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:7191898
- 负责人:
- 金额:$ 155.08万
- 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 2012-03-31
- 项目状态:已结题
- 来源:
- 关键词:
项目摘要
DESCRIPTION (provided by applicant): The goals of this research proposal are to elucidate the molecular signaling pathways that contribute to tumor development and physiology in the hamartoma syndromes resulting from loss of the tumor suppressor genes TSC1, TSC2, LKB1, and PTEN, and to identify and explore potential therapeutic targets. This research will provide insight into the pathogenesis of tuberous sclerosis complex (TSC), Peutz-Jeghers syndrome (PJS), and the variety of PTEN syndromes (e.g., Cowden disease), and will also have broader implications since the pathways these tumor suppressors control are activated in the majority of the common adult malignancies. A multi-tiered approach will be used for these studies, involving biochemistry, cell biology, yeast genetics, Drosophila genetics, high-throughput screens, genomics, proteomics, a variety of mouse models, and human tissue samples. These approaches will be used in a highly complementary and collaborative manner toward a more complete understanding of the cellular functions of these tumor suppressors and the pathways they regulate. Project 1 (Kwiatkowski/Manning) -- Tuberous Sclerosis-Pathway and Pathogenesis: evaluate the in vivo role of phosphorylation sites in TSC2 function, explore feedback regulation in TSC cells and tumors, explore how estrogen influences growth in TSC, and identify Rheb signaling events and interacting proteins; Project 2 (Cantley) -- LKB1/AMPK Signaling and Peutz-Jeghers Syndrome: examine the function of LKB1/AMPK in regulation of TSC2 and its cross talk with PI3K-AKT signaling and test a novel benign therapeutic approach for tumors arising in mouse models of PJS and TSC; Project 3 (Perrimon) -- Dissection of Tsc1/Tsc2/TOR/S6K Signaling in Drosophila: perform hypothesis driven RNAi screens to identify additional pathway components and perform genome-wide RNAi screens for regulators of AMPK, Akt and effectors of Tsc1/Tsc2-Rheb signaling. These projects will be supported by cores for Administration (Kwiatkowski), Mass Spectrometry and Proteomics (Cantley), and Human Pathology and Immunohistochemistry (Wu). Collectively these studies will enhance an ongoing effort among these investigators to understand the pathways that cause these hamartoma syndromes, and are critical in cancer development in general, for the purpose of identifying potential points of therapeutic intervention.
描述(由申请人提供):本研究提案的目标是阐明肿瘤抑制基因TSC 1、TSC 2、LKB 1和PTEN缺失导致的错构瘤综合征中有助于肿瘤发展和生理学的分子信号传导途径,并鉴定和探索潜在的治疗靶点。这项研究将深入了解结节性硬化症(TSC)、Peutz-Jeghers综合征(PJS)和各种PTEN综合征(例如,Cowden病),也将有更广泛的影响,因为这些肿瘤抑制剂控制的途径在大多数常见的成人恶性肿瘤中被激活。这些研究将采用多层次的方法,涉及生物化学、细胞生物学、酵母遗传学、果蝇遗传学、高通量筛选、基因组学、蛋白质组学、各种小鼠模型和人体组织样本。这些方法将以高度互补和协作的方式用于更全面地了解这些肿瘤抑制因子的细胞功能及其调节的途径。项目1(Kwiatkowski/Manning)--检查LKB 1/AMPK在调节TSC 2中的功能及其与PI 3 K-AKT信号传导的串扰,并测试PJS和TSC小鼠模型中出现的肿瘤的新型良性治疗方法;项目3(Perrimon)--果蝇中Tsc 1/Tsc 2/TOR/S6 K信号转导的剖析:进行假设驱动的RNAi筛选以鉴定额外的通路组分,并对AMPK、Akt的调节剂和Tsc 1/Tsc 2-Rheb信号传导的效应物进行全基因组RNAi筛选。这些项目将得到管理核心(Kwiatkowski),质谱和蛋白质组学(Cantley)以及人类病理学和免疫组织化学(Wu)的支持。总的来说,这些研究将加强这些研究人员正在进行的努力,以了解导致这些错构瘤综合征的途径,并在癌症发展中发挥关键作用,以确定潜在的治疗干预点。
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:
$ 155.08万 - 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:
$ 155.08万 - 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:
$ 155.08万 - 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:
$ 155.08万 - 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:
$ 155.08万 - 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:
$ 155.08万 - 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:
9120313 - 财政年份:2007
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