Molecular Pathogenesis of the Hamartoma Syndromes
错构瘤综合征的分子发病机制
基本信息
- 批准号:9120313
- 负责人:
- 金额:$ 178.16万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2007
- 资助国家:美国
- 起止时间:2007-04-24 至 2018-07-31
- 项目状态:已结题
- 来源:
- 关键词:AdultAllelesAwardBRAF geneBannayan SyndromeBindingCancer cell lineCellsComplexCorrelative StudyDevelopmentDissectionDrosophila genusDrug TargetingEndometrial CarcinomaEnzymesEssential GenesEventGenesGeneticGenetic EngineeringGenetically Engineered MouseGenomic approachGenotypeGerm-Line MutationGoalsGrowthHamartomaHumanIslet Cell TumorLeadMalignant NeoplasmsMalignant neoplasm of lungMalignant neoplasm of urinary bladderMammalian CellMass Spectrum AnalysisMetabolicMetabolic PathwayModelingMolecularMultiple Hamartoma SyndromeMutationNF1 geneNeoplasm with Perivascular Epithelioid Cell DifferentiationNutrientOutcomePTEN genePathogenesisPathologyPathway interactionsPatient CarePeutz-Jeghers SyndromePharmaceutical PreparationsPhosphoric Monoester HydrolasesPhosphorylationPhosphorylation SitePhosphotransferasesProgram Research Project GrantsPropertyProteomicsRegulationSTK11 geneSignal PathwaySignal TransductionSpecimenStressSyndromeSynthetic GenesSystemTSC1 geneTSC1/2 geneTSC2 geneTXNIP geneTechniquesTestingTherapeuticTimeTranslatingTranslational ResearchTranslationsTuberous SclerosisTumor Suppressor GenesTumor Suppressor Proteinsbasebladder Carcinomacancer typecell growthcombinatorialgene functionkinase inhibitormTOR Signaling Pathwaymalignant breast neoplasmmetabolomicsmouse modelnew therapeutic targetnovelnovel therapeutic interventionnovel therapeuticsphosphoproteomicspreclinical studyprogramssmall hairpin RNAtargeted biomarkertargeted treatmenttherapeutic targettreatment strategytumortumor metabolism
项目摘要
DESCRIPTION (provided by applicant): The hamartoma syndromes include tuberous sclerosis (TSC), due to mutations in TSC1 orTSC2; Cowden syndrome and Bannayan-Riley-Ruvalcaba syndrome, due to mutations in PTEN; and Peutz-Jeghers syndrome, due to mutations in LKB1. Genetically, these genes function in classic tumor suppressor gene fashion, with germline inactivation of a single allele, followed by second hit loss of the remaining wild type allele in the tumors that develop. Although germline mutations cause these genetic syndromes, each of these genes is also involved in the development of typical adult malignancies: TSC1 - bladder carcinoma; TSC2 - PEComas pancreatic neuroendocrine tumors, and bladder cancer; PTEN - many adult cancers, including breast, lung, and bladder cancer; and LKB1 - lung cancer and endometrial cancer. In addition, a variety of cancer studies have shown that the mTOR signaling pathway is a consistent target in the majority of cancers. During the past 4 years of this award, we have focused on dissection of the wiring of this pathway, treatment implications, and translation of the findings to the care of patients with the hamartoma syndromes. In this renewal application, we continue to dissect this pathway, but have shifted our focus to translational and therapeutic strategies for the tumors and cancers in which these genes are involved. Project 1 will dissect the wiring of the TSC1/TSC2 node in greater detail, and use advanced high-throughput techniques in Drosophila to identify phosphorylation events and synthetic lethal genetic partners, and translate the findings to mammalian systems. Project 2 will dissect effects downstream of LKB1 loss and AMPK inactivation to identify potential druggable targets, as well as explore the metabolic consequences of LKB1 loss, and translate these findings to preclinical studies In genetically-engineered mouse (GEM) models to define the genotype selectivity of energy stress targeted drugs. Project 3 will use integrated analyses of transcriptional, phosphoproteomic, and metabolic effects of loss of hamartoma genes, and synthetic lethal screens to identify l<ey targets due to loss of any of these genes in both GEM models and human cancer cell lines. All three projects will lead to development of novel therapeutic approaches and testing in GEM models. The projects are supported by Core A Administrative; Core B mass spectroscopy, proteomics and metabolomics, which is critical for the kinase and metabolomic studies to be performed; and Core C Pathology and Translational Research, which is critical for translation to human specimens and analysis of GEM pathology.
描述(由申请人提供):由于TSC1 ORTSC2中的突变,Hamartoma综合征包括结节硬化症(TSC);由于PTEN突变,Cowden综合征和Bannayan-Riley-Ruvalcaba综合征;由于LKB1突变,Peutz-Jeghers综合征。从遗传上讲,这些基因在经典的肿瘤抑制基因时尚中起作用,单个等位基因的种系失活,然后在发展的肿瘤中剩余的野生型等位基因的第二次命中丧失。尽管种系突变引起了这些遗传综合征,但这些基因中的每一个也参与典型的成年恶性肿瘤的发展:TSC1-膀胱癌; TSC2 -Pecomas胰腺神经内分泌肿瘤和膀胱癌; PTEN-许多成年癌症,包括乳腺癌,肺和膀胱癌;和LKB1-肺癌和子宫内膜癌。此外,多种癌症研究表明,MTOR信号通路是大多数癌症的一致目标。在该奖项的过去4年中,我们专注于解剖此途径的接线,治疗含义以及将发现的结果转化为Hamartoma综合征患者的护理。在这种续签应用中,我们继续剖析这一途径,但已将重点转移到了涉及这些基因的肿瘤和癌症的转化和治疗策略上。项目1将详细介绍TSC1/TSC2节点的接线,并在果蝇中使用先进的高通量技术来鉴定磷酸化事件和合成致命的遗传伴侣,并将发现转化为哺乳动物系统。项目2将剖析LKB1损失和AMPK失活下游的影响,以识别潜在的可药物靶标,并探索LKB1损失的代谢后果,并将这些发现转化为遗传工程研究的小鼠(GEM)模型中的临床前研究,以降低能量应力靶向药物的基因型选择性。项目3将使用对Hamartoma基因丧失的转录,磷酸蛋白质组学和代谢作用的综合分析以及合成致死筛选,以鉴定由于GEM模型和人类癌细胞系中这些基因的丢失而导致的L <EY靶标。这三个项目将导致新型治疗方法和宝石模型中的测试发展。这些项目得到了核心管理的支持;核心B质谱,蛋白质组学和代谢组学,这对于要进行的激酶和代谢组学至关重要。以及核心病理和转化研究,这对于翻译到人类标本和宝石病理分析至关重要。
项目成果
期刊论文数量(0)
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科研奖励数量(0)
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DAVID J. KWIATKOWSKI其他文献
DAVID J. KWIATKOWSKI的其他文献
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{{ truncateString('DAVID J. KWIATKOWSKI', 18)}}的其他基金
Integrative molecular dissection of acquired resistance to PD1/PD-L1 blockade in localized and metastatic urothelial carcinoma
局部和转移性尿路上皮癌对 PD1/PD-L1 阻断获得性耐药的综合分子解剖
- 批准号:
10218294 - 财政年份:2021
- 资助金额:
$ 178.16万 - 项目类别:
Integrated analyses of cancers harboring STK11 vs. TSC1/2 vs. PTEN Loss
含有 STK11、TSC1/2 和 PTEN 缺失的癌症的综合分析
- 批准号:
8567633 - 财政年份:2007
- 资助金额:
$ 178.16万 - 项目类别:
Molecular Pathogenesis of the Hamartoma Syndromes
错构瘤综合征的分子发病机制
- 批准号:
8549956 - 财政年份:2007
- 资助金额:
$ 178.16万 - 项目类别:
Molecular Pathogenesis of the Hamartoma Syndromes
错构瘤综合征的分子发病机制
- 批准号:
8719031 - 财政年份:2007
- 资助金额:
$ 178.16万 - 项目类别:
Integrated analyses of cancers harboring STK11 vs. TSC1/2 vs. PTEN Loss
含有 STK11、TSC1/2 和 PTEN 缺失的癌症的综合分析
- 批准号:
8719034 - 财政年份:2007
- 资助金额:
$ 178.16万 - 项目类别:
Project 2: Identifying Metabolic vulnerabilities and targets in cancers with mutations in hamartoma genes
项目 2:识别错构瘤基因突变癌症的代谢脆弱性和靶点
- 批准号:
10715600 - 财政年份:2007
- 资助金额:
$ 178.16万 - 项目类别:
Molecular Pathogenesis of the Hamartoma Syndromes
错构瘤综合征的分子发病机制
- 批准号:
7191898 - 财政年份:2007
- 资助金额:
$ 178.16万 - 项目类别:
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