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:
- 金额:$ 2.6万
- 依托单位:
- 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:
- 关键词:AdhesionsAnimalsBinding ProteinsBrainBrain StemCTNNB1 geneCell Culture TechniquesCell ProliferationCell modelCellsCerebellumChildChromatinDataDevelopmentDevelopment PlansDorsalEZH2 geneEpigenetic ProcessExperimental ModelsFamilyFundingGene ActivationGene ExpressionGene SilencingHumanIntellectual functioning disabilityKnockout MiceKnowledgeLeadLip structureMBD2 proteinMalignant NeoplasmsMalignant neoplasm of central nervous systemMentorsMorbidity - disease rateMusNeuraxisNeurologicOncogenicOperative Surgical ProceduresOrphanPatientsPediatric NeoplasmPhysiologicalPredispositionPropertyPublic HealthRadiation therapyRepressionResearchRoleSecondary toSignal TransductionSurvival RateTestingTherapeuticTumor Suppressor Proteinsanti-cancer therapeuticbasebeta catenincareer developmentcell growthchemotherapydevelopmental neurobiologyepigenetic silencingepigenetic therapyhistone methyltransferasemedulloblastomamutantnerve stem cellnovelnovel therapeutic interventionnovel therapeuticsparent grantphysically handicappedpromoterreceptorrestorationseven-transmembrane G-protein-coupled receptortumortumor growthtumorigenic
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.
研究、辅导和职业发展课程:
研究报告:
项目摘要/资助家长补助金摘要:
目前迫切需要为髓母细胞瘤(MB)患者开发新的治疗方法,
儿童中枢神经系统恶性肿瘤目前的治疗方法包括手术、放疗、
和化疗,根据亚型,5年生存率为40-90%。然而,
严重的继发于治疗的疾病,包括神经、智力和身体残疾。的
本项目的总体目的是研究ADGRB 3受体在以下疾病易感性中的作用:
小脑转化,并根据相关机制探索MB的新疗法。ADGRB 3是一种
孤儿七跨膜G蛋白偶联受体(GPCR),在脑中特异性表达,和
属于粘附型亚家族。我们的新的初步数据表明,ADGRB 3表达是
在WNT组的MB患者中显著降低,并且启动子在表观遗传学上沉默,
这表明ADGRB 3损失可能促进WNT-MB形成。我们提供的证据表明
甲基化的CpG结合蛋白MBD 2和组蛋白甲基转移酶EZH 2转变为沉默的染色质。
此外,我们发现ADGRB 3的重新激活可以减少细胞增殖和肿瘤生长,支持了对肿瘤的治疗。
肿瘤抑制作用。为了在生理环境中测试这一点,我们产生了ADGRB 3敲除(KO)小鼠,
我们计划将其与在菱形唇和背侧的神经祖细胞中表达突变的b-连环蛋白的小鼠杂交,
脑干,其是WNT-MB的起源细胞。基于这些结果,我们假设ADGRB 3是一种
小脑中的肿瘤抑制因子,通过表观遗传治疗恢复其表达可能代表
一种治疗WNT-MB儿童的新型干预措施。为了验证我们的假设,我们提出以下建议
目的:(i)鉴定和靶向WNT-MB中ADGRB 3基因沉默的表观遗传机制,(ii)
确定ADGRB 3表达的恢复是否以及如何抑制MB细胞生长、致癌信号传导
和致瘤特性,以及(iii)确定在肿瘤背景下ADGRB 3基因表达的丧失是否
致癌Ctnnb 1激活使小鼠容易发生小脑转化和MB肿瘤发展。这些
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,
从而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(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
数据更新时间:{{ journalArticles.updateTime }}
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
ERWIN G VAN MEIR其他文献
ERWIN G VAN MEIR的其他文献
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
{{ truncateString('ERWIN G VAN MEIR', 18)}}的其他基金
Mechanisms underlying BAI1/ADGRB1 negative regulation of glioblastoma mesenchymal transition and invasion.
BAI1/ADGRB1 胶质母细胞瘤间质转化和侵袭负调控的机制。
- 批准号:
10034438 - 财政年份:2021
- 资助金额:
$ 2.6万 - 项目类别:
Mechanisms underlying BAI1/ADGRB1 negative regulation of glioblastoma mesenchymal transition and invasion.
BAI1/ADGRB1 胶质母细胞瘤间质转化和侵袭负调控的机制。
- 批准号:
10687227 - 财政年份:2021
- 资助金额:
$ 2.6万 - 项目类别:
Mechanisms underlying BAI1/ADGRB1 negative regulation of glioblastoma mesenchymal transition and invasion.
BAI1/ADGRB1 胶质母细胞瘤间质转化和侵袭负调控的机制。
- 批准号:
10488569 - 财政年份:2021
- 资助金额:
$ 2.6万 - 项目类别:
Targeting Mechanisms of Medulloblastoma Formation
髓母细胞瘤形成的靶向机制
- 批准号:
10179178 - 财政年份:2020
- 资助金额:
$ 2.6万 - 项目类别:
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
- 批准号:
9965891 - 财政年份:2019
- 资助金额:
$ 2.6万 - 项目类别:
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
- 批准号:
10358481 - 财政年份:2019
- 资助金额:
$ 2.6万 - 项目类别:
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
- 批准号:
10057681 - 财政年份:2019
- 资助金额:
$ 2.6万 - 项目类别:
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
- 批准号:
10583473 - 财政年份:2019
- 资助金额:
$ 2.6万 - 项目类别:
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
- 批准号:
10738336 - 财政年份:2019
- 资助金额:
$ 2.6万 - 项目类别:
相似海外基金
The earliest exploration of land by animals: from trace fossils to numerical analyses
动物对陆地的最早探索:从痕迹化石到数值分析
- 批准号:
EP/Z000920/1 - 财政年份:2025
- 资助金额:
$ 2.6万 - 项目类别:
Fellowship
Animals and geopolitics in South Asian borderlands
南亚边境地区的动物和地缘政治
- 批准号:
FT230100276 - 财政年份:2024
- 资助金额:
$ 2.6万 - 项目类别:
ARC Future Fellowships
The function of the RNA methylome in animals
RNA甲基化组在动物中的功能
- 批准号:
MR/X024261/1 - 财政年份:2024
- 资助金额:
$ 2.6万 - 项目类别:
Fellowship
Ecological and phylogenomic insights into infectious diseases in animals
对动物传染病的生态学和系统发育学见解
- 批准号:
DE240100388 - 财政年份:2024
- 资助金额:
$ 2.6万 - 项目类别:
Discovery Early Career Researcher Award
Zootropolis: Multi-species archaeological, ecological and historical approaches to animals in Medieval urban Scotland
Zootropolis:苏格兰中世纪城市动物的多物种考古、生态和历史方法
- 批准号:
2889694 - 财政年份:2023
- 资助金额:
$ 2.6万 - 项目类别:
Studentship
Using novel modelling approaches to investigate the evolution of symmetry in early animals.
使用新颖的建模方法来研究早期动物的对称性进化。
- 批准号:
2842926 - 财政年份:2023
- 资助金额:
$ 2.6万 - 项目类别:
Studentship
Study of human late fetal lung tissue and 3D in vitro organoids to replace and reduce animals in lung developmental research
研究人类晚期胎儿肺组织和 3D 体外类器官在肺发育研究中替代和减少动物
- 批准号:
NC/X001644/1 - 财政年份:2023
- 资助金额:
$ 2.6万 - 项目类别:
Training Grant
RUI: Unilateral Lasing in Underwater Animals
RUI:水下动物的单侧激光攻击
- 批准号:
2337595 - 财政年份:2023
- 资助金额:
$ 2.6万 - 项目类别:
Continuing Grant
RUI:OSIB:The effects of high disease risk on uninfected animals
RUI:OSIB:高疾病风险对未感染动物的影响
- 批准号:
2232190 - 财政年份:2023
- 资助金额:
$ 2.6万 - 项目类别:
Continuing Grant
A method for identifying taxonomy of plants and animals in metagenomic samples
一种识别宏基因组样本中植物和动物分类的方法
- 批准号:
23K17514 - 财政年份:2023
- 资助金额:
$ 2.6万 - 项目类别:
Grant-in-Aid for Challenging Research (Exploratory)