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: 6576778
• 负责人: Iva S Greenwald
• 金额: $ 17.9万
• 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 2007-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6576778
• 关键词: Caenorhabditis elegans; biological signal transduction; cell cell interaction; cell cycle; cell cycle proteins; chimeric proteins; gene expression; gene induction /repression; gene interaction; genetic mapping; genetic screening; green fluorescent proteins; membrane proteins; molecular cloning; phenotype; protein protein interaction; yeast two hybrid system

DESCRIPTION (provided by applicant): LIN-12/Notch proteins are receptors that mediate cell-cell interactions that specify cell fate during animal development. Studies of LIN-12/Notch proteins are directly relevant to understanding the molecular mechanisms underlying two serious and common human diseases. Constitutive activation of LIN-12/Notch proteins has been associated with the development of certain cancers in human patients and in mammalian models, and the activity of a key component of the LIN-12/Notch signal transduction pathway, presenilin, is central to the development of Alzheimer's disease. Other, less common, diseases have also been associated with aberrations in LIN-12/Notch pathway components. Our work on lin-12 in C. elegans has contributed to the current state of understanding of conserved developmental roles and molecular mechanisms of LIN-12/Notch proteins. This proposal is concerned with identifying and characterizing new genes that influence lin-12 activity in C. elegans. Our first specific aim encompasses new variations on a proven genetic screen, based on suppression of phenotypes associated with constitutive lin-12 activation [lin-12 (d) alleles]. Our second specific aim is concerned with the basic characterization of new sel [suppressor/enhancer of lin-12] genes, and our third specific aim is concerned with understanding how the new genes we identify work together. The last two specific aims are involved with the LIN-12-mediated lateral signaling during vulval precursor cell specification. The fourth aim is concerned with identifying and characterizing the ligand for LIN-12 in this signaling event, and the fifth aim is concerned with characterizing a gene that may be involved in the interplay between Ras-mediated vulval induction and LIN-12-mediated lateral signaling. When these specific aims are completed, we hope to have identified conserved components and illuminated fundamental mechanisms of the regulation and execution of LIN-12/Notch signaling in animal development.

描述（由申请人提供）：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命运。 LIN-12/NOTCH蛋白的研究与了解两种严重和常见人类疾病的分子机制直接相关。 LIN-12/NOTCH蛋白的组成型激活与人类患者和哺乳动物模型中某些癌症的发展有关，LIN-12/Notch信号转导途径的关键成分（Presenilin）是阿尔茨海默氏病发展的核心。其他较不常见的疾病也与LIN-12/Notch途径成分中的畸变有关。我们在秀丽隐杆线虫中对LIN-12的工作有助于对LIN-12/NOTCH蛋白的保守发育作用和分子机制的当前了解。该建议涉及识别和表征影响秀丽隐杆线虫中LIN-12活性的新基因。我们的第一个特定目的基于对与组成型LIN-12激活相关的表型的抑制[Lin-12（d）等位基因]，涵盖了经过验证的遗传筛选上的新变化。我们的第二个具体目的是涉及新的SEL [抑制剂/增强子]基因的基本表征，而我们的第三个特定目的与了解我们识别的新基因如何共同起作用。在外阴前体细胞规范期间，LIN-12介导的横向信号传导涉及最后两个特定目标。第四个目标是在此信号事件中识别和表征LIN-12的配体，第五个目标涉及表征可能与RAS介导的外阴诱导与LIN-12介导的横向信号之间相互作用的基因。当这些特定目标完成后，我们希望已经确定了lin-12/Notch信号在动物发育中调节和执行的保守组成部分和照明的基本机制。