Characterization of microRNA cell death regulators

microRNA 细胞死亡调节因子的表征

基本信息

批准号：
7195102
负责人：
BRUCE A HAY
金额：
$ 22.46万
依托单位：
CALIFORNIA INSTITUTE OF TECHNOLOGY
依托单位国家：
美国
项目类别：
财政年份：
2004
资助国家：
美国
起止时间：
2004-04-01 至 2008-09-30
项目状态：
已结题

项目摘要

DESCRIPTION (provided by applicant): Apoptotic cell death is an evolutionarily conserved process by which organisms remove cells that are superfluous, that have outlived their usefulness, or that are dangerous for the survival of the organism. Deregulation of cell death is associated with a number of human diseases, including cancer and autoimmuity (decreased in cell death), and neurodegenerative diseases (increased cell death). Essentially all of the identified cell death regulatory genes encode proteins. Screens for protein-encoding genes made sense given what we knew at the time - that proteins are the dominant effectors and regulators of cellular functions. However, within the last several years it has become clear that genomes of plants and animals contain on the order of hundreds of small, noncoding RNAs (miRNAs) that regulate gene function through interactions with target mRNAs. A number of these are evolutionarily conserved. The functions of almost all of them are unknown. We have identified multiple Drosophila miRNAs that encode potent cell death inhibitors. At least one of these has a clear human homolog. These observations are important because they define new points and mechanisms of cell death regulation. In addition, they suggest a heretofore hidden resource of cell death regulators whose deregulation may contribute to human disease. For example, death-inhibiting miRNAs, being very small and noncoding, would not have been identified in previous screens for genes that promote oncogenesis by inhibiting cell death. They also would have been missed in experiments designed to identify candidate oncogenes through transcriptional profiling of normal and transformed cells because these experiments were not designed to detect miRNAs. In this proposal we describe genetic and biochemical experiments designed to explore the roles that miRNAs play as cell death regulators. Our efforts will be focused on several goals: to identify evolutionarily conserved cell death-inhibiting miRNAs, to determine the mechanisms by which these miRNAs function - the identities of their mRNA targets - and the contexts in which they are important. We will also search for human homologs of the miRNAs we identify. Where studied, signaling pathways in flies and mammals utilize similar components and regulatory mechanisms. Therefore, it is likely that successful completion of the proposed experiments will increase our understanding of how cell death is regulated in human health and disease.

描述（由申请人提供）：凋亡细胞死亡是一个进化保守的过程，通过该过程，有机体消除了多余的细胞，其实用性已经超过了其有用性，或者对生物体的生存是危险的。细胞死亡的放松管制与许多人类疾病有关，包括癌症和自身脱位（细胞死亡减少）和神经退行性疾病（细胞死亡增加）。本质上，所有已鉴定的细胞死亡调节基因编码蛋白质。鉴于我们当时所知，蛋白质编码基因的筛选是有意义的 - 蛋白质是细胞功能的主要效应子和调节剂。但是，在过去的几年中，很明显，动植物的基因组在数百个非编码RNA（miRNA）的顺序中包含，这些rNA（miRNA）通过与靶标mRNA相互作用来调节基因功能。其中许多是进化保守的。它们几乎所有的功能都是未知的。我们已经确定了编码有效细胞死亡抑制剂的多个果蝇miRNA。其中至少有一个具有清晰的人类同源性。这些观察结果很重要，因为它们定义了细胞死亡调节的新点和机制。此外，他们提出了迄今一种细胞死亡调节剂的隐藏资源，其放松管制可能会导致人类疾病。例如，在先前的筛选中，无法通过抑制细胞死亡来促进肿瘤发生的基因，在先前的筛选中尚未鉴定出死亡的miRNA。它们在旨在通过正常细胞和转化细胞的转录分析鉴定候选癌症的实验中也会错过，因为这些实验不是为检测miRNA的设计。在此提案中，我们描述了旨在探索miRNA作为细胞死亡调节剂的作用的遗传和生化实验。我们的努力将集中在几个目标上：确定进化保守的细胞死亡抑制miRNA，以确定这些miRNA功能的机制 - 其mRNA靶标的身份及其重要的环境。我们还将搜索我们识别的miRNA的人类同源物。在研究的地方，苍蝇和哺乳动物中的信号通路利用类似的组件和调节机制。因此，拟议的实验成功完成可能会增加我们对细胞死亡如何在人类健康和疾病中调节的理解。