Molecular Pathways to Thymic Lymphoma and Leukemia
胸腺淋巴瘤和白血病的分子途径
基本信息
- 批准号:7483248
- 负责人:
- 金额:$ 197.46万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2004
- 资助国家:美国
- 起止时间:2004-08-11 至 2010-04-14
- 项目状态:已结题
- 来源:
- 关键词:
项目摘要
DESCRIPTION (provided by applicant): The often aggressive and unpredictable behavior of T-cell malignancies continues to pose major clinical management problems in children and adults. This proposal is based on the central hypothesis that improved understanding of the molecular pathways that contributing to the disordered regulation of cell proliferation, differentiation, and apoptosis in T cell lymphoblastic leukemia and lymphoma (T-ALL/T-LL) will ultimately lead to improved therapy of these diseases. This Program Project Grant (PPG) brings together investigators with expertise in the molecular pathways regulating normal thymocyte development (Drs. von Boehmer, Bassing and Alt), the molecular control of thymocyte cell division (Dr. Sicinski), the regulation of early T cell survival (Drs. von Boehmer, AIt and Look), transcriptional networks regulating development (Drs. Young, Look and von Boehmer), the control of normal and aberrant TCR gene rearrangement (Drs. Bassing and AIt), the molecular pathogenesis of T-cell leukemia and lymphoma in humans (Dr. Look) and in murine models (Drs. Bassing, AIt, Sicinski, and von Boehmer), biostatistics and bioinformatics (Drs. Neuberg and Liu), and gene expression and comparative genomic hybridization (CGH) arrays (Dr. Fox). The research will be accomplished through the coordinated efforts of 4 research projects and 3 cores. In Project 1, Drs. Look and Young will identify downstream target genes within TAL1-mediated transcriptional networks that contribute to the disordered regulation of cell proliferation, differentiation, and apoptosis in human T-cell malignancies. In Project 2, Dr. von Boehmer will investigate the synergy between abnormalities in developmental transcriptional control networks and pre-TCR signaling in the generation of thymic T-LL. In Project 3, Dr. Sicinski will identify how overexpression of TAL1 and LYL1 is connected to the cell cycle machinery in T-ALL cells, specifically to the key cell cycle regulatory cyclins, D3 and D2. In Project 4, Drs. Bassing and AIt will elucidate the molecular mechanisms that lead to chromosomal translocations associated with thymic lymphomas, with focus on pathways involving ATM and H2AX. These projects will be augmented with a Biostatistics Core (Drs Neuberg and Liu), to assist with the analysis of microarray data and the optimal design of animal experiments; a Molecular Core (Dr. Fox) to perform gene expression and comparative genomic hybridization arrays; and an Administrative Core (Drs. Look and von Boehmer), to oversee the administration and coordination of the research interactions among program investigators with expertise in the molecular pathogenesis of human T-LL and T-ALL (Dr Look, Project 1), genome-scale location analysis (Dr. Young, Project 1), T-cell development (Dr. von Boehmer, Project 2), cell cycle regulation (Dr. Sicinski, Project 3), genetic regulation of chromosome stability (Drs. AIt and Bassing, Project 4), gene expression arrays (Drs. Neuberg and Liu, Biostatistics Core, and Dr. Fox, Molecular Core), and computational approaches to the identification of shared binding motifs (Dr. Liu, Biostatistics Core). Such interactions are expected to accelerate the pace at which important discoveries are generated in these projects and in the program as a whole. Successful completion of this 5-year program will improve understanding of how T-cell regulatory pathways are disrupted to initiate and maintain the transformed phenotype in TALL and T-LL, with the long-term goal to pinpoint genes whose inhibition could lead to the development of new and highly specific treatment strategies for these two malignant diseases.
描述(由申请人提供):T细胞恶性肿瘤通常具有侵袭性和不可预测的行为,继续在儿童和成人中造成主要的临床管理问题。这一建议基于一个中心假设,即提高对T细胞淋巴母细胞白血病和淋巴瘤(T-ALL/T-LL)中细胞增殖、分化和凋亡的无序调节的分子途径的理解,最终将改善这些疾病的治疗。 该项目资助(PPG)汇集了在调节正常胸腺细胞发育的分子途径方面具有专业知识的研究人员(冯·博默、巴辛和阿尔特博士),胸腺细胞分裂的分子控制(Sicinski博士),早期T细胞存活的调节(Drs. von Boehmer,AIt and Look),转录网络调节发育(Young,Look和von Boehmer博士),正常和异常TCR基因重排的控制(Drs. Bassing和AIt),人类T细胞白血病和淋巴瘤的分子发病机制(Dr. Look)和鼠模型(Drs. Bassing,AIt,Sicinski和von Boehmer)、生物统计学和生物信息学(Drs. Neuberg和Liu)以及基因表达和比较基因组杂交(CGH)阵列(Dr. Fox)。该研究将通过4个研究项目和3个核心的协调努力来完成。在项目1中,Look和Young博士将确定TAL 1介导的转录网络中的下游靶基因,这些基因有助于人类T细胞恶性肿瘤中细胞增殖,分化和凋亡的无序调节。在项目2中,von Boehmer博士将研究发育转录控制网络异常与胸腺T-LL生成中的前TCR信号传导之间的协同作用。在项目3中,Sicinski博士将确定TAL 1和LYL 1的过表达如何与T-ALL细胞中的细胞周期机制相关联,特别是与关键的细胞周期调节细胞周期蛋白D3和D2相关联。在项目4中,Bassing和AIt博士将阐明导致与胸腺淋巴瘤相关的染色体易位的分子机制,重点关注涉及ATM和H2 AX的途径。这些项目将增加一个生物统计学核心(Drs Neuberg和Liu),以协助微阵列数据的分析和动物实验的最佳设计;一个分子核心(福克斯博士)进行基因表达和比较基因组杂交阵列;行政核心(Look和von Boehmer博士),监督管理和协调具有人类T-LL和T-ALL分子发病机制专业知识的项目研究者之间的研究互动(Look博士,项目1),基因组规模定位分析(Young博士,项目1),T细胞发育(冯·博默博士,项目2),细胞周期调控(Sicinski博士,项目3),染色体稳定性的遗传调控(Ait和Bassing博士,项目4),基因表达阵列(Drs. Neuberg和Liu,Biostatistics Core,和Dr. Fox,Molecular Core),以及鉴定共享结合基序的计算方法(Dr. Liu,Biostatistics Core)。预计这种相互作用将加快这些项目和整个计划中产生重要发现的速度。这个为期5年的计划的成功完成将提高对T细胞调节途径如何被破坏以启动和维持TALL和T-LL中转化表型的理解,其长期目标是查明其抑制可能导致这两种恶性疾病的新的和高度特异性治疗策略的发展的基因。
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)
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A. THOMAS LOOK其他文献
A. THOMAS LOOK的其他文献
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{{ truncateString('A. THOMAS LOOK', 18)}}的其他基金
Mechanisms and Vulnerabilities of Aberrant Transcriptional Enhancers in Cancer
癌症中异常转录增强子的机制和脆弱性
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9341186 - 财政年份:2016
- 资助金额:
$ 197.46万 - 项目类别:
Mechanisms and Vulnerabilities of Aberrant Transcriptional Enhancers in Cancer
癌症中异常转录增强子的机制和脆弱性
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10238895 - 财政年份:2016
- 资助金额:
$ 197.46万 - 项目类别:
Mechanisms and Vulnerabilities of Aberrant Transcriptional Enhancers in Cancer
癌症中异常转录增强子的机制和脆弱性
- 批准号:
10004576 - 财政年份:2016
- 资助金额:
$ 197.46万 - 项目类别:
Role of LMO1 in Neuroblastoma Initiation and Maintenance
LMO1 在神经母细胞瘤发生和维持中的作用
- 批准号:
9452737 - 财政年份:2015
- 资助金额:
$ 197.46万 - 项目类别:
Role of LMO1 in Neuroblastoma Initiation and Maintenance
LMO1 在神经母细胞瘤发生和维持中的作用
- 批准号:
9032459 - 财政年份:2015
- 资助金额:
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Role of LMO1 in Neuroblastoma Initiation and Maintenance
LMO1 在神经母细胞瘤发生和维持中的作用
- 批准号:
9238724 - 财政年份:2015
- 资助金额:
$ 197.46万 - 项目类别:
Role of LMO1 in Neuroblastoma Initiation and Maintenance
LMO1 在神经母细胞瘤发生和维持中的作用
- 批准号:
8888225 - 财政年份:2015
- 资助金额:
$ 197.46万 - 项目类别:
Discovery of New Targets and Pathways for T-ALL Therapy
T-ALL 治疗新靶点和途径的发现
- 批准号:
8710114 - 财政年份:2012
- 资助金额:
$ 197.46万 - 项目类别:
Discovery of New Targets and Pathways for T-ALL Therapy
T-ALL 治疗新靶点和途径的发现
- 批准号:
8901763 - 财政年份:2012
- 资助金额:
$ 197.46万 - 项目类别:
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