Genomic analysis of C. elegans fat regulatory pathways

描述（由申请人提供）： 我们已经测试了C.线虫，并发现了数百个有希望的候选人，可能会决定如何储存和使用脂肪在各种动物。我们鉴定了大约300个蠕虫基因，当失活时会减少脂肪含量，大约100个基因，当失活时会增加脂肪储存。这400个基因构成了控制动物体内储存多少脂肪的代谢和通讯途径。鉴定的基因非常多样化，包括预期的参与脂肪和胆固醇代谢的基因以及其他新的候选基因，包括一些预计在中枢神经系统中发挥作用的基因。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物。因此，在估计的30，000个人类基因中，我们的蠕虫基因组学突出了大约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的开发具有吸引力。 哺乳动物tub基因编码一种进化上保守的蛋白质，该蛋白质在中枢神经系统中高度表达，特别是在摄食控制中心下丘脑中。肾小管功能缺失突变导致迟发性肥胖、视网膜变性和听力丧失。tubby的蠕虫直系同源物也在纤毛感觉神经元中表达。为了更好地理解tub的分子功能，显然需要鉴定在tub通路中起作用的其他基因。这些tub通路基因可能介导神经系统中的tub功能，或在外周组织中起远端作用以响应神经元tub活动而影响能量平衡和脂肪代谢。在C. elegans，从而避免了当存在多个基因家族成员时功能冗余的并发症。更重要的是，C。秀丽隐杆线虫适合于大规模遗传和功能基因组筛选，这在小鼠中是不可行的。因此，对C.线虫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.