Genetic Elucidation of AMP-Activated Protein Kinase Signaling Mechanisms

描述（由申请人提供）：amp活化蛋白激酶（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疾病——沃尔夫-帕金森-怀特综合征。我们正在果蝇中使用遗传模型来鉴定体内调节AMPK信号的基因。利用这种新的正向遗传筛选，我们已经确定核苷二磷酸激酶（NDPK）是AMPK信号传导的潜在修饰剂和靶点。我们发现了一种新的机制，通过ampk依赖的NDPK磷酸化可以关闭NDPK。这个关闭位点对应于在晚期人类神经母细胞瘤中发生突变的位置。通过鉴定抑制AMPK RNAi致死率的新基因，建立AMPK突变导致人类疾病的遗传模型，我们希望在体内发现调节AMPK功能的新机制和分子。

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.