukotriene inhibitors in treating MBs in mice. These studies would significantly deepen our understanding of the molecular basis for MB development, and pave the road for the application of leukotriene inhibitors in treating human MB.

描述（由申请人提供）：髓母细胞瘤（MB）是儿童中最常见的恶性脑肿瘤。它的快速生长和通过神经系统传播的趋势需要使用极端的侵略性和有毒疗法。即使使用这种疗法，大部分患者死于这种疾病，幸存者经常遭受严重的长期副作用，例如认知缺陷和内分泌疾病。迫切需要改善治疗MB的策略。这项研究的目的是探索针对MB的靶向治疗方法。初步研究表明，Nestin的细胞骨架蛋白对于MB细胞增殖至关重要。在该提案中，研究人员将进一步确定Nestin在促进MB开发方面的机制。此外，最近的研究表明，脂质介质在肿瘤细胞中表达和抑制白三烯合成需要明显阻止肿瘤细胞增殖所必需的白细胞介质。因此，这项研究建议检查白细胞抑制剂在治疗小鼠中的MBS的治疗潜力。这些研究将大大加深我们对MB发育的分子基础的理解，并为白细胞抑制剂在治疗人MB中的应用铺平道路。