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Evaluating ADGRB3 as a tumor suppressor epigenetically silenced in WNT medulloblastoma

评估 ADGRB3 作为 WNT 髓母细胞瘤中表观遗传沉默的肿瘤抑制因子

基本信息

批准号：
10599504
负责人：
ERWIN G VAN MEIR
金额：
$ 2.6万
依托单位：
UNIVERSITY OF ALABAMA AT BIRMINGHAM
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-09-01 至 2025-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10599504
关键词：
Adhesions Animals Binding Proteins Brain Brain Stem CTNNB1 gene Cell Culture Techniques Cell Proliferation Cell model Cells Cerebellum Child Chromatin Data Development Development Plans Dorsal EZH2 gene Epigenetic Process Experimental Models Family Funding Gene Activation Gene Expression Gene Silencing Human Intellectual functioning disability Knockout Mice Knowledge Lead Lip structure MBD2 protein Malignant Neoplasms Malignant neoplasm of central nervous system Mentors Morbidity - disease rate Mus Neuraxis Neurologic Oncogenic Operative Surgical Procedures Orphan Patients Pediatric Neoplasm Physiological Predisposition Property Public Health Radiation therapy Repression Research Role Secondary to Signal Transduction Survival Rate Testing Therapeutic Tumor Suppressor Proteins anti-cancer therapeutic base beta catenin career development cell growth chemotherapy developmental neurobiology epigenetic silencing epigenetic therapy histone methyltransferase medulloblastoma mutant nerve stem cell novel novel therapeutic intervention novel therapeutics parent grant physically handicapped promoter receptor restoration seven-transmembrane G-protein-coupled receptor tumor tumor growth tumorigenic

项目摘要

RESEARCH, MENTORING, AND CAREER DEVELOPMENT PLAN: RESEARCH PLAN: Project Summary/Abstract of Funded Parent Grant: 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. However, 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 ADGRB3 receptor in susceptibility of cerebellar transformation, and explore new therapies for MB based on the related mechanisms. ADGRB3 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 ADGRB3 expression is significantly reduced in patients with MBs of the WNT group, and the promoter is epigenetically silenced, suggesting that ADGRB3 loss may facilitate WNT-MB formation. We present evidence for the involvement of methylated CpG binding protein MBD2 and histone methyltransferase EZH2 in switch to a silent chromatin. Moreover, we show that reactivation of ADGRB3 can reduce cell proliferation and tumor growth, supporting a tumor suppressive role. To test this in the physiological setting, we generated ADGRB3 knockout (KO) mice, which we plan to cross with mice expressing mutant b-catenin in neural progenitors of the rhombic lip and dorsal brainstem, which are the cells of origin of WNT-MB. Based on these results, we hypothesize that ADGRB3 is a tumor suppressor in the cerebellum and that restoration of its expression with epigenetic therapy may represent a novel therapeutic intervention for children with WNT-MB. To test our hypothesis, we propose the following aims: (i) identify and target the epigenetic mechanism(s) underlying ADGRB3 gene silencing in WNT-MB, (ii) determine whether and how restoration of ADGRB3 expression can inhibit MB cell growth, oncogenic signaling and tumorigenic properties, and (iii) determine whether loss of ADGRB3 gene expression in the background of oncogenic Ctnnb1 activation predisposes mice to cerebellar transformation and MB tumor development. 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.

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