Genes that influence LIN-12/Notch activity in C. elegans

描述(由研究人员提供)：LIN-12/Notch蛋白是一种受体，调节细胞与细胞之间的相互作用，决定动物发育过程中细胞的命运。缺口活性在哺乳动物发育的许多细胞命运决定中起着重要的作用。在成年期，Notch活性继续在更新种群中发挥重要作用，包括干细胞、免疫系统和上皮细胞。在人类患者和小鼠模型中，LIN-12/Notch蛋白的异常、结构性激活会导致某些癌症；在其他情况下，LIN-12/Notch活性可以作为肿瘤抑制因子发挥作用。线虫LIN-12/Notch信号的研究一直是，并将继续与理解哺乳动物正常发育和严重人类疾病的分子机制直接相关。这项建议涉及到通过强大的遗传方法在线虫中识别和表征影响Lin-12/Notch信号转导的基因。遗传学研究可以识别和阐明影响LIN-12/Notch信号转导的因素的作用，并可以为癌症治疗的新方法提供信息。例如，最初被描述为激活线虫Lin-12/Notch的相同类型的点突变随后被发现会导致T急性淋巴细胞白血病(T-ALL)。早老素/伽马分泌酶首先通过激活LIN-12点突变的抑制物与LIN-12/Notch信号联系在一起，现在是对抗T-ALL的临床试验的治疗靶点。然而，对这种疗法的耐药性与肿瘤抑制基因SEL-10/Fbw7的突变有关，该基因最初是作为线虫LIN-12活性的负调节因子分离出来的。像早老素一样，激活的Lin-12/Notch的新抑制因子可能识别新的积极因子，具有潜在的治疗靶点；像SEL-10/Fbw7一样，新的负面因子可能阐明使肿瘤对治疗药物产生耐药性的过程。针对这些目标，我们提出了四个具体目标。首先，鉴定通过RNAi筛选激活的LIN-12/Notch蛋白的抑制子而获得的新的LIN-12/Notch活性的候选正调控因子。第二，从分子上鉴定一种基因，sel-4，在类似的常规基因筛查中被鉴定出来。第三，寻找新的LIN-12靶基因，因为过去的分析表明，一些LIN-12靶基因调节LIN-12的活性并与其他途径相互作用。第四，鉴定在RNAi筛选中获得的新的候选负调控因子，并探索RNAi与LIN-12活性调节之间的潜在联系。与公共健康相关：LIN-12/Notch蛋白是一种受体，调节细胞与细胞之间的相互作用，决定动物发育过程中细胞的命运。Notch活性在哺乳动物发育过程中的许多细胞命运决定中起着重要的作用，而Lin-12/Notch蛋白的异常、结构性激活会导致某些癌症。这项建议的重点是识别和表征影响LIN-12/Notch信号转导的基因，利用线虫中可用的强大遗传方法。

DESCRIPTION (provided by investigator): LIN-12/Notch proteins are receptors that mediate cell-cell interactions that specify cell fate during animal development. Notch activity plays a prominent role in many cell fate decisions in mammalian development. During adulthood, Notch activity continues to play important roles in renewing populations, including stem cells, the immune system, and epithelial cells. Aberrant, constitutive activation of LIN-12/Notch proteins causes certain cancers in human patients and in murine models; in other contexts, LIN-12/Notch activity can function as a tumor suppressor. Studies of LIN-12/Notch signaling in C. elegans have been, and continue to be, directly relevant to understanding the molecular mechanisms underlying normal mammalian development and serious human diseases. This proposal is concerned with identifying and characterizing genes that influence LIN-12/Notch signaling through powerful genetic methods in C. elegans. Genetic studies can identify and illuminate the roles of factors that influence LIN-12/Notch signaling and can inform new approaches to cancer treatment. For example, the same kinds of point mutations first described as activating C. elegans LIN-12/Notch were subsequently found to cause T acute lymphoblastic leukemia (T-ALL). Presenilin/gamma-secretase, first linked to LIN-12/Notch signaling through suppressors of activating point mutations in lin-12, is now a therapeutic target in clinical trials for combating T-ALL. Resistance to this therapy, however, has been linked to mutations in a tumor suppressor, SEL- 10/Fbw7, first isolated as a negative regulator of lin-12 activity in C. elegans. Like presenilin, new suppressors of activated LIN-12/Notch may identify new positive factors with the potential to serve as therapeutic targets; like SEL-10/Fbw7, new negative factors may illuminate processes that make tumors resistant to therapeutic agents. We propose four specific aims with these goals. First, to characterize new candidate positive regulators of lin-12/Notch activity obtained through an RNAi screen for suppressors of an activated LIN-12/Notch protein. Second, to identify molecularly a gene, sel-4, identified in a similar conventional genetic screen. Third, to identify new LIN-12 target genes, as past analysis indicates some LIN-12 target genes modulate lin-12 activity and cross-talk with other pathways. Fourth, to characterize new candidate negative regulators obtained in an RNAi screen and to explore a potential connection between RNAi and regulation of lin-12 activity. PUBLIC HEALTH RELEVANCE: LIN-12/Notch proteins are receptors that mediate cell-cell interactions that specify cell fate during animal development. Notch activity plays a prominent role in many cell fate decisions in mammalian development, and aberrant, constitutive activation of LIN- 12/Notch proteins causes certain cancers. This proposal is focused on identifying and characterizing genes that influence LIN-12/Notch signaling, exploiting the powerful genetic methods available in C. elegans.