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：
8567630
负责人：
LEWIS C. CANTLEY
金额：
$ 19.26万
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
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/8567630
关键词：
Autophagocytosis Binding Biochemical Pathway Biological Markers Bolus Infusion Cancer Cell Growth Cancer cell line Cell Survival Cells 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 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 Technology Therapeutic Therapeutic Intervention Therapy Clinical 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 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 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.

STK11（编码 Ser/Thr 蛋白激酶）功能缺失突变，LKB1 负责家族性错构瘤综合征、黑斑息肉综合征 (PJS)。重要的是，最近的研究表明包括肺腺癌在内的多种人类癌症中 STK11 的孢子突变。 LKB1 磷酸化并激活 AMP 依赖性蛋白激酶以响应能量压力，从而发挥在能量稳态中发挥关键作用。指导该提议的假设是 LKB1-AMPK 信号轴进化到在能量应激和遗传或表观遗传畸变的条件下限制细胞生长，如以及抑制 LKBI 功能的转录和转录后事件，使肿瘤细胞能够超越通常在能量压力下限制细胞生长的代谢控制机制。总体目标该提案的目的是阐明 LKB、1-AMPK 控制的信号传导和代谢网络，并利用该网络确定缺乏 LKB1 的肿瘤的治疗干预靶标的信息。具体目标是：1）利用上一个授权期间开发的技术来识别可成药的下游 LKB1/AMPK 信号网络中的目标； 2）利用质谱代谢组学来鉴定代谢由于 LKB1 缺失而导致癌症的通路发生改变，以及 3) 使用基因工程小鼠在人类肺部观察到的其他遗传畸变的背景下，由于 LKBI 缺失而发展为癌症癌症，以评估根据目标 1 和 2 中的体外研究预测的药物或药物组合。