Genetic Elucidation of AMP-Activated Protein Kinase Signaling Mechanisms

说明(申请人提供)：AMPK是一种关键的能量感应器和代谢变阻器，主要通过维持ATP水平来维持细胞的能量需求。AMPK信号的中断会导致神经元死亡，而人类AMPK亚单位的突变会导致致命的心脏疾病，Wolff-Parkinson-White综合征。我们正在使用果蝇的遗传模型来识别体内调节AMPK信号的基因。利用这一新的正向遗传筛选，我们已经确定核苷二磷酸激酶(NDPK)是AMPK信号的潜在修饰物和靶标。我们发现了一种依赖AMPK的NDPK磷酸化使其关闭的新机制。这个开关位置对应于晚期人类神经母细胞瘤中的一个突变位置。通过识别抑制AMPK RNAi致死性的新基因，以及建立导致人类疾病的AMPK突变的遗传模型，我们希望识别在体内调节AMPK功能的新机制和分子。 与公共健康相关：我们正在识别介导AMP激活的蛋白激酶(AMPK)信号的新基因。AMPK基因突变会导致人类Wolff-Parkinson-White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功能的基因可能会导致更好地治疗糖尿病/代谢综合征。

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.