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

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，其在动物发育期间指定细胞命运。LIN-12/Notch蛋白的研究与理解两种严重和常见的人类疾病的分子机制直接相关。LIN-12/Notch蛋白的组成性激活与人类患者和哺乳动物模型中某些癌症的发展相关，LIN-12/Notch信号转导途径的关键组分早老素的活性对阿尔茨海默病的发展至关重要。其他不太常见的疾病也与LIN-12/Notch通路组分的畸变相关。我们在C. elegans的研究为理解LIN-12/Notch蛋白的保守发育作用和分子机制做出了贡献。该建议涉及鉴定和表征影响C中lin-12活性的新基因。优雅我们的第一个具体目标包括一个已证实的遗传筛选的新变化，基于抑制与组成型lin-12激活[lin-12（d）等位基因]相关的表型。我们的第二个具体目标是关注新的sel [lin-12抑制/增强]基因的基本特征，我们的第三个具体目标是了解我们发现的新基因如何协同工作。最后两个具体的目标涉及在外阴前体细胞特化过程中LIN-12介导的侧向信号传导。第四个目的是关于识别和表征LIN-12在该信号传导事件中的配体，第五个目的是关于表征可能参与Ras介导的外阴诱导和LIN-12介导的侧向信号传导之间的相互作用的基因。当这些特定的目标完成后，我们希望已经确定了保守的组件，并阐明了动物发育中LIN-12/Notch信号传导的调节和执行的基本机制。

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.