Genetic Elucidation of AMP-Activated Protein Kinase Signaling Mechanisms

AMP 激活蛋白激酶信号传导机制的遗传阐明

基本信息

批准号：
8287211
负责人：
JAY BRENMAN
金额：
$ 32.03万
依托单位：
UNIV OF NORTH CAROLINA CHAPEL HILL
依托单位国家：
美国
项目类别：
财政年份：
2004
资助国家：
美国
起止时间：
2004-12-01 至 2016-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8287211
关键词：
5&apos -AMP-activated protein kinase AMP-activated protein kinase kinase Address Adenosine Monophosphate Adenosine Triphosphate Adult Affect Amino Acids Animals Binding Biochemical Biochemical Genetics Biological Biology Candidate Disease Gene Catalytic Domain Cells Cessation of life Complex Consumption Data Development Diabetes Mellitus Diphosphates Disease Dominant-Negative Mutation Drosophila genus Genes Genetic Genetic Models Genetic Screening Genotype Glycine Heart Diseases Homeostasis Human Lead Location Mammals Measures Mediating Metabolic Metabolic syndrome Modeling Mutate Mutation Nerve Degeneration Neuroblastoma Neurons Non-Insulin-Dependent Diabetes Mellitus Nucleoside-Diphosphate Kinase Nucleotides Pathway interactions Phenocopy Phenotype Phosphorylation Population Production Protein Kinase Protein Subunits Protein-Serine-Threonine Kinases Proteins RNA Interference Regulation Serine Signal Pathway Signal Transduction Site Syndrome Tissues Transgenic Animals Wolff-Parkinson-White Syndrome cell type design human disease in vivo inorganic phosphate loss of function man mutant novel pre-clinical protein complex sensor stressor tripolyphosphate

项目摘要

DESCRIPTION (provided by applicant): AMP-activated protein kinase (AMPK) functions as a key energy sensor and metabolic rheostat to maintain cells' energy needs, largely through maintaining ATP levels. Disruption of AMPK signaling leads to neuronal death, while mutations in human AMPK subunits cause the fatal cardiac disorder, Wolff-Parkinson-White syndrome. We are using a genetic model in Drosophila to identify genes that modulate AMPK signaling in vivo. Using this novel forward genetic screen we have identified nucleoside diphosphate kinase (NDPK) as a potential modifier and target of AMPK signaling. We have found a new mechanism whereby AMPK-dependent phosphorylation of NDPK turns it off. This off switch site corresponds to a location mutated in advanced human neuroblastoma. Through identification of new genes that suppress AMPK RNAi lethality, and making a genetic model of mutations in AMPK that cause human disease, we hope to identify both new mechanisms and molecules that modulate AMPK function in vivo. PUBLIC HEALTH RELEVANCE: We are identifying new genes that mediate AMP-activated protein kinase (AMPK) signaling. Mutations in AMPK cause human Wolff-Parkinson-White syndrome, a fatal cardiac disorder. In addition, AMPK is a pre-clinical Type 2 diabetes target so identifying genes that affect AMPK function could lead to better treatment of diabetes/metabolic syndrome.

描述（由申请人提供）：AMP激活的蛋白激酶（AMPK）充当关键的能量传感器和代谢风湿病，以维持细胞的能量需求，主要是通过维持ATP水平。 AMPK信号传导的破坏会导致神经元死亡，而人AMPK亚基的突变会导致致命心脏疾病，Wolff-Parkinson-White综合征。我们正在果蝇中使用遗传模型来识别在体内调节AMPK信号传导的基因。使用这种新型的正向遗传筛选，我们已经将核苷双磷酸激酶（NDPK）确定为AMPK信号传导的潜在修饰符和靶标。我们发现了一种新的机制，从而将NDPK的AMPK依赖性磷酸化关闭。此关闭开关位点对应于晚期人神经母细胞瘤中突变的位置。通过鉴定抑制AMPK RNAi致死性的新基因，并在引起人类疾病的AMPK中产生突变的遗传模型，我们希望识别调节AMPK在体内功能的新机制和分子。公共卫生相关性：我们正在确定介导AMP激活蛋白激酶（AMPK）信号传导的新基因。 AMPK突变引起人类Wolff-Parkinson-White综合征，这是一种致命的心脏疾病。此外，AMPK是一种临床前2型糖尿病靶标，因此鉴定影响AMPK功能的基因可能会导致更好地治疗糖尿病/代谢综合征。