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

项目总结/摘要 血管重建和血脑屏障（BBB）功能的恢复是重建脑血管病的关键。 缺血性中风后支持组织修复和功能恢复的微环境。期间 Wnt/β-catenin信号传导功能将中枢神经系统（CNS）血管生成与 屏障形成然而，在有关介导这些疾病的潜在机制方面， 缺血性损伤后血管稳态的恢复。损伤相关的分子模式，从 缺血性脑损伤期间死亡的细胞，引发炎症反应， 组织修复因此，这种反应的可塑性代表了一种有希望的治疗靶点，但这种临床 对无菌炎症如何调节血管修复的不完全理解阻碍了这种潜力。我 初步数据表明，脑梗死触发I型干扰素（IFN 1）的局部上调， 在时间上与梗死周围血管生成的诱导一致的信号传导，Wnt/β-连环蛋白信号传导， 外周免疫细胞浸润。当与先前的工作一起查看时，这些数据令人信服， IFN 1信号调节外周血管成熟、BBB完整性和免疫细胞募集， 其他疾病的背景。然而，内源性IFN 1信号对缺血后血管修复的影响， 脑损伤不详。这一建议的中心假设是，缺血性脑损伤引起的IFN 1信号的上调， 脑损伤通过以下方式协调血管重塑和血流动力学功能的恢复：1）直接作用于 脑内皮细胞（BEC）恢复BBB功能和2）间接通过募集外周血 单核细胞和活化的小胶质细胞以促进血管生成。这一假设将使用以下组合进行检验： 基因、分子、计算方法，以及用扫描的啮齿动物大脑的体内功能成像， 共焦对准平面激发（SCAPE）和双光子显微术。目标1将决定IFN 1 BEC和CNS髓样细胞中的信号传导调节血管生成、屏障形成和先天免疫 脑梗死后的反应。目标2将建立一个强大的体内范例，用于绘制自然轨迹 脑缺血损伤后脑血管功能的变化及BEC和CNS髓系细胞的影响 IFN 1信号对纵向血管功能的影响。拟议的研究将阐明 IFN 1信号影响缺血性脑损伤后血管可塑性，将建立一种新的技术 候选治疗靶点的分子研究和功能验证的框架。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， 缺血性卒中，并有可能指导未来的治疗干预，以改善功能结局 脑缺血后。

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.