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

血管系统由复杂的血管网络组成，确保将营养物质和氧气分配到人体的所有组织。新血管在胚胎发育期间形成，并且在成年个体中在伤口愈合等过程中也形成。新血管的形成主要通过一种被称为萌芽血管生成的严格控制的机制发生。在此过程中，内皮细胞作为组成血管的主要块，从现有的血管系统中分支形成新的芽。特别是在人类条件下，血管生成不足可能是缺血组织的原因。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，糖尿病患者往往在他们的眼睛后面患有失调的血管生成，如果不加以控制，这可能导致失明。在癌症进展过程中，肿瘤在其局部环境中促进血管生成，因此它们可以获得营养和氧气进行扩张，并找到扩散到身体其他部位的方法。尽管现在已经有了一些神奇的疗法，可以成功地阻止不良血管的形成，用于治疗特定的并发症，但仍有一些问题使这些策略远非完美。例如，某些药物对某些患者没有影响，甚至可能由于缺乏特异性而损害其他组织。因此，寻找新的药物来控制血管生成而不需要这些注意事项是血管医学领域的主要兴趣之一。我们最近发现，一些信使（m）RNA，基因和蛋白质之间的中间人，在内皮细胞发芽形成新血管时，并不均匀地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，我们正在组建一支强大的研究团队，他们拥有独特的关键技能，并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。我们将首先研究哪些分子可以以最有效的方式实现这一目标。之后，我们将使用一系列在培养皿中模拟血管生成早期阶段的试验，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，我们将把我们所学到的转移到小鼠模型中，以研究这些分子的治疗潜力。我们的实验将集中在一个非常好理解的血管网络中发现的眼睛后面。我们将研究mRNA定位的破坏如何停止失调的血管生成，确保最小的动物使用和痛苦。总而言之，我们希望我们高度新颖的方法将导致新药的开发，这可能有助于规避目前在治疗血管生成相关并发症方面的挫折。重要的是，我们的工作还将为开发针对各种人类疾病中局部mRNA的药物打开新的大门。

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.