Genomic analysis of C. elegans fat regulatory pathways

描述(由申请人提供)： 我们已经测试了数千种线虫的基因，并发现了数百种有希望的候选基因，它们可能决定脂肪在各种动物中的储存和使用方式。我们确定了大约300个蠕虫基因，它们在灭活时会减少脂肪含量，而大约100个基因在灭活时会增加脂肪储存。这400个基因组成了新陈代谢和通讯途径，控制着动物体内储存了多少脂肪。已识别的基因非常多样化，既包括与脂肪和胆固醇代谢有关的预期基因，也包括其他新的候选基因，包括一些预计在中枢神经系统发挥作用的基因。大约一半的脂肪调节基因在人类和其他哺乳动物中有对应的基因。因此，在估计的30,000个人类基因中，我们的蠕虫基因组学强调了大约200个基因可能在调节脂肪水平方面发挥关键作用。在某些情况下，这些基因编码的蛋白质对药物开发具有吸引力。 哺乳动物的tub基因编码一种进化保守的蛋白，在中枢神经系统中高度表达，特别是在下丘脑，这是一个摄食控制的中心。小管功能突变的丧失与迟发性肥胖、视网膜变性和听力损失有关。Tubby的蠕虫直系同源物也在纤毛感觉神经元中表达。为了更好地了解TUB的分子功能，显然需要识别与TUB一起作用于该途径的其他基因。这些Tub通路基因可能在神经系统中调节Tub功能，或在外周组织中远端作用，从而影响能量平衡和脂肪代谢，以响应神经元Tub的活动。线虫中只有一个管状同源物，因此当存在多个基因家族成员时，避免了功能冗余的并发症。更重要的是，线虫能够接受大规模的遗传和功能基因组筛选，这在小鼠身上是不可行的。因此，线虫Tub途径基因的鉴定可能为人类肥胖的干预提供靶点。

DESCRIPTION (provided by applicant): We have tested thousands of genes in the C. elegans worm and have discovered hundreds of promising candidates that may determine how fat is stored and used in a variety of animals. We identified about 300 worm genes that when inactivated decrease fat content and about 100 genes that when inactivated caused increased fat storage. This list of 400 genes constitutes the metabolism and communications pathway that controls how much fat is stored in an animal body. The identified genes were very diverse, including both the expected genes involved in fat and cholesterol metabolism as well as other new candidates, including some that are expected to function in the central nervous system. About half of the fat regulatory genes have counterparts in humans and other mammals. Thus, of the estimated 30,000 human genes, our worm genomics highlights about 200 genes as likely to play key roles in regulation of fat levels. In some cases, the genes encode proteins that are attractive for the development of drugs. The mammalian tub gene encodes an evolutionary conserved protein that is highly expressed in the central nervous system, notably in the hypothalamus, a center of feeding control. Loss of function mutations in tublead to late-onset obesity, retinal degeneration and hearing loss. The worm ortholog of tubby is also expressed in ciliated sensory neurons. To better understand the molecular function of tub will clearly require the identification of additional genes that act in the pathway with tub. These tub pathway genes may mediate tub function in the nervous system or act distally in peripheral tissues to affect energy balance and fat metabolism in response to neuronal tub activity. There is a single tub homologue in C. elegans, thus avoiding complications from functional redundancy when multiple gene family members are present. More importantly, C. elegans is amenable to large scale genetic and functional genomic screens which is not feasible in mice. Therefore, identification of tub pathway genes in C. elegans may provide targets for intervention of obesity in human.