Lipid Homeostasis in C. elegans

描述(由申请人提供)： 肥胖和肥胖相关疾病每年造成30万人死亡。识别参与能量代谢的分子并了解它们的功能对于抗击这种毁灭性的疾病至关重要。控制能量代谢的因素在哺乳动物和线虫之间是保守的，这一发现为描绘导致肥胖的分子途径提供了一种新的强有力的策略。我们的重点是消化道代谢控制的转录部分。我们发现PHA-4/FoxA转录因子是线虫体内脂类平衡的关键调节因子，并受TOR和胰岛素信号通路的控制。最近的发现表明，在哺乳动物中，FoxA因子也起着控制脂代谢的作用。因此，我们在惠根线虫身上发现的途径很可能与人类健康和疾病有关。我们建议从三个方面扩展我们最初的观察结果。 I)首先，我们将研究调节消化道中PHA-4活性的调节电路。我们将使用遗传和分子方法将PHA-4放置在信号通路中，并将启动结构/功能研究以阐明调节的性质。 Ii)其次，我们将使用分子和生物信息学方法来识别和表征直接的PHA-4靶基因。这一分析将区分不同型号的PHA-4功能。 Iii)第三，我们将使用与PhA-4的遗传相互作用作为筛选脂质储存途径中新基因的基础。我们的初步数据表明，我们的策略将发现之前筛查中遗漏的基因。 这三种方法将阐明线虫消化道内脂肪代谢的转录网络。

DESCRIPTION (provided by applicant): Obesity and obesity-related diseases account for -300,000 deaths each year. Identification of molecules involved in energy metabolism and an understanding of their function is critical to combat this devastating disease. The discovery that factors controlling energy metabolism are conserved between mammals and C. elegans has provided a new and powerful strategy to delineate the molecular pathways that lead to obesity. Our focus is the transcriptional component of metabolic control in the digestive tract. We have discovered that the PHA-4/FoxA transcription factor is a key regulator of lipid homeostasis in C. elegans and is controlled by components of the TOR and insulin signalling pathways. Recent findings have suggested that that FoxA factors also function in mammals to control lipid metabolism. Therefore, the pathways we discover in C. eiegans are likely to be relevant to human health and disease. We propose to extend our initial observations in three ways. i) First we will investigate the regulatory circuitry that modulates PHA-4 activity in the digestive tract. We will use genetic and molecular approaches to place pha-4 in the signalling pathways, and we will initiate structure/function studies to elucidate the nature of the regulation. ii) Second we will use molecular and bioinformatic approaches to identify and characterize direct PHA-4 target genes. This analysis will distinguish between different models of PHA-4 function. iii) Third, we will use genetic interactions with pha-4 as the basis of a screen for new genes in the lipid storage pathway. Our preliminary data suggest that our strategy will discover genes missed in previous screens. These three approaches will elucidate the transcriptional network for fat metabolism within the C. elegans digestive tract