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

• 批准号: 10709001
• 负责人: Fernando Francisco Gonzalez
• 金额: $ 47.06万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 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/10709001
• 关键词: Acute; Angiogenesis Inhibition; 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; Ischemia; 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; Population; 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; economic impact; 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; repaired; response; socioeconomics; trafficking; treatment strategy

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.

项目总结/摘要 新生儿中风是死亡和残疾的重要原因，诊断往往被延误。有 对局部缺血-再灌注损伤的修复机制认识不足 这是早期中风最常见的原因发生血管生成、纤维化和血管周围细胞再增殖 与支持内皮细胞相互作用的旁分泌信号密切相关，这对修复至关重要。 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靶点， 大脑发育。促红细胞生成素和基于细胞的疗法已成为有希望的延迟治疗 治疗中风的策略，尽管其获益机制仍不完全清楚。很可能， 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 受体在不同脑区和不同时间对内皮细胞亚型有不同的作用 受伤后的分数此外，局部纤维化在早期损伤后损伤进展和修复中的明确作用， 局灶性脑损伤是未知的。有效地诱导长期的功能性血管生成需要了解 并模仿大脑发育中的机制。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 在发育中的大脑损伤，并确定再生和修复的机制， 延迟促红细胞生成素通过关注血管反应。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， 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， 脑卒中后急性、亚急性和慢性阶段梗死周围半暗带的变化，并确定促红细胞生成素 信号传导影响局部纤维化和修复。最后，在目标3中，我们将确定和修改特定的信令 测试红细胞生成素调节的动态内皮细胞信号传导是至关重要的假设的途径 用于促进局灶性脑损伤后的局部血管生成。这将决定关键的、可修改的途径 对新生儿卒中后损伤进展和修复非常重要。我们的主要假设是 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， 星形胶质细胞增殖的缺血核心，并加强血管周围的信号，以改善 新生儿卒中后的组织学和功能结局。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局 目前还没有治疗方法