Elucidating the role of neuropilin-mediated intercellular adhesion in tissue vascularisation

心脏缺血、糖尿病性肢体神经病和一些神经退行性疾病等大量疾病都以重要器官缺氧为特征。正在不断开发能够调节关键血管生长因子VEGF及其受体活性的试剂，用于旨在恢复缺氧器官血液供应的医学治疗。然而，在最近的几个小鼠模型中，VEGF的传递导致了危险的扭曲和泄漏血管的形成，这些血管与周围组织的整合很差。因此，我们需要更好地了解血管内皮生长因子信号在健康器官中如何被其血管受体解释，以及VEGF信号如何与其他信号通路相结合，以确保血管对缺氧组织的协调和有效入侵。本提案中描述的项目将确定细胞表面蛋白NRP1在血管发育过程中的功能。了解NRP1的活性尤为重要，因为该蛋白在血管生长过程中可能具有双重功能，首先，作为VEGF受体，其次，作为生长血管与其入侵组织之间细胞间粘附的介质，以响应VEGF信号。

A large number of conditions such as heart ischemia, diabetic limb neuropathy and several neurodegenerative diseases are characterized by oxygen-deficiency in vital organs. Reagents are continually being developed that modulate the activity of the critical blood vessel growth factor VEGF and its receptors for use in medical therapies aimed at restoring blood supply to such oxygen-deficient organs. However, in several recent mouse models, VEGF delivery resulted in the formation of dangerously tortuous and leaky vessels that were poorly integrated into the surrounding tissue. We therfore need to undestand better how VEGF signals are interpreted by their blood vessel receptors in healthy organs, and how VEGF signals are integrated with other signaling pathway to ensure the coordinated and productive vessel invasion into the oxygen-deficient tissues. The project described in this proposal will determine how the cell surface protein NRP1 functions during blood vessel development. Understanding NRP1 activity is particularly important, because this protein is likely to perform a dual function during blood vessel growth, firstly, as a VEGF receptor, and, secondly, as a mediator of cell-to-cell adhesion between growing vessels and the tissues they invade in response to VEGF signals.