A Role for RIP1 in Gliomagenesis
A Role for RIP1 in Gliomagenesis
批准号:
8308027
负责人:
AMYN HABIB
金额:
$30.77万
依托单位国家:
美国
项目类别:
财政年份:
2009
资助国家:
美国
项目状态:
已结题
起止时间:
2009-09-29 至 2014-07-31
关键词:
AdultAlkylating AgentsAnimal ModelApoptosisBenchmarkingBiologicalBiologyCellsCouplingDNA DamageDeath DomainFeedbackGlioblastomaGliomaGliomagenesisGoalsGrowthInflammationInflammatoryLaboratoriesLeadLinkMalignant GliomaMalignant NeoplasmsMalignant neoplasm of brainMediatingMolecularOncogenicPTEN genePathogenesisPathway interactionsPatientsPhosphotransferasesPlayPositioning AttributeProtein p53ProteinsRegulationResistanceRoleSignal PathwaySignal TransductionSirolimusStimulusTSC1/2 geneTumor Suppressor ProteinsWorkanticancer researchchemotherapyclinical efficacydesigneffective therapyhuman FRAP1 proteinhuman RIPK1 proteinimprovedin vivo Modelinhibitor/antagonistinsightmTOR inhibitionmalignant phenotypemouse modelneoplastic celloutcome forecastoverexpressionprognostic indicatorresponsetherapy designtreatment strategy
中文摘要
识别分子改变和信号异常启动和
保持胶质母细胞瘤(GBM)的恶性表型是设计
治疗。在GBM中,NF-B和PI3K-Akt通路被解除调控,并可能发挥作用
在GBM的发病机制和耐药中起关键作用。核因子-B的激活是
发炎的标志。在这项提案中,我们的目标是描述死亡的角色
RIP,RIP1,在基底膜生物学中。
RIP1可同时激活胶质瘤细胞中的核因子-B和PI3K-Akt信号通路。此外,RIP1
负调控两个关键的肿瘤抑制信号网络,PTEN和
P53通路。RIP1水平在高达30%的GBM中升高,但在II-III级中不会
神经胶质瘤。此外,RIP1的表达使GBM的预后更差。
RIP1过表达诱导胶质瘤细胞增殖及沉默抑制
胶质瘤动物模型中胶质瘤细胞的增殖。这一点的中心假设是
有观点认为,RIP1在GBM的发病机制中起着关键作用,并对
通过调节肿瘤细胞中的关键信号通路进行治疗。这样做的总体目标是
建议通过实验证明RIP1促进恶性表型
是GBM的。在具体目标1中,我们将探索耦合RIP1的机制关系
对胶质瘤细胞增殖的影响及RIP1特异性效应机制的研究
影响胶质瘤细胞的增殖和对化疗的耐药性。以特定的目标
2,我们将确定RIP1介导的机制和生物学意义
抑制肿瘤抑制信号。在具体目标3中,我们将对效果进行基准测试
利用原位动物模型研究RIP1在胶质瘤细胞中的表达。这项研究可能
为炎症在GBM中的作用提供有用的见解,并有助于设计
更有效的针对基底膜炎症信号通路的治疗。
英文摘要
Identification of molecular alterations and signaling abnormalities that initiate and
maintain the malignant phenotype in glioblastoma (GBM) is a key step in designing
treatment. The NF-¿B and PI3K-Akt pathways are deregulated in GBM and likely to play
key roles in the pathogenesis of GBM and in resistance to treatment. NF-¿B activation is
a hallmark of inflammation. In this proposal, we aim to characterize the role of the death
domain containing kinase receptor interacting protein (RIP, RIP1), in the biology of GBM.
RIP1 activates both the NF-¿B and PI3K-Akt pathways in glioma cells. In addition, RIP1
negatively regulates two key tumor suppressor signaling networks, the PTEN and the
p53 pathways. RIP1 levels are increased in up to 30% of GBMs but not in Grade II-III
gliomas. Furthermore, RIP1 expression confers a worse prognosis in GBM,
overexpressing RIP1 induces proliferation of glioma cells and silencing RIP1 inhibits
proliferation of glioma cells in an animal model of glioma. The central hypothesis of this
proposal is that RIP1 plays a key role in the pathogenesis of GBM and resistance to
treatment by regulating key signaling pathways in tumor cells. The broad goal of this
proposal is to demonstrate experimentally that RIP1 promotes the malignant phenotype
of GBM. In Specific Aim 1, we will explore the mechanistic relationships coupling RIP1
to the proliferation of glioma cells and identify RIP1 specific effector mechanisms
influencing proliferation and resistance to chemotherapy in glioma cells. In Specific Aim
2, we will determine the mechanisms and biological significance of RIP1 mediated
inhibition of tumor suppressor signaling. In Specific Aim 3 we will benchmark the effect
of RIP1 expression in glioma cells using an orthotopic animal model. This study may
provide useful insights into the role of inflammation in GBM and help in the design of
more effective treatments targeting inflammatory signaling pathways in GBM.
期刊论文(2)
专著(0)
科研奖励(0)
会议论文
Analysis of Constitutive EGFR Signaling Regulating IRF3 Transcriptional Activity in Cancer Cells.
癌细胞中调节 IRF3 转录活性的组成型 EGFR 信号转导分析。
DOI:
10.1007/978-1-4939-7219-7_14
发表时间:
2017
期刊:
Methods in molecular biology (Clifton, N.J.)
影响因子:
--
作者:
[Guo,Gao, Gong,Ke, Habib,AmynA]
通讯作者:
Habib,AmynA
Bimodal EGFR signaling in glioblastoma
-
批准号:10363582
-
项目类别:
-
资助金额:$42.99万
-
财政年份:2022
-
负责人:AMYN HABIB
-
依托单位:
Bimodal EGFR signaling in glioblastoma
-
批准号:10544555
-
项目类别:
-
资助金额:$41.39万
-
财政年份:2022
-
负责人:AMYN HABIB
-
依托单位:
The role of Nrf2 in mediating resistance to EGFR inhibition in glioblastoma
-
批准号:10404075
-
项目类别:
-
资助金额:$36.76万
-
财政年份:2020
-
负责人:AMYN HABIB
-
依托单位:
The role of Nrf2 in mediating resistance to EGFR inhibition in glioblastoma
-
批准号:10615766
-
项目类别:
-
资助金额:$36.76万
-
财政年份:2020
-
负责人:AMYN HABIB
-
依托单位:
Interactions between inflammatory and oncogenic signaling pathways in GBM
-
批准号:8735239
-
项目类别:
-
资助金额:$0.0万
-
财政年份:2014
-
负责人:AMYN HABIB
-
依托单位:
Interactions between inflammatory and oncogenic signaling pathways in GBM
-
批准号:10266003
-
项目类别:
-
资助金额:$0.0万
-
财政年份:2014
-
负责人:AMYN HABIB
-
依托单位:
Interactions between inflammatory and oncogenic signaling pathways in GBM
-
批准号:9339563
-
项目类别:
-
资助金额:$0.0万
-
财政年份:2014
-
负责人:AMYN HABIB
-
依托单位:
A Role for RIP1 in Gliomagenesis
-
批准号:8147853
-
项目类别:
-
资助金额:$30.77万
-
财政年份:2009
-
负责人:AMYN HABIB
-
依托单位:
A Role for RIP1 in Gliomagenesis
-
批准号:7785369
-
项目类别:
-
资助金额:$31.4万
-
财政年份:2009
-
负责人:AMYN HABIB
-
依托单位:
EGFR MEDIATED APOPTOSIS IN GLIOMAS
-
批准号:6633249
-
项目类别:
-
资助金额:$6.2万
-
财政年份:1999
-
负责人:AMYN HABIB
-
依托单位:
EGFR MEDIATED APOPTOSIS IN GLIOMAS
-
批准号:2843476
-
项目类别:
-
资助金额:$13.2万
-
财政年份:1999
-
负责人:AMYN HABIB
-
依托单位:
EGFR MEDIATED APOPTOSIS IN GLIOMAS
-
批准号:6513157
-
项目类别:
-
资助金额:$13.2万
-
财政年份:1999
-
负责人:AMYN HABIB
-
依托单位:
EGFR MEDIATED APOPTOSIS IN GLIOMAS
-
批准号:6844036
-
项目类别:
-
资助金额:$7.01万
-
财政年份:1999
-
负责人:AMYN HABIB
-
依托单位:
EGFR MEDIATED APOPTOSIS IN GLIOMAS
-
批准号:6174075
-
项目类别:
-
资助金额:$13.2万
-
财政年份:1999
-
负责人:AMYN HABIB
-
依托单位:
EGFR MEDIATED APOPTOSIS IN GLIOMAS
-
批准号:6377189
-
项目类别:
-
资助金额:$13.2万
-
财政年份:1999
-
负责人:AMYN HABIB
-
依托单位:
海外基金