Elucidating the role of pericytes in angiogenesis in the brain using a tissue-engineered microvessel model

使用组织工程微血管模型阐明周细胞在大脑血管生成中的作用

基本信息

批准号：
10648177
负责人：
Peter C Searson
金额：
$ 20.47万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-03-15 至 2025-02-28
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10648177
关键词：
3-Dimensional Acceleration Address Adult Altitude Angiogenic Factor Animal Model Back Biological Assay Biological Process Blood - brain barrier anatomy Blood Vessels Blood capillaries Brain Cell Therapy Cells Central Nervous System Cerebrovascular system Complex Cues Development Disease Endothelial Cells Endothelium Engineering Exercise Exposure to FGF2 gene Fluorescent in Situ Hybridization Foundations Genes Genetic Engineering Goals Growth Growth Factor Human Hypoxia In Situ Injury Knowledge Lead Malignant neoplasm of brain Modeling Mus Neurodegenerative Disorders Neurons Pathologic Pathologic Processes Pericytes Phase Phenotype Physiological Physiological Processes Play Process RNA Reporting Retina Role Stroke Testing Tissue Engineering Trauma Traumatic Brain Injury Vascularization angiogenesis cerebral microvasculature cerebrovascular experimental study human model migration novel therapeutics postcapillary venule repaired response response to injury stem cell technology therapy design tissue repair transcriptome sequencing transcriptomics venule wound healing

项目摘要

Project Summary Angiogenesis is a complex and tightly regulated process essential for tissue repair in response to injury or disease. In the adult human brain, the cerebrovasculature is largely quiescent but angiogenesis is associated with disease (e.g. stroke, neurodegenerative disease, and brain cancer), wound healing (e.g. traumatic brain injury), and physiological factors (e.g. exercise, high altitude adaptation, etc.). In the generally accepted model of brain angiogenesis, when blood vessels are exposed to angiogenic cues, pericytes detach from activated endothelial cells and are passive bystanders during sprout formation and growth, only migrating back to surround the newly formed endothelium in the maturation phase. However, a few studies in humans and animal models have reported that pericytes can play an active role in angiogenesis, leading sprout growth and promoting the migration of stalk cells. The objective of this project is to identify the role of pericytes during angiogenesis in the brain. Our major hypothesis is that pericytes can be selectively activated to become the tip cells and lead the growth of angiogenic sprouts. The objective will be addressed in three aims. In Aim 1, we will use a tissue-engineered post-capillary venule model to assess the role of hypoxia and growth factor gradients on pericyte-guided angiogenesis. In Aim 2, we will evaluate the transcriptomic profile of pericytes during angiogenesis. Immunostaining and in situ RNA hybridization will be used to examine key markers of tip cells as well as to validate key sequencing results. In Aim 3, we will perform a proof-of-concept experiment to test the hypothesis that gene editing can be used to engineer tip cell phenotype. Understanding the role of pericytes in adult brain angiogenesis is important in understanding the response to the cerebrovasculature to a wide range of perturbations and will enable the development of new therapies for cerebrovascular repair.

项目概要血管生成是一个复杂且严格调控的过程，对于响应损伤或组织修复至关重要疾病。在成人大脑中，脑血管系统大部分处于静止状态，但血管生成与之相关疾病（如中风、神经退行性疾病和脑癌）、伤口愈合（如脑外伤）损伤）和生理因素（如运动、高海拔适应等）。在普遍接受的模型中脑血管生成的过程中，当血管暴露于血管生成信号时，周细胞就会从激活的血管中分离出来。内皮细胞在芽形成和生长过程中是被动的旁观者，仅迁移回周围环境成熟阶段新形成的内皮细胞。然而，一些针对人类和动物模型的研究据报道，周细胞可以在血管生成中发挥积极作用，引导芽生长并促进茎细胞的迁移。该项目的目的是确定周细胞在大脑血管生成过程中的作用。我们的专业假设是周细胞可以被选择性地激活成为尖端细胞并导致血管生成的生长豆芽。该目标将通过三个目标来实现。在目标 1 中，我们将使用组织工程毛细血管后小静脉模型评估缺氧和生长因子梯度对周细胞引导的血管生成的作用。瞄准 2，我们将评估血管生成过程中周细胞的转录组学特征。免疫染色和原位 RNA 杂交将用于检查尖端细胞的关键标记以及验证关键测序结果。在目标 3，我们将进行概念验证实验来检验基因编辑可用于工程师尖端细胞表型。了解周细胞在成人脑血管生成中的作用对于了解脑血管系统对各种扰动的反应，并将使开发脑血管修复新疗法。