Determining the structure and endothelial signalling function of the CLEC14A-Multimerin2 complex

血管生成在发育过程中、在伤口愈合等生理过程中以及在癌症和糖尿病视网膜病变等疾病的发病机制中发挥着关键作用。CLEC14A-MMRN2-CD248复合体调节血管生成，本项目旨在表征其结构和功能。CLEC14A是一种在多种肿瘤类型的血管系统中表达的肿瘤内皮标记物，正被开发为旨在破坏实体肿瘤血管的新型抗癌治疗的靶点。我们和其他人发现多聚体2(MMRN2)是CLEC14A的配体，随后发现CD93和CD248也与MMRN2结合。与CLEC14A类似，CD93由内皮细胞表达，与CLEC14A相同的MMRN2区域相互作用，而CD248由周细胞和成纤维细胞表达，与MMRN2的不同区域相互作用。因此，CLEC14A-MMRN2-CD248复合体在内皮细胞和邻近的间充质细胞(如周细胞和成纤维细胞)之间形成了一座分子桥梁；本项目将使用分子和细胞生物学以及生物物理学中的一系列最先进方法来研究其结构和信号功能。了解这种复合体的结构将有助于CLEC14A的有效靶向治疗，并可能发现在各种病理中调节血管生成的新策略。

Angiogenesis plays a critical role during development, in physiological processes such as wound healing and in the pathogenesis of diseases including cancer and diabetic retinopathy. The CLEC14A-MMRN2-CD248 complex modulates angiogenesis and this project aims to characterise its structure and function. CLEC14A is a tumour endothelial marker expressed in the vasculature of multiple tumour types, and is being developed as a target for novel anti-cancer therapies aimed at destroying the vessels of solid tumours. We and others identified multimerin 2 (MMRN2) as a ligand for CLEC14A and subsequently discovered that CD93 and CD248 also bind MMRN2. Like CLEC14A, CD93 is expressed by endothelial cells and interacts with the same region of MMRN2 as CLEC14A, by contrast CD248 is expressed by pericytes and fibroblasts and interacts with a distinct region of MMRN2. The CLEC14A-MMRN2-CD248 complex thus forms a molecular bridge between the endothelial cells and adjacent mesenchymal cells such as pericytes and fibroblasts; this project will investigate its structure and signalling function using a range of state-of-art methodologies in molecular and cellular biology and biophysics. Understanding the structure of this complex will facilitate efficient therapeutic targeting of CLEC14A and may uncover new strategies to modulate angiogenesis in a variety of pathologies.