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LKB1/AMPK signaling and Peutz-Jeghers syndrome

LKB1/AMPK 信号传导与黑斑息肉综合征

基本信息

批准号：
8915514
负责人：
Reuben Shaw
金额：
$ 27.13万
依托单位：
BRIGHAM AND WOMEN'S HOSPITAL
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 2016-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8915514
关键词：
Autophagocytosis Binding Biochemical Pathway Biological Markers Bolus Infusion Cancer Cell Growth Cancer cell line Cell Survival Clinical Trials Culture Media Defect Dependence Drug Combinations Drug Targeting Enzymes Epigenetic Process Event Family Funding Gene Deletion Genetic Genetic Transcription Genetically Engineered Mouse Glucose Glutamine Goals Grant Growth Hamartoma Histone Deacetylase Inhibitor Homeostasis Hormonal Human Hypoxia In Vitro Injection of therapeutic agent Instruction Joints KRAS2 gene Kinesin Knowledge Light Lung Adenocarcinoma Lung Neoplasms Malignant Neoplasms Malignant neoplasm of lung Mediating Metabolic Metabolic Control Metabolic Pathway Metabolism Mitogen-Activated Protein Kinases Molecular Monitor Mus Mutant Strains Mice Mutate Mutation Non-Small-Cell Lung Carcinoma Nude Mice Nutrient Oncogenic Other Genetics Pathogenesis Pathology Pathway interactions Patients Peutz-Jeghers Syndrome Pharmaceutical Preparations Phosphorylation Phosphotransferases Play Protein Kinase Proteins Research Personnel Role STK11 gene Serum Shapes Signal Pathway Signal Transduction Solid Neoplasm Stress Structure of parenchyma of lung Syndrome Technology Therapeutic Therapeutic Intervention Therapeutic Trials Tumor Suppressor Proteins Tumor Tissue Xenograft procedure base cell growth design glucose metabolism human FRAP1 protein in vitro Model in vivo in vivo Model inhibitor/antagonist lipid biosynthesis loss of function mutation mTOR Inhibitor metabolomics mouse model mutant neoplastic cell novel pre-clinical preclinical study response small hairpin RNA targeted treatment transcription factor tumor

项目摘要

Loss of function mutations in STK11, encoding the Ser/Thr protein kinase, LKB1 are responsible for the familial hamartoma syndrome, Peutz Jeghers Syndrome (PJS). Importantly, recent studies have revealed sporatic mutations in STK11 in a variety of human cancers, including lung adenocarcinomas. LKB1 phosphorylates and activates AMP dependent protein kinase in response to energy stress and thus plays a key role in energy homeostasis. The hypothesis guiding this proposal is that the LKB1-AMPK signaling axis evolved to limit cell growth under conditions of energy stress and that genetic or epigenetic aberrations, as well as transcriptional and post-transcriptional events that suppress LKBI function, allow tumor cells to override metabolic control mechanisms that normally limit cell growth under energy stress. The overall goal of the proposal is to elucidate the signaling and metabolic network controlled by LKB,1-AMPK and use this information to identify targets for therapeutic intervention in tumors that lack LKB1. The specific aims are: 1) to utilize technologies developed during the previous granting period to identify druggable downstream targets in the LKB1/AMPK signaling network; 2) to utilize mass spec metabolomics to identify metabolic pathways that are altered in cancers that result from loss of LKB1 and, 3) to use genetically engineered mice that develop cancers due to loss of LKBI, in the context of other genetic aberrations observed in human lung cancers, to evaluate drugs or drug combinations, predicted on the basis of in vitro studies in Aims 1 and 2.

编码丝氨酸/苏氨酸蛋白激酶的STK11的功能突变缺失是家族性错构瘤综合征Peutz Jeghers综合征（PJS）的原因。重要的是，最近的研究揭示了STK11在包括肺腺癌在内的多种人类癌症中的散发性突变。LKB1在能量应激反应中磷酸化并激活AMP依赖性蛋白激酶，因此在能量稳态中起关键作用。指导这一建议的假设是，LKB1-AMPK信号传导轴的进化是为了限制能量应激条件下的细胞生长，而遗传或表观遗传畸变以及抑制LKBI功能的转录和转录后事件，允许肿瘤细胞超越通常在能量应激下限制细胞生长的代谢控制机制。该提案的总体目标是阐明LKB，1-AMPK控制的信号传导和代谢网络，并利用该信息确定缺乏LKB1的肿瘤的治疗干预靶点。具体目标是：1)利用先前批准期间开发的技术来识别LKB1/AMPK信号网络中的可药物下游靶点；2)利用质谱代谢组学来识别由于LKB1缺失而导致的癌症的代谢途径改变；3)在人类肺癌中观察到的其他遗传畸变的背景下，使用由于LKBI缺失而发生癌症的基因工程小鼠来评估基于Aims 1和2中体外研究预测的药物或药物组合。