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Molecular and Cellular functions of membrane peptides encoded by small ORFs

小 ORF 编码的膜肽的分子和细胞功能

基本信息

批准号：
BB/N001753/1
负责人：
Juan Couso
金额：
$ 94.18万
依托单位：
University of Sussex
依托单位国家：
英国
项目类别：
Research Grant
财政年份：
2016
资助国家：
英国
起止时间：
2016 至无数据
项目状态：
已结题

来源：
https://gtr.ukri.org/projects?ref=BB%2FN001753%2F1
关键词：
Molecular Cellular functions membrane peptides

项目摘要

Small Open Reading Frames, or smORFs, are putative genes sequences that are 10 to 100 times smaller than the normal genes that are already known about. smORFs typically encode for proteins that have less than 100 amino acids in a chain, and in some known cases as few as 11. However, a smORF could either be used to make a short protein (called a peptide), or it could just be 'junk' DNA - distinguishing between these two possibilities is not easy. An animal genome typically contains tens of thousands of 'normal' genes, but it also contains hundreds of thousands of smORFs of less than 100 amino acids. Given that using only computer methods it is almost impossible to predict which of these smORFs are made into peptides and which are not, the prevailing strategy has been to simply ignore them. Our research team uses multidisciplinary, cutting edge laboratory and computational techniques to detect which smORFs actually get made into short proteins, and thus, are actual active genes. This is important because, by so far ignoring these smORF genes, we could be missing the solutions to many biological and medical problems, and we may have attributed some solutions to the wrong genes.Our previous work indicates that there is a class composed or about 800 smORFs that offers the best chance to i) understand general principles of smORF function, and ii) produce peptides with functions of biomedical importance. Our previous work suggests that this class of smORF produces short proteins that locate to the membranes of cells and other cell organelles; and that these short membrane proteins work as repressors (or 'brakes') of normal proteins (i.e. those longer than 100 amino acids). In this project we plan to corroborate these hypotheses by: A) characterising in detail the molecular function of two smORF peptides, for which we already know their general function, and the normal proteins that they are regulating. The first smORF peptide regulates a type of cell-to-cell signalling that is involved in cancer and stem-cell-biology; the second peptide is needed by the cells of the immune system to digest bacteria, but in the presence of a specific pollutant called TMT, can produce brain damage.B) corroborating that these 800 smORF peptides localise to cell membranes, using a cutting edge technique that we have developed in our laboratory. In addition, we aim to identify also the normal proteins that these smORF membrane peptides may be regulating.

小型开放阅读框架（Small Open Reading frame, smorf）是一种假定的基因序列，比已知的正常基因小10到100倍。smorf通常编码一条链中氨基酸少于100个的蛋白质，在一些已知的情况下只有11个。然而，smORF既可以用来制造短蛋白质（称为肽），也可以只是“垃圾”DNA——区分这两种可能性并不容易。动物基因组通常包含数万个“正常”基因，但它也包含数十万个少于100个氨基酸的smorf。考虑到仅使用计算机方法几乎不可能预测这些smorf中哪些会被制成肽，哪些不会，普遍的策略是简单地忽略它们。我们的研究团队使用多学科、尖端的实验室和计算技术来检测哪些smorf实际上被制成了短蛋白，因此是真正的活性基因。这一点很重要，因为到目前为止，如果忽视这些smORF基因，我们可能会错过许多生物学和医学问题的解决方案，而且我们可能把一些解决方案归因于错误的基因。我们之前的工作表明，有一个由大约800个smORF组成的类，它提供了最好的机会，i)了解smORF功能的一般原理，ii)产生具有生物医学重要性的肽。我们之前的工作表明，这类smORF产生定位于细胞膜和其他细胞器的短蛋白；这些短膜蛋白是正常蛋白（即长度超过100个氨基酸的蛋白）的抑制因子（或“刹车”）。在这个项目中，我们计划通过以下方式来证实这些假设：A)详细描述两个smORF肽的分子功能，我们已经知道它们的一般功能，以及它们调节的正常蛋白质。第一个smORF肽调节一种参与癌症和干细胞生物学的细胞间信号传导；第二种肽是免疫系统细胞消化细菌所需要的，但在一种叫做TMT的特殊污染物存在的情况下，会对大脑造成损伤。B)使用我们在实验室开发的尖端技术，证实这800种smORF肽定位于细胞膜。此外，我们的目标是确定这些smORF膜肽可能调节的正常蛋白。