Type I Interferon Mediated Restoration of Brain Endothelial Cell Function after Cerebral Infarction

I型干扰素介导脑梗塞后脑内皮细胞功能的恢复

• 批准号: 10606276
• 负责人: Mary Claire Tuohy
• 金额: $ 4.77万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-01-15 至 2026-01-14
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10606276
• 关键词: Ablation; Blood - brain barrier anatomy; Blood Vessels; Brain; Brain Ischemia; Cause of Death; Cell physiology; Cells; Central Nervous System; Central Nervous System Viral Diseases; Cerebral Infarction; Chronic; Clinical; Confocal Microscopy; Data; Development; Disease; Endothelial Cells; Flow Cytometry; Fluorescent in Situ Hybridization; Functional Imaging; Future; Genetic; Genetic Transcription; Homeostasis; Hour; Hyperemia; IFNAR1 gene; Immune; Immunofluorescence Immunologic; Infarction; Infection; Inflammation; Inflammatory; Inflammatory Response; Innate Immune Response; Interferon Activation; Interferon Receptor; Interferon Type I; Interferons; Investigation; Ischemia; Ischemic Brain Injury; Ischemic Stroke; Knock-out; Knowledge; Maps; Mediating; Microglia; Molecular; Mouse Strains; Multiple Sclerosis; Mus; Myeloid Cells; Pathway interactions; Pattern; Peripheral; Process; RNA; Recovery; Recovery of Function; Rodent; Role; Rose Bengal; Shapes; Signal Pathway; Signal Transduction; Sterility; Structure; Survivors; Testing; Therapeutic; Therapeutic Intervention; Transgenic Organisms; Up-Regulation; Validation; Vascular remodeling; Work; angiogenesis; beta catenin; blood-brain barrier function; brain endothelial cell; candidate validation; cerebrovascular; disability; functional improvement; hemodynamics; immune cell infiltrate; immunoregulation; improved; in vivo; in vivo imaging; inflammatory modulation; ischemic injury; microbial; monocyte; mouse model; novel; recruit; repaired; response; restoration; single-cell RNA sequencing; therapeutic target; tissue injury; tissue repair; tumor microenvironment; two photon microscopy

PROJECT SUMMARY/ABSTRACT Vascular remodeling and restoration of blood-brain barrier (BBB) function are critical for the reestablishment of a microenvironment that supports tissue repair and functional recovery after ischemic stroke. During development, Wnt/β-catenin signaling functions to tightly couple central nervous system (CNS) angiogenesis to barriergenesis. However, there is a critical gap in knowledge regarding the underlying mechanisms that mediate restoration of vascular homeostasis after ischemic injury. Damage-associated molecular patterns, released from dying cells during ischemic brain injury, trigger an inflammatory response which can either promote or exacerbate tissue repair. The plasticity of this response thus represents a promising therapeutic target, but this clinical potential is hindered by an incomplete understanding of how sterile inflammation regulates vascular repair. My preliminary data demonstrate that cerebral infarction triggers a local upregulation of type I interferon (IFN1) signaling that is temporally aligned with the induction of peri-infarct angiogenesis, Wnt/β-catenin signaling, and peripheral immune cell infiltration. This data is compelling when viewed together with previous work showing that IFN1 signaling regulates peripheral vascular maturation, BBB integrity, and immune cell recruitment in the context of other diseases. However, the impact of endogenous IFN1 signaling on vascular repair after ischemic brain injury is unknown. The central hypothesis of this proposal is that upregulation of IFN1 signaling by ischemic brain injury coordinates vascular remodeling and restoration of hemodynamic function by acting 1) directly on brain endothelial cells (BECs) to restore BBB function and 2) indirectly through recruitment of peripheral monocytes and activated microglia to promote angiogenesis. This hypothesis will be tested using a combination of genetic, molecular, computational approaches, and in vivo functional imaging of the rodent brain with swept, confocally aligned planar excitation (SCAPE) and two photon microscopy. Aim 1 will determine how IFN1 signaling in BECs and CNS myeloid cells regulates angiogenesis, barriergenesis and the innate immune response after cerebral infarction. Aim 2 will establish a robust in vivo paradigm for mapping the natural trajectory of cerebrovascular function after ischemic brain injury and determine the impact of BEC and CNS myeloid cell IFN1 signaling on longitudinal vascular function. The proposed studies will elucidate the mechanisms by which IFN1 signaling impacts vascular plasticity after ischemic brain injury and will establish a novel technical framework for the molecular investigation and functional validation of candidate therapeutic targets. This knowledge will enhance our understanding of how sterile inflammatory pathways regulate vascular repair after ischemic stroke and has the potential to guide future therapeutic interventions to improve functional outcomes after brain ischemia.

项目摘要/摘要 血管重构和血脑屏障(BBB)功能的恢复是血管重建的关键 支持缺血性卒中后组织修复和功能恢复的微环境。在.期间 开发Wnt/β-连环蛋白信号功能将中枢神经系统血管生成与 障碍发生。然而，对调解的基本机制的认识存在严重差距 缺血损伤后血管内稳态的恢复。与损伤相关的分子模式，从 在缺血性脑损伤期间死亡的细胞，触发炎症反应，可以促进或加剧 组织修复。因此，这种反应的可塑性代表了一个有希望的治疗靶点，但临床上 对无菌炎症如何调节血管修复的不完全理解阻碍了潜力的发挥。我的 初步数据显示，脑梗塞会触发I型干扰素(IFN1)的局部上调 与梗塞周围血管生成的诱导时间相一致的信号，Wnt/β-连环蛋白信号，以及 外周免疫细胞浸润。如果将这些数据与以前的工作结合在一起，就会发现这些数据很有说服力 IFN1信号调节外周血管成熟、血脑屏障完整性和免疫细胞募集 其他疾病的背景。然而，内源性IFN1信号对缺血后血管修复的影响 脑部损伤尚不清楚。这一建议的中心假设是缺血导致IFN1信号的上调 脑损伤通过直接作用于1)来协调血管重塑和血流动力学功能的恢复 脑内皮细胞(BECs)恢复血脑屏障功能；2)通过外周血细胞募集间接恢复血脑屏障功能 单核细胞和激活的小胶质细胞促进血管生成。这一假设将通过组合进行检验。 对啮齿动物大脑的遗传、分子、计算方法和体内功能成像进行扫描， 共焦平面激发(SCAPE)和双光子显微镜。目标1将决定IFN1如何 BECs和CNS髓系细胞中的信号调节血管生成、屏障形成和先天免疫 脑梗塞后的反应。目标2将建立一个健壮的体内范例来绘制自然轨迹图 对缺血性脑损伤后脑血管功能的影响及BEC和CNS髓系细胞的影响 IFN1信号对纵向血管功能的影响。拟议的研究将阐明 IFN1信号对缺血性脑损伤后血管可塑性的影响 候选治疗靶点的分子研究和功能验证框架。这 知识将增强我们对无菌炎症途径如何调节血管修复的理解 并有可能指导未来的治疗干预以改善功能预后 在脑缺血后。