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

描述(申请人提供)：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。对LIN-12/Notch蛋白的研究直接关系到理解人类两种严重和常见疾病的分子机制。在人类患者和哺乳动物模型中，LIN-12/Notch蛋白的结构性激活与某些癌症的发生有关，而LIN-12/Notch信号转导通路的关键成分早老素的活性在阿尔茨海默病的发展中起着关键作用。其他不太常见的疾病也与LIN-12/Notch途径组件的异常有关。我们在线虫中对LIN-12的研究有助于了解LIN-12/Notch蛋白的保守发育作用和分子机制。这项建议涉及识别和表征影响线虫LIN-12活性的新基因。我们的第一个具体目标是在已证实的遗传筛查上包含新的变异，基于与构成LIN-12激活相关的表型抑制[LIN-12(D)等位基因]。我们的第二个特定目标是关于新的SEL[LIN-12的抑制子/增强子]基因的基本特征，我们的第三个特定目标是关于我们识别的新基因是如何协同工作的。后两个特定的目的涉及到LIN-12介导的外阴前体细胞的侧向信号转导。第四个目标是确定和表征这个信号事件中LIN-12的配体，第五个目标是研究一个基因，该基因可能参与RAS介导的外阴诱导和LIN-12介导的侧向信号的相互作用。当这些特定的目标完成后，我们希望能够识别保守的成分，并阐明在动物发育中调节和执行Lin-12/Notch信号的基本机制。

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.