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 激活蛋白激酶 (AMPK) 作为关键的能量传感器和代谢变阻器，主要通过维持 ATP 水平来维持细胞的能量需求。 AMPK 信号传导的破坏会导致神经元死亡，而人类 AMPK 亚基的突变会导致致命的心脏病，即沃尔夫-帕金森-怀特综合征。我们正在使用果蝇的遗传模型来识别体内调节 AMPK 信号传导的基因。利用这种新颖的正向遗传筛选，我们确定了核苷二磷酸激酶 (NDPK) 作为 AMPK 信号传导的潜在修饰剂和靶标。我们发现了一种新机制，NDPK 的 AMPK 依赖性磷酸化可将其关闭。这个关闭开关位点对应于晚期人类神经母细胞瘤中的突变位置。通过鉴定抑制 AMPK RNAi 致死性的新基因，并建立导致人类疾病的 AMPK 突变的遗传模型，我们希望鉴定出体内调节 AMPK 功能的新机制和分子。公共健康相关性：我们正在鉴定介导 AMP 激活蛋白激酶 (AMPK) 信号传导的新基因。 AMPK 突变会导致人类沃尔夫-帕金森-怀特综合征，这是一种致命的心脏疾病。此外，AMPK 是临床前 2 型糖尿病的靶标，因此识别影响 AMPK 功能的基因可以更好地治疗糖尿病/代谢综合征。