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）作为一种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信号传导的破坏导致神经元死亡，而人类AMPK亚基的突变导致致命的心脏疾病，沃尔夫-帕金森-白色综合征。我们正在使用果蝇的遗传模型来鉴定体内调节AMPK信号的基因。使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）作为一个潜在的修饰剂和AMPK信号转导的目标。我们已经发现了一种新的机制，使AMPK依赖的磷酸化NDPK关闭它。这个关闭开关位点对应于晚期人类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，并建立导致人类疾病的AMPK突变的遗传模型，我们希望鉴定体内调节AMPK功能的新机制和分子。 公共卫生相关性：我们正在鉴定介导AMP激活蛋白激酶（AMPK）信号的新基因。AMPK的突变导致人类沃尔夫-帕金森-白色综合征，这是一种致命的心脏疾病。此外，AMPK是临床前2型糖尿病的靶点，因此识别影响AMPK功能的基因可能会导致更好的糖尿病/代谢综合征治疗。

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.