mRNA localisation: a subcellular mechanistic target to treat pathological angiogenesis.

mRNA 定位：治疗病理性血管生成的亚细胞机制靶点。

• 批准号: MR/X001164/1
• 负责人: Guilherme Costa
• 金额: $ 43.79万
• 依托单位: Queen's University Belfast
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2022
• 资助国家: 英国
• 起止时间: 2022 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FX001164%2F1
• 关键词: mRNA; localisation; subcellular; mechanistic; target

The vascular system is comprised of an intricate network of vessels that ensure the distribution of nutrients and oxygen to all the tissues in the human body. New vessels are formed during embryonic development and also in adult individuals during processes such as wound healing. The formation of new vessels occurs principally through a tightly controlled mechanism called sprouting angiogenesis. During this process, endothelial cells which are the main blocks composing vessels, branch from existing vasculature to form a new sprout. In particular human conditions, insufficient angiogenesis could be the cause of ischaemic tissue. On the other hand, excessive growth of blood vessels is the hallmark of impairing or even life-threatening diseases. For example, diabetic patients tend to suffer from dysregulated angiogenesis in the back of their eyes and if left unchecked, this can lead to blindness. During cancer progression, tumours promote angiogenesis in their local environment so they can receive nutrients and oxygen for expansion, as well as find a way to spread to other parts of the body. Although fantastic therapies that successfully halt the formation of undesirable blood vessels are now used to treat particular complications, several problems make these strategies far from perfect. For instance, particular drugs have no effects on some patients or they may even damage some other tissues due to lack of specificity. For this reason, finding new drugs that can control angiogenesis without these caveats is one of the main interests in the field of vascular medicine.We recently found that some messenger (m)RNAs, the middlemen between genes and the proteins, are not equally distributed throughout endothelial cells when they sprout to form a new vessel. We also found that taking these mRNAs to particular regions within the cell, where they are translated into proteins, is important to help the vessel grow. Hence, we sought to study whether perturbing the localisation of mRNAs can help inhibiting angiogenesis. For this, we are forming a strong team of researchers with distinct key skills and who will provide invaluable expertise at particular stages of the project. We plan to use molecules complementary to sequences in the mRNAs to inhibit their transport towards the correct location. We will firstly examine which molecules can achieve this goal in the most effective way. Afterwards we will use a collection of assays that simulate early stages of angiogenesis in a petri dish, to understand how these molecules inhibit endothelial cell sprouting and vessel formation. Next, we will transfer what we learned to mouse models to investigate the therapeutic potential of these molecules. Our experiments will be focused on a very well understood network of vessels found in the back of the eye. We will study how the disruption of mRNA localisation halts dysregulated angiogenesis, ensuring minimal animal usage and suffering. Altogether, we hope that our highly novel approach will lead to the development of new drugs, which could help circumvent current setbacks in the treatments of angiogenesis-related complications. Importantly, our work will also open new doors for the development of drugs to target localised mRNAs in a wide range of human diseases.

血管系统由错综复杂的血管网络组成，确保营养物质和氧气分布到人体的所有组织中。新血管在胚胎发育过程中形成，也在成人伤口愈合过程中形成。新血管的形成主要是通过一种被称为发芽血管生成的严格控制的机制发生的。在这一过程中，内皮细胞（构成血管的主要屏障）从现有的血管分支形成新的芽。在特定的人体条件下，血管生成不足可能是导致组织缺血的原因。另一方面，血管的过度生长是损害甚至危及生命的疾病的标志。例如，糖尿病患者往往会遭受眼睛后部血管生成失调的困扰，如果不加以控制，可能会导致失明。在癌症发展过程中，肿瘤促进局部环境中的血管生成，这样它们就可以获得营养和氧气来扩张，并找到扩散到身体其他部位的方法。虽然现在有一些神奇的疗法可以成功地阻止不良血管的形成，用于治疗特定的并发症，但一些问题使这些策略远非完美。例如，某些药物由于缺乏特异性，对某些患者没有作用，甚至可能损害其他组织。因此，寻找能够在没有这些警告的情况下控制血管生成的新药是血管医学领域的主要兴趣之一。我们最近发现，当内皮细胞发芽形成新血管时，一些信使rna（基因和蛋白质之间的中间人）并不是均匀分布在整个内皮细胞中。我们还发现，将这些mrna带到细胞内的特定区域，在那里它们被翻译成蛋白质，对帮助血管生长很重要。因此，我们试图研究干扰mrna的定位是否有助于抑制血管生成。为此，我们正在组建一支拥有独特关键技能的强大研究团队，他们将在项目的特定阶段提供宝贵的专业知识。我们计划使用与mrna序列互补的分子来抑制它们向正确位置的运输。我们将首先检查哪些分子可以以最有效的方式实现这一目标。之后，我们将在培养皿中模拟血管生成的早期阶段，以了解这些分子如何抑制内皮细胞发芽和血管形成。接下来，我们将把我们学到的知识转移到小鼠模型上，以研究这些分子的治疗潜力。我们的实验将集中在眼睛后部的血管网络上。我们将研究mRNA定位的破坏如何阻止失调的血管生成，确保最小的动物使用和痛苦。总之，我们希望我们高度新颖的方法将导致新药的开发，这将有助于避免目前血管生成相关并发症治疗的挫折。重要的是，我们的工作也将为开发针对广泛人类疾病的局部mrna的药物打开新的大门。