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How are meiotic genes re-activated in cancer and can we exploit this in the clinic?

减数分裂基因如何在癌症中重新激活？我们可以在临床中利用它吗？

基本信息

批准号：
MR/X00855X/1
负责人：
Urszula McClurg
金额：
$ 59.74万
依托单位：
University of Liverpool
依托单位国家：
英国
项目类别：
Research Grant
财政年份：
2023
资助国家：
英国
起止时间：
2023 至无数据
项目状态：
未结题

来源：
https://gtr.ukri.org/projects?ref=MR%2FX00855X%2F1
关键词：
How meiotic genes re activated

项目摘要

Under normal circumstances, reproductive proteins make sure that a baby receives half of its genetic material, DNA, from the mother (through the egg) and half from the father (through the sperm). This means that the baby contains a mixture of both their mother's and father's genes. Reproductive proteins are believed to be present only in organs that take part in reproduction and have no other known roles in the body.Unexpectedly, we recently discovered that some of these reproductive proteins, known as 'SC proteins', are also found in cancer cells. Furthermore, when the levels of SC proteins are high, patients have a more aggressive disease and die earlier. Currently, we do not understand why and how cancer cells make these reproductive proteins. However, we have observed that chemotherapies used to treat certain cancers can cause reproductive factors to turn back on. This, in turn, can lead to therapy resistance and worsening of the cancer. Our goal is to determine how SC proteins are switched back on in cancer, and which chemotherapies cause the proteins to be switched on. We will address these questions through three pieces of work, each with specific aims.Aim 1. Characterise promoter binding proteins responsible for SC promoter production in cancer.Production of a protein inside a cell is triggered by activating proteins - promoter binding proteins - interacting with the DNA which encodes the protein. Cells have a wide range of promoter binding proteins. We will use a novel approach developed in my lab to discover which promoter binding proteins interact with DNA encoding SC proteins and activate protein production.Aim 2. Characterise the network of regulators involved in SC re-expression in cancer.It is essential that the correct promoter binding proteins are active at the right time. The availability of each type of promoter binding protein is controlled by a network of other proteins. This network of proteins can therefore indirectly affect whether SC proteins are made in cancer cells. In this section of work we will use a combination of laboratory and computational experiments to characterise the protein networks responsible for SC protein production. Aim 3. Determine which anti-cancer therapeutics activate SC expression and the impact this has on treatment outcome.Finally, we will perform experiments analysing the levels of SC proteins produced in cancer cells in the presence of a range of commonly-used anti-cancer therapies. We will identify therapies that cause SC proteins to be made in cancer cells, and also establish the impact SC protein production has on resistance development.Our project has important implications for future cancer treatment. Currently, more than 166,000 people die from cancer in the UK each year. Becoming resistant to chemotherapy and the resulting treatment failure is responsible for 90% of these deaths. Our research will help to identify those whose cancers are becoming treatment resistant and - in the longer term - paves the way for new drugs to prevent resistance developing.In addition, one of the main challenges in cancer treatment is to selectively kill tumour cells whilst sparing healthy cells. Unfortunately, most anti-cancer treatments also kill healthy cells, which is the reason for side-effects like nausea and weakness. As reproductive proteins are absent in normal healthy organs, they could be important new targets for the development of anti-cancer drugs. Killing cancer cells that express these proteins might be specific, and protect healthy non-cancer cells, resulting in less side-effects for patients.

在正常情况下，生殖蛋白确保婴儿从母亲（通过卵子）接收一半的遗传物质 DNA，一半从父亲（通过精子）接收。这意味着婴儿混合了母亲和父亲的基因。生殖蛋白被认为只存在于参与生殖的器官中，在体内没有其他已知的作用。出乎意料的是，我们最近发现其中一些被称为“SC蛋白”的生殖蛋白也存在于癌细胞中。此外，当 SC 蛋白水平较高时，患者的病情会更严重，并且会更早死亡。目前，我们不明白癌细胞为何以及如何产生这些生殖蛋白。然而，我们观察到用于治疗某些癌症的化疗可能会导致生殖因素重新启动。反过来，这可能导致治疗抵抗和癌症恶化。我们的目标是确定 SC 蛋白如何在癌症中重新开启，以及哪些化疗导致这些蛋白被开启。我们将通过三项工作来解决这些问题，每项工作都有特定的目标。目标 1. 表征癌症中负责 SC 启动子产生的启动子结合蛋白。细胞内蛋白质的产生是通过激活蛋白质（启动子结合蛋白）与编码该蛋白质的 DNA 相互作用来触发的。细胞具有多种启动子结合蛋白。我们将使用我的实验室开发的一种新方法来发现哪些启动子结合蛋白与编码 SC 蛋白的 DNA 相互作用并激活蛋白质产生。目标 2. 表征癌症中参与 SC 再表达的调节因子网络。正确的启动子结合蛋白在正确的时间激活至关重要。每种类型的启动子结合蛋白的可用性均由其他蛋白的网络控制。因此，这种蛋白质网络可以间接影响癌细胞中是否产生 SC 蛋白。在这部分工作中，我们将结合实验室和计算实验来表征负责 SC 蛋白质生产的蛋白质网络。目标 3. 确定哪种抗癌疗法可激活 SC 表达以及这对治疗结果的影响。最后，我们将进行实验，分析在一系列常用抗癌疗法存在的情况下癌细胞中产生的 SC 蛋白的水平。我们将确定导致癌细胞中产生 SC 蛋白的疗法，并确定 SC 蛋白的产生对耐药性发展的影响。我们的项目对未来的癌症治疗具有重要意义。目前，英国每年有超过 166,000 人死于癌症。 90% 的死亡是由于对化疗产生耐药性以及由此导致的治疗失败造成的。我们的研究将有助于识别那些正在对治疗产生耐药性的癌症，并从长远来看，为防止耐药性发展的新药铺平道路。此外，癌症治疗的主要挑战之一是选择性杀死肿瘤细胞，同时保留健康细胞。不幸的是，大多数抗癌治疗也会杀死健康细胞，这就是恶心和虚弱等副作用的原因。由于正常健康器官中不存在生殖蛋白，因此它们可能成为抗癌药物开发的重要新靶标。杀死表达这些蛋白质的癌细胞可能是特异性的，并保护健康的非癌细胞，从而减少对患者的副作用。