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）：细胞凋亡是一种进化上保守的过程，生物体通过该过程去除多余的细胞、已经失去作用的细胞或对生物体的生存有危险的细胞。细胞死亡的失调与许多人类疾病有关，包括癌症和自身免疫（细胞死亡减少）以及神经退行性疾病（细胞死亡增加）。基本上所有已识别的细胞死亡调节基因都编码蛋白质。鉴于我们当时所知道的——蛋白质是细胞功能的主要效应器和调节器——筛选蛋白质编码基因是有意义的。然而，在过去的几年里，人们已经清楚地认识到，植物和动物的基因组包含数百个小型非编码 RNA (miRNA)，它们通过与目标 mRNA 相互作用来调节基因功能。其中许多在进化上是保守的。几乎所有它们的功能都是未知的。我们已经鉴定出多种编码有效细胞死亡抑制剂的果蝇 miRNA。其中至少有一种具有明确的人类同源物。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，他们还提出了迄今为止隐藏的细胞死亡调节因子资源，其失调可能导致人类疾病。例如，死亡抑制 miRNA 非常小且非编码，在之前筛选通过抑制细胞死亡促进肿瘤发生的基因时不会被识别。在旨在通过正常细胞和转化细胞的转录谱来识别候选癌基因的实验中，它们也可能会被遗漏，因为这些实验并不是为了检测 miRNA 而设计的。在本提案中，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：识别进化上保守的抑制细胞死亡的 miRNA，确定这些 miRNA 发挥作用的机制——它们的 mRNA 靶标的身份——以及它们发挥重要作用的背景。我们还将寻找我们确定的 miRNA 的人类同源物。研究发现，果蝇和哺乳动物的信号传导途径利用相似的成分和调节机制。因此，成功完成所提出的实验可能会增加我们对人类健康和疾病中细胞死亡如何调节的理解。