Molecular Pathogenesis of the Hamartoma Syndromes

描述（由申请人提供）：本研究计划的目标是阐明由肿瘤抑制基因TSC1、TSC2、LKB1和PTEN缺失引起的误构瘤综合征中促进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。这项研究将为结节性硬化症（TSC）、Peutz-Jeghers综合征（PJS）和各种PTEN综合征（如Cowden病）的发病机制提供深入的见解，并且还将具有更广泛的意义，因为这些肿瘤抑制因子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，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、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) -结节性硬化症-途径和发病机制：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 (Cantley) - LKB1/AMPK信号和Peutz-Jeghers综合征：研究LKB1/AMPK在调节TSC2及其与PI3K-AKT信号的串导中的功能，并测试PJS和TSC小鼠模型中肿瘤的新型良性治疗方法；项目3 (Perrimon) -果蝇Tsc1/Tsc2/TOR/S6K信号的解剖：进行假设驱动的RNAi筛选，以确定其他途径组分，并对AMPK， Akt调节因子和Tsc1/Tsc2- rheb信号的效应物进行全基因组RNAi筛选。这些项目将由行政管理（Kwiatkowski），质谱和蛋白质组学（Cantley）和人类病理和免疫组织化学（Wu）的核心提供支持。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，并且在癌症发展中是至关重要的，目的是确定治疗干预的潜在点。

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.