Molecular Pathogenesis of the Hamartoma Syndromes

错构瘤综合征的分子发病机制

• 批准号: 7191898
• 负责人: DAVID J. KWIATKOWSKI
• 金额: $ 155.08万
• 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 2012-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7191898
• 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（由申请人提供）：该研究建议的目标是阐明由于肿瘤抑制基因TSC1，TSC2，LKB1和PTEN损失而导致肿瘤发育和生理的分子信号传导途径，并识别和探索潜在的治疗靶标。这项研究将洞悉结节性硬化症复合物（TSC），PEUTZ-JEGHERS综合征（PJS）以及PTEN综合征（例如Cowden病）的种类，并且由于这些肿瘤抑制器的控制在常见的成年人的大多数中都激活，因此PTEN综合征（例如Cowden疾病）也将具有更广泛的意义。这些研究将使用多层方法，包括生物化学，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，多种小鼠模型和人类组织样品。这些方法将以高度互补和协作的方式使用，以更完整地了解这些肿瘤抑制器及其调节途径的细胞功能。项目1（Kwiatkowski/Manning） - 结节性硬化性 - 通道和发病机理：评估磷酸化位点在TSC2功能中的体内作用，探索TSC细胞和肿瘤中的反馈调节，探索雌激素在TSC中的影响以及鉴定RHEB信号事件和相互作用的蛋白；项目2（CANTLEY） - LKB1/AMPK信号传导和PEUTZ-JEGHERS综合征：检查LKB1/AMPK在调节TSC2中的功能及其与PI3K-AKT信号的交流，并测试一种新型的PJS和TSC小鼠模型中肿瘤的良性治疗方法；项目3（Perrimon） - 果蝇中TSC1/TSC2/TOR/S6K信号传导的解剖：执行假设驱动的RNAi筛选，以识别其他途径成分并对EMPK，AKT和akt的调节剂进行TSC1/TSC2-RHEB信号的AKT和效应子的调节剂进行跨基因组RNAI筛选。这些项目将得到核心（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。这些研究总的来说，这些研究将加强这些研究者的持续努力，以了解引起这些ham瘤综合征的途径，并且在癌症发展中至关重要，目的是确定治疗性干预的潜在点。