Molecular and Cellular functions of membrane peptides encoded by small ORFs

小开放阅读框架，或smORF，是假定的基因序列，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，在某些已知情况下甚至只有11个氨基酸。然而，smORF既可以用来制造短蛋白质(称为肽)，也可以仅仅是垃圾DNA--区分这两种可能性并非易事。一个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不到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中的哪些是多肽，哪些不是，流行的策略一直是干脆忽略它们。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实际上被制成短蛋白质，因此，是真正的活性基因。这一点很重要，因为到目前为止，我们忽略了这些smORF基因，我们可能错过了许多生物学和医学问题的解决方案，并且我们可能将一些解决方案归因于错误的基因。我们以前的工作表明，有一类或大约800个smORF组成的类提供了最好的机会：i)理解smORF功能的一般原理，以及ii)生产具有生物医学重要性的多肽。我们以前的工作表明，这类smORF产生定位于细胞膜和其他细胞器的短蛋白质；这些短膜蛋白作为正常蛋白质(即那些长于100个氨基酸的蛋白质)的抑制物(或刹车)。在这个项目中，我们计划通过以下方式证实这些假设：a)详细表征两个smORF肽的分子功能，我们已经知道它们的一般功能，以及它们正在调节的正常蛋白质。第一个smORF肽调节一种与癌症和干细胞生物学有关的细胞间信号传递；第二个肽是免疫系统细胞消化细菌所必需的，但在存在一种名为TMT的特定污染物时，可能会产生脑损伤。b)使用我们实验室开发的一种尖端技术，证实这800个smORF肽定位于细胞膜。此外，我们的目标也是确定这些smORF膜肽可能调节的正常蛋白质。

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.