Targeting Mechanisms of Medulloblastoma Formation

髓母细胞瘤形成的靶向机制

基本信息

批准号：
10179178
负责人：
ERWIN G VAN MEIR
金额：
$ 36.79万
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：
2020
资助国家：
美国
起止时间：
2020-07-01 至 2023-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10179178
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 Pediatric Neoplasm Physiological Predisposition Process Property Radiation therapy Reagent Research Role Secondary to Signal Pathway Signal Transduction Solid Somatic Mutation Survival Rate 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 epigenetic therapy experience gene function histone methyltransferase improved in vivo innovation irradiation malignant breast neoplasm medulloblastoma mouse model nervous system development neuron development neuronal tumor new therapeutic target novel novel therapeutic intervention novel therapeutics overexpression physically handicapped 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.

描述（由申请人提供）：髓母细胞瘤（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，迫切需要开发新的疗法。根据亚型，5 年生存率为 40-90%。此外，儿童会因治疗而出现严重的并发症，包括神经、智力和身体残疾。本项目的总体目的是调查该疾病的作用。脑特异性血管生成抑制剂1（BAI1）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的新疗法。BAI1是一种在脑中特异性表达的孤儿七跨膜G蛋白偶联受体（GPCR）。我们新的初步数据表明，MB 患者中 BAI1 的表达显着降低，并且启动子在表观遗传上被沉默。 BAI1 缺失可能促进 MB 形成。为了在生理环境中测试这一点，我们生成了 Bai1 敲除 (KO) 小鼠，发现 Bai1 单倍体不足会在 Ptch1+/- 转基因小鼠模型中显着加速 MB 肿瘤发生，这是 Bai1 减少的首次证明。可以隐含地促进体内MB形成，我们在出生后早期小脑发育过程中检测到Gli1/2表达增强和外部颗粒层（EGL）增厚。因此，我们的初步研究将 BAI1 与小脑发育和肿瘤转化联系起来，基于这些结果，我们发现 BAI1 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一种新的干预疗法。为了检验我们的假设，我们提出以下目标：(i) 确定 Bai1 缺失是否会通过发育中小脑中生长信号通路的异常激活来加速小鼠 MB 的形成，(ii)确定人类 MB 细胞中 BAI1 的恢复如何抑制其生长并改变其致瘤特性，以及 (iii) 确定 MB 中 BAI1 失活的机制，并确定 BAI1 表达的表观遗传重新激活是否具有体内治疗作用。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，并可能导致为髓母细胞瘤患者开发新的治疗方法。

项目成果

期刊论文数量（5）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

A Chimeric Signal Peptide-Galectin-3 Conjugate Induces Glycosylation-Dependent Cancer Cell-Specific Apoptosis.

嵌合信号肽-Galectin-3 缀合物诱导糖基化依赖性癌细胞特异性细胞凋亡。

DOI：
发表时间：
2020-06-01
期刊：
影响因子：
0
作者：
Lee, Sok;Khwaja Rehman, Fatima;Tyler, Kari C;Yu, Bing;Zhang, Zhaobin;Osuka, Satoru;Zerrouqi, Abdessamad;Kaluzova, Milota;Hadjipanayis, Costas G;Cummings, Richard D;Olson, Jeffrey J;Devi, Narra S;Van Meir, Erwin G
通讯作者：
Van Meir, Erwin G

Generation and initial characterization of mice lacking full-length BAI3 (ADGRB3) expression.

缺乏全长 BAI3 (ADGRB3) 表达的小鼠的生成和初步表征。

DOI：
发表时间：
2023-10
期刊：
影响因子：
3.1
作者：
Shiu, Fu Hung;Wong, Jennifer C;Bhattacharya, Debanjan;Kuranaga, Yuki;Parag, Rashed R;Alsharif, Haifa A;Bhatnagar, Sushant;Van Meir, Erwin G;Escayg, Andrew
通讯作者：
Escayg, Andrew

Correction: EZH2 targeting reduces medulloblastoma growth through epigenetic reactivation of the BAI1/p53 tumor suppressor pathway.

更正：EZH2 靶向通过 BAI1/p53 肿瘤抑制通路的表观遗传重新激活来减少髓母细胞瘤的生长。

DOI：
发表时间：
2020-01
期刊：
影响因子：
8
作者：
Zhang, Hanwen;Zhu, Dan;Zhang, Zhaobin;Kaluz, Stefan;Yu, Bing;Devi, Narra S;Olson, Jeffrey J;Van Meir, Erwin G
通讯作者：
Van Meir, Erwin G

Author Correction: Failure of human rhombic lip differentiation underlies medulloblastoma formation.

作者更正：人类菱形唇分化失败是髓母细胞瘤形成的基础。

DOI：
发表时间：
2022-12
期刊：
影响因子：
64.8
作者：
Hendrikse, Liam D;Haldipur, Parthiv;Saulnier, Olivier;Millman, Jake;Sjoboen, Alexandria H;Erickson, Anders W;Ong, Winnie;Gordon, Victor;Coudière;Mercier, Audrey L;Shokouhian, Mohammad;Suárez, Raúl A;Ly, Michelle;Borlase, St
通讯作者：
Borlase, St

BAI1: from cancer to neurological disease.

BAI1：从癌症到神经系统疾病。