TRAIL Mediated Apoptosis in Renal Cell Carcinoma
肾细胞癌中 TRAIL 介导的细胞凋亡
基本信息
- 批准号:7127664
- 负责人:
- 金额:$ 12.78万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2005
- 资助国家:美国
- 起止时间:2005-09-29 至 2010-08-31
- 项目状态:已结题
- 来源:
- 关键词:AgeAnimalsApoptosisApoptosis InhibitorApoptosis RegulatorApoptoticBiological AssayBiological Response Modifier TherapyCell DeathCell LineCell surfaceClinicalClinical TrialsDNADeath DomainDevelopmentDiseaseDisease ResistanceDoctor of MedicineExonsFamily memberFlow CytometryGenderHistologyHumanImmunoprecipitationIn complete remissionInterferon Type IInterferon-alphaInterferonsInterleukin-2LigandsMalignant - descriptorMalignant Epithelial CellMalignant NeoplasmsMediatingMediator of activation proteinMentored Clinical Scientist Development Award (K08)Metastatic Renal Cell CancerModelingMolecularMutationNational Institute of Diabetes and Digestive and Kidney DiseasesNephrectomyNormal CellNorthern BlottingOutcomeParaffin EmbeddingPatientsPerformance StatusPersonal SatisfactionPlasmidsPolymerase Chain ReactionPrognostic MarkerProgram DevelopmentProtein FamilyRateReceptor SignalingRecurrenceRelative (related person)Renal Cell CarcinomaResearch PersonnelResistanceRoleSamplingScreening procedureSeriesSignal TransductionSite-Directed MutagenesisSomatic MutationStagingStandards of Weights and MeasuresSurfaceSyndromeTNF geneTNFRSF10A geneTNFRSF10B geneTestingTimeTissuesTreatment EfficacyTreatment ProtocolsTumor Necrosis Factor-alphaTumor Necrosis FactorsUrologic SurgeonWestern BlottingYeastsantitumor agentbasecancer cellcareercaspase-8cell typechemotherapycohortcytotoxichuman TNF proteinlaser capture microdissectionmembermutantneoplasticneoplastic cellprognosticreceptorresearch studyresponsetumoryeast two hybrid system
项目摘要
DESCRIPTION (provided by applicant):
This is an application for a NIDDK Mentored Clinical Scientist Development Award for Peter E. Clark, M.D. and is in response to NOT-DK-03-004: NIDDK Career Development Programs for Urologic Surgeons. Advanced renal cell carcinoma (RCC) is a deadly, chemotherapy resistant disease usually treated with biologic therapy such as interferon alpha (IFNa). New forms of therapy for advanced RCC are needed. Apo2 ligand/Tumor necrosis factor related apoptosis inducing ligand (TRAIL) is a member of the TNF superfamily and is an attractive potential anti-tumor agent as it induces apoptosis preferentially in malignant cells. TRAIL is well tolerated in animal tumor models and preliminary clinical trials are ongoing in various cancers, including RCC. TRAIL mediated apoptosis is dependent on its death domain (DD) containing cognate receptors, DR4 and DR5, as well as the DD adaptor molecule FADD. TRAIL mediated signaling may be modulated by two receptors that lack a functional DD, DcR1 and DcR2 and by other downstream regulators of apoptosis (FLIP, Bel family members, etc.). This project examines three complementary aspects of TRAIL receptor signaling in RCC. Our preliminary studies indicate that IFNa and TRAIL cooperate to increase RCC cell death. In aim one we will determine the molecular mechanism by which this occurs. In other cancers the expression of TRAIL and its receptors predicts outcome but this has not been studied in RCC. In aim two we will analyze a large well characterized cohort of RCC patients to determine the expression level of TRAIL and its cognate receptors and test if this predicts clinical outcome. Finally, functionally significant somatic mutations exist in DR4 and DR5 in a variety of cancers but this has not been studied in RCC. In aim 3 we will identify mutations in RCC and determine their functional significance. Together, these studies provide a detailed picture of the role of TRAIL in RCC and could provide a mechanistic basis for combining TRAIL with IFNa as therapy for RCC and using TRAIL receptor levels and/or mutations as clinical prognostic markers.
描述(由申请人提供):
这是 Peter E. Clark 医学博士申请 NIDDK 指导临床科学家发展奖的申请,是对 NOT-DK-03-004:NIDDK 泌尿外科医生职业发展计划的回应。 晚期肾细胞癌 (RCC) 是一种致命的化疗耐药性疾病,通常采用干扰素 α (IFNa) 等生物疗法进行治疗。晚期肾细胞癌需要新的治疗方法。 Apo2 配体/肿瘤坏死因子相关凋亡诱导配体 (TRAIL) 是 TNF 超家族的成员,是一种有吸引力的潜在抗肿瘤药物,因为它优先诱导恶性细胞凋亡。 TRAIL 在动物肿瘤模型中具有良好的耐受性,并且针对包括肾细胞癌在内的各种癌症的初步临床试验正在进行中。 TRAIL 介导的细胞凋亡依赖于其包含同源受体 DR4 和 DR5 的死亡结构域 (DD),以及 DD 接头分子 FADD。 TRAIL 介导的信号传导可能受到缺乏功能性 DD、DcR1 和 DcR2 的两种受体以及其他细胞凋亡下游调节因子(FLIP、Bel 家族成员等)的调节。该项目研究了 RCC 中 TRAIL 受体信号传导的三个互补方面。我们的初步研究表明 IFNa 和 TRAIL 协同作用以增加 RCC 细胞死亡。在目标一中,我们将确定发生这种情况的分子机制。在其他癌症中,TRAIL 及其受体的表达可预测结果,但尚未在肾细胞癌中进行研究。在目标二中,我们将分析一大群特征明确的 RCC 患者,以确定 TRAIL 及其同源受体的表达水平,并测试这是否可以预测临床结果。最后,在多种癌症中,DR4 和 DR5 中存在功能显着的体细胞突变,但尚未在 RCC 中进行研究。在目标 3 中,我们将识别 RCC 突变并确定其功能意义。总之,这些研究提供了 TRAIL 在 RCC 中作用的详细情况,并可为将 TRAIL 与 IFNa 联合治疗 RCC 以及使用 TRAIL 受体水平和/或突变作为临床预后标志物提供机制基础。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
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PETER E CLARK其他文献
PETER E CLARK的其他文献
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{{ truncateString('PETER E CLARK', 18)}}的其他基金
TRAIL Mediated Apoptosis in Renal Cell Carcinoma
肾细胞癌中 TRAIL 介导的细胞凋亡
- 批准号:
7922783 - 财政年份:2009
- 资助金额:
$ 12.78万 - 项目类别:
TRAIL Mediated Apoptosis in Renal Cell Carcinoma
肾细胞癌中 TRAIL 介导的细胞凋亡
- 批准号:
7494949 - 财政年份:2005
- 资助金额:
$ 12.78万 - 项目类别:
TRAIL Mediated Apoptosis in Renal Cell Carcinoma
肾细胞癌中 TRAIL 介导的细胞凋亡
- 批准号:
6901749 - 财政年份:2005
- 资助金额:
$ 12.78万 - 项目类别:
TRAIL Mediated Apoptosis in Renal Cell Carcinoma
肾细胞癌中 TRAIL 介导的细胞凋亡
- 批准号:
7685292 - 财政年份:2005
- 资助金额:
$ 12.78万 - 项目类别:
TRAIL Mediated Apoptosis in Renal Cell Carcinoma
肾细胞癌中 TRAIL 介导的细胞凋亡
- 批准号:
7275168 - 财政年份:2005
- 资助金额:
$ 12.78万 - 项目类别:
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