Molecular Pathogenesis of the Hamartoma Syndromes

错构瘤综合征的分子发病机制

• 批准号: 8070486
• 负责人: DAVID J. KWIATKOWSKI
• 金额: $ 155.83万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-04-24 至 2012-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8070486
• 关键词: Molecular; Pathogenesis; Hamartoma; Syndromes

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(申请人提供)：这项研究计划的目标是阐明由于肿瘤抑制基因TSC1、TSC2、LKB1和PTEN缺失而导致的错构瘤综合征中有助于肿瘤发展和生理的分子信号通路，并确定和探索潜在的治疗靶点。这项研究将有助于深入了解结节性硬化症(TSC)、黑斑狼疮综合征(PJS)和各种PTEN综合征(如考登病)的发病机制，并将具有更广泛的意义，因为这些肿瘤抑制因子控制的通路在大多数常见的成人恶性肿瘤中都被激活。这些研究将采用多层次方法，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、各种小鼠模型和人类组织样本。这些方法将以高度互补和协作的方式使用，以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)-结节性硬化症的途径和发病机制：评估TSC2功能中磷酸化位点的体内作用，探索TSC细胞和肿瘤中的反馈调节，探索雌激素如何影响TSC的生长，并确定Rheb信号事件和相互作用蛋白；项目2(坎特利)--LKB1/AMPK信号和Peutz-Jeghers综合征：研究LKB1/AMPK在调节TSC2中的功能及其与PI3K-AKT信号的相互作用，并测试一种新的良性治疗方法，用于治疗PJS和TSC小鼠模型中的肿瘤；项目3(Perrimon)--在果蝇中剖析TSC1/TSC2/TOR/S6K信号：进行假说驱动的RNAi筛选，以确定其他途径组件，并对AMPK、Akt和TSC1/TSC2-Rheb信号的调节因子进行全基因组RNAi筛选。这些项目将得到行政核心(Kwiatkowski)、质谱学和蛋白质组学(坎特利)以及人类病理学和免疫组织化学(Wu)的支持。总体而言，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，并在总体上对癌症的发展至关重要，以确定潜在的治疗干预点。