Targeting mechanisms of medulloblastoma formation

髓母细胞瘤形成的靶向机制

• 批准号: 9213395
• 负责人: ERWIN G VAN MEIR
• 金额: $ 38.65万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-07-01 至 2021-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9213395
• 关键词: Abnormal Cell; Adhesions; Angiogenesis Inhibitors; Animal Model; BAI1 gene; BAI2 gene; BAI3 gene; Brain; Cells; Central Nervous System Neoplasms; Cerebellum; Cessation of life; Child; Cytoplasmic Granules; DNA-Binding Proteins; Data; Development; Disease; EZH2 gene; Ensure; Epigenetic Process; Family; Family member; Genes; Glioma; Growth; Histones; Human; Intellectual functioning disability; Knockout Mice; Knowledge; Laboratories; Lead; Link; Lysine; MBD2 protein; Malignant Neoplasms; Malignant neoplasm of brain; Malignant neoplasm of central nervous system; Malignant neoplasm of lung; Malignant neoplasm of ovary; Mediating; Methylation; Molecular; Morbidity - disease rate; Mus; Neoplastic Cell Transformation; Neuraxis; Neurobiology; Neurologic; Operative Surgical Procedures; Orphan; Outcome; Pathway interactions; Patients; Physically Handicapped; Physiological; Predisposition; Process; Property; Radiation therapy; Reagent; Research; Role; Secondary to; Signal Pathway; Signal Transduction; Solid; Somatic Mutation; Survival Rate; Systems Development; TP53 gene; Tertiary Protein Structure; Testing; Therapeutic; Therapeutic Effect; Thick; Time; Transgenic Mice; Tumor Suppression; Tumor Suppressor Proteins; Tumorigenicity; Vertebral column; base; cell growth; chemotherapy; developmental neurobiology; disability; dosage; drug candidate; experience; gene function; histone methyltransferase; improved; in vivo; innovation; irradiation; malignant breast neoplasm; medulloblastoma; mouse model; neuron development; neuronal tumor; new therapeutic target; novel; novel therapeutic intervention; novel therapeutics; overexpression; postnatal; promoter; public health relevance; restoration; seven-transmembrane G-protein-coupled receptor; small molecule; small molecule inhibitor; therapeutic target; tumor; tumor growth; tumorigenesis; tumorigenic

 DESCRIPTION (provided by applicant): There is an urgent need to develop novel therapies for patients with medulloblastoma (MB), the most common malignant central nervous system (CNS) tumor in children. Current treatments include surgery, radiotherapy, and chemotherapy and result in 5-year survival rates of 40-90% depending on subtype. Moreover, children suffer important morbidity secondary to treatment, including neurological, intellectual and physical disabilities. The overall purpose of the present project is to investigate the role of the Brain-specific Angiogenesis Inhibitor 1 (BAI1) in cerebellar development and susceptibility to transformation, and explore new therapies for MB based on the related mechanisms. BAI1 is an orphan seven transmembrane G protein-coupled receptor (GPCR) specifically expressed in the brain, and belonging to the adhesion-type sub-family. Our new preliminary data show that BAI1 expression is significantly reduced in patients with MBs, and the promoter is epigenetically silenced, suggesting that BAI1 loss may facilitate MB formation. To test this in the physiological setting, we generated Bai1 knockout (KO) mice and found haploinsufficiency of Bai1 dramatically accelerates MB tumorigenesis in Ptch1+/- transgenic mouse models of MB, the first demonstration that a reduction in Bai1 dosage can promote MB formation in vivo. Interestingly, we detected enhanced Gli1/2 expression and a thicker external granule layer (EGL) during early postnatal cerebellum development in the Bai1 KO mice. Therefore, our preliminary studies link BAI1 with cerebellar development and neoplastic transformation. Based on these results, we hypothesize that BAI1 is a tumor suppressor in the cerebellum and that restoration of its expression with epigenetic therapy may represent a novel therapeutic intervention for MB. To test our hypothesis, we propose the following aims: (i) determine whether Bai1 loss accelerates MB formation in mice through abnormal activation of a growth-signaling pathway in the developing cerebellum, (ii) determine how BAI1 restoration in human MB cells can inhibit their growth, and alter their tumorigenic properties, and (iii) define the mechanisms of BAI1 inactivation in MB, and determine whether epigenetic reactivation of BAI1 expression has therapeutic effects in vivo. These studies are important as they increase our knowledge about developmental neurobiology in the CNS, and may lead to the development of novel therapeutic approaches for patients with medulloblastoma.

 描述（由申请人提供）：迫切需要为髓母细胞瘤（MB）患者开发新的治疗方法，MB是儿童中最常见的恶性中枢神经系统（CNS）肿瘤。目前的治疗方法包括手术、放疗和化疗，根据亚型的不同，5年生存率为40-90%。此外，儿童因治疗而发病率很高，包括神经、智力和身体残疾。本课题的总体目的是研究脑特异性血管生成抑制因子1（BAI 1）在小脑发育和转化易感性中的作用，并基于相关机制探索MB的新治疗方法。BAI 1是一种在脑内特异性表达的孤儿七跨膜G蛋白偶联受体（GPCR），属于粘附型亚家族。我们的新的初步数据显示，在MB患者中，BAI 1表达显著降低，并且启动子在表观遗传学上沉默，这表明BAI 1缺失可能促进MB形成。为了在生理环境中测试这一点，我们产生了Bai 1敲除（KO）小鼠，并发现Bai 1的单倍不足显著加速了MB的Ptch 1 +/-转基因小鼠模型中的MB肿瘤发生，这首次证明了Bai 1剂量的减少可以促进体内MB的形成。有趣的是，我们检测到增强的Gli 1/2表达和较厚的外部颗粒层（EGL）在出生后早期小脑发育的Bai 1 KO小鼠。因此，我们的初步研究与小脑发育和肿瘤转化的BAI 1。基于这些结果，我们假设BAI 1是小脑中的肿瘤抑制因子，并且通过表观遗传疗法恢复其表达可能代表MB的新的治疗干预。为了验证我们的假设，我们提出以下目标：（i）确定BAI 1丢失是否通过发育中小脑中生长信号传导途径的异常激活而加速小鼠中MB的形成，（ii）确定人MB细胞中BAI 1恢复如何能够抑制其生长并改变其致瘤特性，以及（iii）确定MB中BAI 1失活的机制，并确定BAI 1表达的表观遗传再激活是否具有体内治疗效果。这些研究很重要，因为它们增加了我们对中枢神经系统发育神经生物学的了解，并可能导致髓母细胞瘤患者新的治疗方法的发展。