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Targeting mechanisms of medulloblastoma formation

髓母细胞瘤形成的靶向机制

基本信息

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
项目类别：
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

项目摘要

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.