Endothelial tip cell-mediated angiogenesis and repair after neonatal stroke

新生儿中风后内皮尖端细胞介导的血管生成和修复

基本信息

批准号：
10585348
负责人：
Fernando Francisco Gonzalez
金额：
$ 46.79万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-09-22 至 2027-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10585348
关键词：
Acute Area Astrocytes Behavioral Blood Vessels Brain Brain Injuries Brain region Cause of Death Cell Communication Cell Therapy Cells Chronic Cicatrix Critical Pathways Data Diagnosis Dose Early treatment Endothelial Cells Endothelium Erythropoietin Erythropoietin Receptor Fibroblasts Fibrosis Focal Brain Injuries Functional disorder Gene Expression Genetic Transcription Goals Growth Growth Factor Heme Histologic Hypoxia Immunophenotyping Infarction Injury Knockout Mice Knowledge Measures Mediating Methodology Middle Cerebral Artery Occlusion Molecular Mus Natural regeneration Neonatal Neonatal Brain Injury Newborn Infant Outcome Paracrine Communication Pathway interactions Pericytes Phase Pre-Clinical Model Proliferating Publishing Recovery Reperfusion Injury Role Signal Pathway Signal Transduction Stroke Stromal Cells Testing Therapeutic Time Validation Vascular Endothelial Growth Factors Work angiogenesis cell type conditional knockout disability functional disability functional outcomes improved improved outcome ischemic injury mesenchymal stromal cell neonatal brain neonatal stroke neurovascular notch protein novel novel therapeutic intervention perinatal ischemic stroke post stroke post-stroke angiogenesis programs public health relevance receptor repaired response socioeconomics trafficking treatment strategy

项目摘要

PROJECT SUMMARY/ABSTRACT Neonatal stroke is an important cause of death and disability, and diagnosis is often delayed. There is insufficient knowledge regarding repair mechanisms that occur in response to focal ischemia-reperfusion injury that is the most common cause of early stroke. Angiogenesis, fibrosis, and perivascular cell repopulation occur in close proximity, with paracrine signaling supporting endothelial cell interactions that are vital for repair. Modulating this neurovascular niche may be a potential target for enhancing outcomes after ischemic injury in the developing brain. Erythropoietin and cell-based therapies have emerged as promising delayed treatment strategies for stroke, although the mechanism of their benefit is still not entirely clear. It is likely that dynamic release of pro-angiogenic growth factors and activation of signaling pathways downstream of erythropoietin receptor have differential effects on endothelial cell subtypes in distinct brain regions and at different time points after injury. In addition, the defined role of local fibrosis in injury progression and repair following early focal brain injury is unknown. Effectively inducing long-term, functional angiogenesis requires understanding and mimicking mechanisms that occur in the developing brain. Our objectives are to understand local angiogenesis and fibrosis in ischemic and peri-infarct regions following focal ischemia-reperfusion injury in the developing brain, and to determine the mechanisms of regeneration and repair with delayed erythropoietin by focusing on the vascular response. In Aim 1, we will test the hypothesis that endothelial tip cells at the vascular front are critical for angiogenesis following neonatal stroke, and that delayed erythropoietin will enhance angiogenesis and alter endothelial cell-subtype gene expression profiles to promote tip cell programs. In Aim 2, we will quantify fibroblasts and perivascular cells in the ischemic core and peri-infarct penumbra in the acute, subacute, and chronic stages after stroke and determine how erythropoietin signaling impacts local fibrosis and repair. Finally, in Aim 3, we will determine and modify specific signaling pathways to test the hypothesis that dynamic endothelial cell signaling modulated by erythropoietin is crucial for promoting local angiogenesis following focal brain injury. This will determine critical, modifiable pathways important for injury progression and repair following neonatal stroke. Our primary hypothesis is that delayed erythropoietin treatment will promote vascular growth and remodeling, reduce subacute fibrosis and astrocytic proliferation in the ischemic core, and enhance perivascular signaling to improve histological and functional outcomes after neonatal stroke. Together, these three aims will explore the roles of specific cellular subtypes and pathways in recovery after focal brain injury, with the broader goal of optimizing therapeutic strategies to improve long-term outcomes after a common cause of full-term brain injury that currently has no therapy.

项目概要/摘要新生儿卒中是死亡和残疾的重要原因，且诊断常常被延误。有对局灶性缺血再灌注损伤的修复机制了解不足这是早期中风的最常见原因。发生血管生成、纤维化和血管周围细胞再生紧密相连，旁分泌信号支持对修复至关重要的内皮细胞相互作用。调节这种神经血管生态位可能是改善缺血性损伤后预后的潜在目标正在发育的大脑。促红细胞生成素和细胞疗法已成为有希望的延迟治疗治疗中风的策略，尽管其益处机制仍不完全清楚。很可能是动态的促血管生成生长因子的释放和促红细胞生成素下游信号通路的激活受体对不同脑区和不同时间的内皮细胞亚型有不同的影响受伤后的积分。此外，局部纤维化在早期损伤进展和修复中的明确作用局灶性脑损伤尚不清楚。有效诱导长期、功能性血管生成需要了解并模仿发育中大脑中发生的机制。我们的目标是了解当地局灶性缺血再灌注后缺血和梗死周围区域的血管生成和纤维化发育中大脑的损伤，并确定再生和修复的机制通过关注血管反应来延迟促红细胞生成素。在目标 1 中，我们将检验以下假设：血管前端的内皮尖端细胞对于新生儿中风后的血管生成至关重要，并且延迟促红细胞生成素将增强血管生成并改变内皮细胞亚型基因表达谱促进尖端细胞计划。在目标 2 中，我们将量化缺血核心中的成纤维细胞和血管周围细胞，并中风后急性、亚急性和慢性阶段的梗塞周围半暗带，并确定促红细胞生成素如何信号传导影响局部纤维化和修复。最后，在目标3中，我们将确定并修改具体的信令检验促红细胞生成素调节动态内皮细胞信号传导至关重要这一假设的途径用于促进局灶性脑损伤后的局部血管生成。这将确定关键的、可修改的途径对于新生儿中风后的损伤进展和修复很重要。我们的主要假设是延迟促红细胞生成素治疗将促进血管生长和重塑，减少亚急性纤维化和缺血核心星形细胞增殖，并增强血管周围信号传导以改善新生儿卒中后的组织学和功能结果。这三个目标将共同探索特定细胞亚型和途径在局灶性脑损伤后恢复中的作用，更广泛的目标是优化治疗策略以改善长期脑损伤常见原因后的长期结果目前尚无治疗方法。