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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：
9120328
负责人：
LEWIS C. CANTLEY
金额：
$ 20.55万
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 2018-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9120328
关键词：
Autophagocytosis Binding Biochemical Pathway Biological Markers Bolus Infusion Cancer Cell Growth Cancer cell line Cell Survival Cells Cellular Metabolic Process Clinical Trials Culture Media Defect Dependence Drug Combinations Drug Targeting Enzymes Epigenetic Process Event FRAP1 gene 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 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 Modeling 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 TP53 gene TXNIP gene Technology Therapeutic Therapeutic Intervention Therapeutic Trials Tumor Suppressor Proteins Tumor Tissue Xenograft procedure base cell growth design glucose metabolism in vitro Model in vivo in vivo Model inhibitor/antagonist knock-down lipid biosynthesis loss of function mutation mTOR Inhibitor metabolomics mouse model mutant neoplastic cell novel phosphoproteomics pre-clinical preclinical trial response small hairpin RNA targeted treatment transcription factor tumor tumor metabolism

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 ofthe 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 aberrationslobserved 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Ser/Thr蛋白激酶LKB 1的STK 11中的功能缺失突变负责家族性错构瘤综合征，Peutz Jeghers综合征（PJS）。重要的是，最近的研究表明， STK 11在包括肺腺癌在内的多种人类癌症中的偶发突变。LKB1 磷酸化和激活AMP依赖性蛋白激酶，从而对能量应激起反应，能量平衡的关键角色指导这一提议的假设是LKB 1-AMPK信号传导轴进化到限制细胞生长的条件下，能源压力和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，使肿瘤细胞在能量压力下，它会超越通常限制细胞生长的代谢控制机制。总目标该建议是阐明LKB，1-AMPK控制的信号传导和代谢网络，并使用此信息，以确定缺乏LKB 1的肿瘤的治疗干预的目标。具体目标是：1）利用上一个资助期开发的技术， LKB 1/AMPK信号网络中的靶点; 2）利用质谱代谢组学来鉴定代谢在癌症中由于LKB 1的缺失而改变的途径，以及，3）使用基因工程小鼠由于LKBI的缺失而发生癌症，在人类肺中观察到的其他遗传异常的背景下，癌症，以评估基于目标1和2中的体外研究预测的药物或药物组合。