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

确定 CLEC14A-Multimerin2 复合物的结构和内皮信号传导功能

基本信息

批准号：
2435622
负责人：
金额：
--
依托单位：
University of Birmingham
依托单位国家：
英国
项目类别：
Studentship
财政年份：
2020
资助国家：
英国
起止时间：
2020 至无数据
项目状态：
已结题

来源：
https://gtr.ukri.org/projects?ref=studentship-2435622
关键词：
Determining structure endothelial signalling function

项目摘要

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.

血管生成在发育过程中、在生理过程如伤口愈合中以及在包括癌症和糖尿病视网膜病变在内的疾病的发病机制中起关键作用。CLEC 14 A-MMRN 2-CD 248复合物调节血管生成，本项目旨在验证其结构和功能。CLEC 14 A是一种在多种肿瘤类型的血管系统中表达的肿瘤内皮标志物，并且正在被开发为旨在破坏实体瘤血管的新型抗癌疗法的靶点。我们和其他人鉴定了多聚体蛋白2（MMRN 2）作为CLEC 14 A的配体，随后发现CD 93和CD 248也结合MMRN 2。与CLEC 14 A一样，CD 93由内皮细胞表达并与CLEC 14 A相同的MMRN 2区域相互作用，相反，CD 248由周细胞和成纤维细胞表达并与MMRN 2的不同区域相互作用。CLEC 14 A-MMRN 2-CD 248复合物因此在内皮细胞和相邻的间充质细胞（如周细胞和成纤维细胞）之间形成分子桥梁;该项目将使用分子和细胞生物学和生物物理学中的一系列最先进的方法来研究其结构和信号功能。了解这种复合物的结构将有助于CLEC 14 A的有效治疗靶向，并可能揭示在各种病理学中调节血管生成的新策略。