IMPC: Phenotyping Cardiovascular Development of Rbms1-null mice

IMPC：Rbms1 缺失小鼠的心血管发育表型分析

• 批准号: MR/P026184/1
• 负责人: Christiana Ruhrberg
• 金额: $ 3.22万
• 依托单位: University College London
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2017
• 资助国家: 英国
• 起止时间: 2017 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FP026184%2F1
• 关键词: IMPC; Phenotyping; Cardiovascular; Development; Rbms1

The therapeutic stimulation of new blood vessel growth is considered a promising treatment for diseases in which organs become oxygen starved, for example after a heart attack or stroke and in diabetic vascular eye disease. Moreover, blood vessel function is thought to contribute to neurodegenerative diseases such as Alzheimer's disease and amyotrophic lateral sclerosis. However, we still have large gaps in our knowledge of how blood vessels normally grow to support the function of the brain, heart and other organs. Moreover, the first therapeutic attempts to stimulate vessel growth to alleviate oxygen starvation were ineffective, because the new vessels were not properly embedded into the organs they should supply. Based on prior work, we now know that two molecules called NRP1 and ITGB1 are essential to guide newly formed blood vessels to the right places in many organs. However, both molecules can also promote the formation of abnormal blood vessels and thereby exacerbate vascular problems in some diseases. Moreover, it is difficult to manipulate these molecules therapeutically, because they also participate in several other essential processes in the body. It is therefore important to identify additional molecules that function together with NRP1 and ITGB1 in blood vessel growth and may provide more selective targets for therapy. Our pilot studies suggest that a molecule termed RBMS1 functions together with NRP1 and ITGB1 in signalling pathways that support blood vessel growth. Moreover, mice lacking RBMS1 die before birth, demonstrating that its normal function is very important. However, very little is still known on the role of RBMS1 in normal cells, how it may support embryonic development and whether it plays a role in blood vessel growth by interacting with NRP1 and ITGB1 or in other pathways. We will therefore establish when during development RBMS1 deficiency causes death, determine which organ systems are affected and examine whether blood vessel growth is defective when RBMS1 is missing.

治疗性刺激新血管生长被认为是治疗器官缺氧疾病的一种很有希望的方法，例如心脏病发作或中风后以及糖尿病血管性眼病。此外，血管功能被认为有助于神经退行性疾病，如阿尔茨海默病和肌萎缩侧索硬化症。然而，对于血管如何正常生长以支持大脑、心脏和其他器官的功能，我们的知识仍有很大的空白。此外，第一次刺激血管生长以缓解缺氧的治疗尝试是无效的，因为新的血管没有正确地嵌入它们应该供应的器官。基于先前的工作，我们现在知道NRP1和ITGB1两种分子对于引导新形成的血管到达许多器官的正确位置至关重要。然而，这两种分子也可以促进异常血管的形成，从而加剧某些疾病的血管问题。此外，由于这些分子还参与体内其他几个重要的过程，因此很难在治疗上操纵这些分子。因此，确定与NRP1和ITGB1在血管生长中一起起作用的其他分子是很重要的，并可能为治疗提供更多的选择性靶点。我们的初步研究表明，一种名为RBMS1的分子与NRP1和ITGB1一起在支持血管生长的信号通路中起作用。此外，缺乏RBMS1的小鼠在出生前死亡，表明其正常功能非常重要。然而，RBMS1在正常细胞中的作用，它如何支持胚胎发育，以及它是否通过与NRP1和ITGB1相互作用或其他途径在血管生长中发挥作用，仍然知之甚少。因此，我们将确定在发育过程中RBMS1缺乏导致死亡的时间，确定哪些器官系统受到影响，并检查当RBMS1缺失时血管生长是否有缺陷。