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

描述（由研究者提供）：LIN-12/Notch蛋白是介导细胞间相互作用的受体，可在动物发育期间指定细胞命运。Notch活性在哺乳动物发育中的许多细胞命运决定中起着重要作用。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。LIN-12/Notch蛋白的异常、组成性激活导致人类患者和鼠模型中的某些癌症;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。C. LIN-12/Notch信号通路的研究秀丽线虫一直并将继续与理解正常哺乳动物发育和严重人类疾病的分子机制直接相关。该建议涉及通过强大的遗传方法在C.优雅遗传学研究可以识别和阐明影响LIN-12/Notch信号传导的因素的作用，并可以为癌症治疗提供新的方法。例如，最初被描述为激活C的相同类型的点突变。随后发现线虫LIN-12/Notch引起T急性淋巴细胞白血病（T-ALL）。早老素/γ-分泌酶，首先通过lin-12中激活点突变的抑制剂与LIN-12/Notch信号传导相关，现在是临床试验中用于对抗T-ALL的治疗靶点。然而，对这种疗法的抗性与肿瘤抑制因子SEL- 10/Fbw 7的突变有关，SEL- 10/Fbw 7最初是作为C.优雅与早老素一样，激活的LIN-12/Notch的新抑制因子可能会识别出具有作为治疗靶点潜力的新的阳性因子;与SEL-10/Fbw 7一样，新的阴性因子可能会阐明使肿瘤对治疗药物产生耐药性的过程。我们针对这些目标提出了四个具体目标。首先，表征通过RNAi筛选活化的LIN-12/Notch蛋白的抑制子获得的lin-12/Notch活性的新候选正调节剂。第二，从分子水平上鉴定一个基因，sel-4，在一个类似的常规遗传筛选中被鉴定出来。第三，鉴定新的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活性并与其他途径交叉作用。第四，表征在RNAi筛选中获得的新的候选负调节因子，并探索RNAi与lin-12活性调节之间的潜在联系。公共卫生相关性：LIN-12/Notch蛋白是介导细胞与细胞相互作用的受体，可指定动物发育期间的细胞命运。Notch活性在哺乳动物发育中的许多细胞命运决定中起着重要作用，并且LIN- 12/Notch蛋白的异常组成性激活导致某些癌症。该提案的重点是识别和表征影响LIN-12/Notch信号传导的基因，利用C.优雅

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.