CAREER: Pericyte-Endothelial Cell Interactions via Extracellular Matrix Deposition Regulates Blood Vessel Formation and Function

血管将氧气输送到人体的每一个组织。许多疾病都与血管系统的问题有关。周细胞是一种特殊的细胞，能够稳定生长中的血管并维持血管健康。当周细胞被破坏时，糖尿病视网膜病变、阿尔茨海默病和癌症等疾病会变得更严重。该项目将通过开发周细胞参与血管形成和功能的实验和计算模型来增加对周细胞的基本理解，并特别关注周细胞与组织中称为细胞外基质的蛋白质支架的相互作用。该项目将测试这样一种假设，即细胞外基质某些成分的生产缺陷对周细胞的行为有深远的负面影响，因此可能导致周细胞在某些疾病中的功能障碍。该项目的教育部分包括与STEM教育领导者合作，扩展研究目标，为中小学教育工作者开发活动和课程，作为“跨学科”补充材料。本科生和研究生的培训机会也将被纳入，以促进对获得研究经验和开发独立项目感兴趣的学生的职业生涯。该项目的重点是阐明细胞外基质（ECM）在介导周细胞(PC)-内皮细胞（EC）相互作用中的作用，以及它们在血管发育和维持血管完整性中的作用。该研究计划旨在验证以下假设：血管的正常发育和功能主要依赖于以下两个因素的精确调控：1)EC生成胶原IV，以及(2)PC合成玻璃体连接蛋白。更具体地说，该计划包括a)开发体外和离体平台，用于成像沿重塑细胞外网络迁移的固定和活PC； b)建立除标准基因表达谱外已经过功能验证的初级PC细胞系；3)建立一个多尺度计算建模平台，在ec的胶原IV生成率范围内，重现PC沿着发育中的血管迁移；4)使用其他体内实验方法来实现两个目标：1)阐明ec来源的IV型胶原对（i)血管发育过程中PC的迁移和投资以及（ii）沿功能性血管保留的影响；2）确定PC来源的玻璃质粘连蛋白在(i)血管形成和（ii）维持成熟血管完整性中的作用。该奖项反映了美国国家科学基金会的法定使命，并通过使用基金会的知识价值和更广泛的影响审查标准进行评估，被认为值得支持。

Blood vessels bring oxygen to every tissue in the human body. Many diseases are related to problems with the vascular system. Pericytes are special cells that stabilize growing blood vessels and maintain vascular health. Illnesses like diabetic retinopathy, Alzheimer's disease, and cancer become worse when pericytes are disrupted. This project will increase fundamental understanding of pericytes by developing experimental and computational models of their involvement in blood vessel formation and function, with a specific focus on their interactions with the protein scaffold in tissues known as the extracellular matrix. The project will test the hypothesis that defects in the production of certain components of the extracellular matrix have profoundly negative consequences for pericyte behaviors and could therefore contribute to their dysfunction in certain diseases. The educational component of this project includes working with STEM education leaders to extend the research goals for the development of activities and lessons for primary and secondary educators to use as "cross-curricular" supplemental material. Training opportunities for undergraduate and graduate students will also be incorporated, advancing the careers of students interested in gaining research experience and developing independent projects.The project focuses on elucidating the role of the extracellular matrix (ECM) in mediating pericyte(PC)-endothelial cell (EC) interactions and their role in vascular development and maintenance of blood vessel integrity. The Research Plan is designed to test the hypothesis that proper vascular development and function depend critically on the precise regulation of 1) EC production of collagen IV, and (2) PC synthesis of vitronectin. More specifically, the Plan includes a) development of in vitro and ex vivo platforms for imaging fixed and live PCs migrating along remodeling extracellular networks, b) establishment of a primary PC cell line that has been functionally validated in addition to standard gene expression profiling, 3) establishment of a multi-scale computational modelingplatform to recapitulate PC migration along developing vessels in the context of a range of collagen IV production rates from ECs and 4) use of other in vivo experimental approaches to achieve two objectives: 1) Elucidate the effect of EC-derived collagen IV on (i) PC migration and investment during vessel development and (ii) PC retention along functional vasculature and 2) Determine the role of PC-derived vitronectin in (i) vascular formation and (ii) maintaining the integrity of mature blood vessels.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.