Role of DDX3 in DR5-Mediated Apoptosis
DDX3 在 DR5 介导的细胞凋亡中的作用
基本信息
- 批准号:7908430
- 负责人:
- 金额:$ 20.49万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2006
- 资助国家:美国
- 起止时间:2006-08-01 至 2011-07-31
- 项目状态:已结题
- 来源:
- 关键词:Adaptor Signaling ProteinAddressAnimal ModelAntibodiesApoptosisBindingBiological MarkersBiological ModelsBoxingCancer PatientCancer cell lineCaspaseCaspase InhibitorCellsCessation of lifeClinicalClinical TrialsComplexDeath DomainDevelopmentDominant-Negative MutationExhibitsFailureFamilyFeedbackGoalsHepatocyteHumanHuman GenomeInterruptionMalignant NeoplasmsMediatingModelingMonoclonal AntibodiesN-terminalPhase I Clinical TrialsPlayPost-Translational Protein ProcessingPredispositionProtein BindingProtein FamilyRNA HelicaseRNA InterferenceRecruitment ActivityRegulationResearch PersonnelResistanceResistance developmentRoleSafetyScienceSignal TransductionTNF-related apoptosis-inducing ligandTNFRSF10A geneTNFRSF10B geneTestingTherapeuticTherapeutic AgentsToxic effectTreatment Efficacyadapter proteincancer cellcancer therapycaspase-3caspase-8chemotherapeutic agentcytotoxicityimprovedinsightmembermimicryneoplastic cellnonhuman primatenovelpreclinical studypreventprogramsreceptorreceptor expressionresistance mechanismresponsesmall moleculetherapy developmenttumor
项目摘要
DESCRIPTION (provided by applicant): The death receptor-induced apoptosis of tumor cells by TRAIL or agonistic antibodies is thought to be an important emerging strategy for cancer therapy. We have developed an agonistic anti-human DR5 monoclonal antibody, TRA-8. Our pre-clinical studies have demonstrated its strong anti-tumor efficacy and safety in animal models, and Phase I clinical trials are planned. However, both pre-existing and induced resistance of tumor cells to DR5-mediated apoptosis is a concern. We have identified a RNA helicase of the DEAD box protein family, DDX3, which serves as a critical adaptor protein in regulation of DR5 signaling transduction, and plays a causative role in induction of DR5 apoptosis resistance. The overall goal of this proposal is to examine the role of DDX3 in the development of resistance to DR5-mediated apoptosis. The central hypothesis is that DDX3, functioning as an adaptor protein, is constitutively associated with DR5 via a specific binding motif in each molecule. Near its N-terminus, DDX3 recruits clAP1 via a CARD/CARD interaction between the two molecules. Thus, a default function of the DR5/DDX3/clAP1 is to negatively regulate DR5-mediated apoptosis. In DR5 apoptosis sensitive cells, activation of the initiator caspase 8 leads to cleavage of DDX3 at aa135, which releases the N-terminal CARD of DDX3 and clAP1 from DR5/DDX3/clAP complex, thereby enabling a positive feedback loop to amplify apoptosis signal. In contrast, in DR5 apoptosis resistant cells, increased recruitment of clAP1 leads to inhibition of caspase 8 activity and failure of DDX3 cleavage, thereby forming a negative feedback loop to prevent amplification of the initial apoptosis signal. The Aims to test four hypotheses are: 1) that the association of DDX3 with DR5 is essential; 2) that the clAP1 recruited by a CARD of DDX3 is a key inhibitory molecule in the initiation of DR5-mediated apoptosis; 3) that the caspase-mediated cleavage of DDX3 releases the N-terminal CARD from DR5 thereby reversing the resistance; and 4) that the interruption of the DR5/DDX3/clAP1 complex may improve the therapeutic efficacy of TRA-8 and other DR5-directed agents. The proposed studies will provide novel insights into the role of DDX3 in DR-5 mediated apoptosis, and also will have implications for the further development of interventions to enhance the therapeutic efficacy of TRA-8 and other agonistic DR5 antibodies and TRAIL.
描述(由申请人提供):死亡受体通过TRAIL或激动抗体诱导肿瘤细胞凋亡被认为是一种重要的新兴癌症治疗策略。我们已经开发了一种激动性抗人DR5单克隆抗体,TRA-8。我们的临床前研究已经在动物模型中证明了其强大的抗肿瘤功效和安全性,并计划进行I期临床试验。然而,肿瘤细胞对dr5介导的凋亡的预先存在和诱导的耐药是一个值得关注的问题。我们已经鉴定出DEAD box蛋白家族的一个RNA解旋酶DDX3,它是调控DR5信号转导的关键接头蛋白,并在诱导DR5细胞凋亡抵抗中起致病作用。本提案的总体目标是研究DDX3在dr5介导的细胞凋亡耐药发展中的作用。核心假设是,DDX3作为一种接头蛋白,通过每个分子中的特定结合基序与DR5构成相关。在其n端附近,DDX3通过两个分子之间的CARD/CARD相互作用招募clAP1。因此,DR5/DDX3/clAP1的默认功能是负调控DR5介导的细胞凋亡。在DR5凋亡敏感细胞中,启动子caspase 8的激活导致DDX3在aa135处发生裂解,从而从DR5/DDX3/clAP复合体中释放DDX3和clAP1的n端CARD,从而形成一个正反馈回路,放大凋亡信号。相反,在DR5抗凋亡细胞中,clAP1募集增加导致caspase 8活性抑制和DDX3切割失败,从而形成一个负反馈回路,阻止初始凋亡信号的扩增。目的是验证四个假设:1)DDX3与DR5的关联是必要的;2) DDX3的CARD募集的clAP1是dr5介导的细胞凋亡启动的关键抑制分子;3) caspase介导的DDX3的裂解释放DR5的n端CARD,从而逆转抗性;4)阻断DR5/DDX3/clAP1复合体可能提高TRA-8和其他DR5导向药物的治疗效果。这些研究将为DDX3在DR-5介导的细胞凋亡中的作用提供新的见解,也将对进一步开发干预措施以提高TRA-8和其他激动性DR5抗体和TRAIL的治疗效果具有重要意义。
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 }}
TONG ZHOU其他文献
TONG ZHOU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('TONG ZHOU', 18)}}的其他基金
Novel Anti-HER3 Strategy for Pancreatic Cancer
治疗胰腺癌的新型抗 HER3 策略
- 批准号:
8640116 - 财政年份:2013
- 资助金额:
$ 20.49万 - 项目类别:
Novel Anti-HER3 Strategy for Pancreatic Cancer
治疗胰腺癌的新型抗 HER3 策略
- 批准号:
8512478 - 财政年份:2013
- 资助金额:
$ 20.49万 - 项目类别:
Death Receptor-mediated Apoptosis and Therapy Strategies in Ovarian Cancer
卵巢癌死亡受体介导的细胞凋亡和治疗策略
- 批准号:
7409970 - 财政年份:2007
- 资助金额:
$ 20.49万 - 项目类别:
Death Receptor-mediated Apoptosis and Therapy Strategies in Ovarian Cancer
卵巢癌死亡受体介导的细胞凋亡和治疗策略
- 批准号:
8018957 - 财政年份:2007
- 资助金额:
$ 20.49万 - 项目类别:
Death Receptor-mediated Apoptosis and Therapy Strategies in Ovarian Cancer
卵巢癌死亡受体介导的细胞凋亡和治疗策略
- 批准号:
7570628 - 财政年份:2007
- 资助金额:
$ 20.49万 - 项目类别:
Death Receptor-mediated Apoptosis and Therapy Strategies in Ovarian Cancer
卵巢癌死亡受体介导的细胞凋亡和治疗策略
- 批准号:
7771690 - 财政年份:2007
- 资助金额:
$ 20.49万 - 项目类别:
Death Receptor-mediated Apoptosis and Therapy Strategies in Ovarian Cancer
卵巢癌死亡受体介导的细胞凋亡和治疗策略
- 批准号:
7264774 - 财政年份:2007
- 资助金额:
$ 20.49万 - 项目类别:
Role of DDX3 in DR5-Mediated Apoptosis
DDX3 在 DR5 介导的细胞凋亡中的作用
- 批准号:
7667182 - 财政年份:2006
- 资助金额:
$ 20.49万 - 项目类别:
Role of DDX3 in DR5-Mediated Apoptosis
DDX3 在 DR5 介导的细胞凋亡中的作用
- 批准号:
7902245 - 财政年份:2006
- 资助金额:
$ 20.49万 - 项目类别:
相似海外基金
Rational design of rapidly translatable, highly antigenic and novel recombinant immunogens to address deficiencies of current snakebite treatments
合理设计可快速翻译、高抗原性和新型重组免疫原,以解决当前蛇咬伤治疗的缺陷
- 批准号:
MR/S03398X/2 - 财政年份:2024
- 资助金额:
$ 20.49万 - 项目类别:
Fellowship
CAREER: FEAST (Food Ecosystems And circularity for Sustainable Transformation) framework to address Hidden Hunger
职业:FEAST(食品生态系统和可持续转型循环)框架解决隐性饥饿
- 批准号:
2338423 - 财政年份:2024
- 资助金额:
$ 20.49万 - 项目类别:
Continuing Grant
Re-thinking drug nanocrystals as highly loaded vectors to address key unmet therapeutic challenges
重新思考药物纳米晶体作为高负载载体以解决关键的未满足的治疗挑战
- 批准号:
EP/Y001486/1 - 财政年份:2024
- 资助金额:
$ 20.49万 - 项目类别:
Research Grant
Metrology to address ion suppression in multimodal mass spectrometry imaging with application in oncology
计量学解决多模态质谱成像中的离子抑制问题及其在肿瘤学中的应用
- 批准号:
MR/X03657X/1 - 财政年份:2024
- 资助金额:
$ 20.49万 - 项目类别:
Fellowship
CRII: SHF: A Novel Address Translation Architecture for Virtualized Clouds
CRII:SHF:一种用于虚拟化云的新型地址转换架构
- 批准号:
2348066 - 财政年份:2024
- 资助金额:
$ 20.49万 - 项目类别:
Standard Grant
The Abundance Project: Enhancing Cultural & Green Inclusion in Social Prescribing in Southwest London to Address Ethnic Inequalities in Mental Health
丰富项目:增强文化
- 批准号:
AH/Z505481/1 - 财政年份:2024
- 资助金额:
$ 20.49万 - 项目类别:
Research Grant
ERAMET - Ecosystem for rapid adoption of modelling and simulation METhods to address regulatory needs in the development of orphan and paediatric medicines
ERAMET - 快速采用建模和模拟方法的生态系统,以满足孤儿药和儿科药物开发中的监管需求
- 批准号:
10107647 - 财政年份:2024
- 资助金额:
$ 20.49万 - 项目类别:
EU-Funded
BIORETS: Convergence Research Experiences for Teachers in Synthetic and Systems Biology to Address Challenges in Food, Health, Energy, and Environment
BIORETS:合成和系统生物学教师的融合研究经验,以应对食品、健康、能源和环境方面的挑战
- 批准号:
2341402 - 财政年份:2024
- 资助金额:
$ 20.49万 - 项目类别:
Standard Grant
Ecosystem for rapid adoption of modelling and simulation METhods to address regulatory needs in the development of orphan and paediatric medicines
快速采用建模和模拟方法的生态系统,以满足孤儿药和儿科药物开发中的监管需求
- 批准号:
10106221 - 财政年份:2024
- 资助金额:
$ 20.49万 - 项目类别:
EU-Funded
Recite: Building Research by Communities to Address Inequities through Expression
背诵:社区开展研究,通过表达解决不平等问题
- 批准号:
AH/Z505341/1 - 财政年份:2024
- 资助金额:
$ 20.49万 - 项目类别:
Research Grant