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

影响线虫 LIN-12/Notch 活性的基因

• 批准号: 8193208
• 负责人: Iva S Greenwald
• 金额: $ 17.33万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-01-22 至 2013-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8193208
• 关键词: Acute Lymphocytic Leukemia; Adult; Animals; Behavioral Genetics; Caenorhabditis elegans; Cell Communication; Cells; Clinical Trials; Development; Disease; Drosophila genus; Enhancers; Epithelial Cells; FBXW7 gene; Future; Gene Targeting; Genes; Genetic; Genetic Screening; Goals; Health; Human; Immune system; In Vitro; Link; Lobular Neoplasia; Malignant Neoplasms; Mediating; Methods; Modeling; Molecular; Molecular Cloning; Mus; Mutation; Notch Signaling Pathway; Orthologous Gene; Pathway interactions; Patients; Phenotype; Play; Point Mutation; Population; Process; RNA Interference; Regulation; Research Personnel; Resistance; Role; Signal Transduction; Specific qualifier value; Stem cells; Therapeutic Agents; Transcript; Transgenes; Transgenic Organisms; Tumor Suppressor Genes; Tumor Suppressor Proteins; base; cancer therapy; clinically relevant; combat; gamma secretase; glucagon-like peptide 1; human disease; inhibitor/antagonist; notch protein; novel strategies; precursor cell; presenilin; promoter; public health relevance; receptor; therapeutic target; therapy resistant; tumor; ubiquitin ligase

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.

描述（由研究者提供）：LIN-12/Notch蛋白是介导动物发育过程中细胞命运的细胞 - 细胞相互作用的受体。 Notch活动在哺乳动物发育中的许多细胞命运决策中起着重要作用。在成年期，Notch活性继续在包括干细胞，免疫系统和上皮细胞在内的更新人群中起重要作用。异常，LIN-12/NOTCH蛋白的本构激活在人类患者和鼠模型中引起某些癌症。在其他情况下，LIN-12/Notch活性可以充当肿瘤抑制器。秀丽隐杆线虫中LIN-12/Notch信号传导的研究与了解正常哺乳动物发育和严重的人类疾病的分子机制有关，并且一直是直接相关的。该建议与识别和表征通过秀丽隐杆线虫中强大的遗传方法影响LIN-12/Notch信号传导的基因。遗传研究可以识别并照亮影响LIN-12/Notch信号传导的因素的作用，并可以为癌症治疗的新方法提供信息。例如，随后发现最初被描述为激活秀丽隐杆线虫的相同点突变引起T急性淋巴细胞白血病（T-ALL）。 Presenilin/gamma-六分泌酶首先通过LIN-12中激活点突变的抑制剂与LIN-12/NOTCH信号传导相关联，现在是临床试验的治疗靶标，用于打击T-All T-All。然而，对这种疗法的耐药性与肿瘤抑制剂Sel-10/fbw7的突变有关，该突变首先被分离为秀丽隐杆线虫中LIN-12活性的负调节剂。像Presenilin一样，活化的LIN-12/NOTCH的新抑制剂可能会识别出具有治疗靶标的潜力的新积极因素。像SEL-10/FBW7一样，新的负面因素可能会阐明使肿瘤具有抗治疗剂的过程。我们提出了这些目标的四个具体目标。首先，要表征通过RNAi筛选获得的LIN-12/NOTCH活性的新候选阳性调节剂，以抑制活化的LIN-12/Notch蛋白。其次，在类似的常规遗传筛选中鉴定出分子的基因SEL-4。第三，为了识别新的LIN-12靶基因，因为过去的分析表明某些LIN-12靶基因调节LIN-12活性并与其他途径进行串扰。第四，为了表征在RNAi筛选中获得的新候选负调节剂，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 - 细胞相互作用的受体，这些相互作用在动物发育过程中指定细胞的命运。 Notch活性在哺乳动物发育中的许多细胞命运决策中起着重要的作用，并且异常，lin-12/Notch蛋白的组成型激活会引起某些癌症。该建议的重点是识别和表征影响LIN-12/Notch信号传导的基因，从而利用了秀丽隐杆线虫中可用的强大遗传方法。