Intraventricular Hemorrhage Disrupts the Blood Brain Barrier in Premature Infants

脑室内出血破坏早产儿的血脑屏障

• 批准号: 10361487
• 负责人: PRAVEEN BALLABH
• 金额: $ 54.1万
• 依托单位: ALBERT EINSTEIN COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-03-01 至 2026-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10361487
• 关键词: Adherens Junction; Adult; Affect; Agonist; Autopsy; Behavioral; Binding; Biology; Blood; Blood - brain barrier anatomy; Blood Circulation; Blood Tests; Blood capillaries; Brain; Brain Hypoxia-Ischemia; Brain Infarction; Brain Injuries; Brain region; Capillary Endothelial Cell; Cardiotoxicity; Cell Maturation; Cells; Cerebral Palsy; Cerebrum; Cognitive deficits; Complication; Coupled; Development; Disease; Endothelium; Engineering; Evaluation; Event; Failure; G-Protein-Coupled Receptors; GTP-Binding Proteins; Genetic Transcription; Glycerol; Human; Hydrocephalus; Immune; Immune response; Immunity; Immunosuppression; Infant; Infiltration; Inflammation; Inflammatory Response; Injury; Intervention; Leukocytes; Lipid A; Lipids; Liquid substance; Magnetic Resonance Imaging; Mediating; Microglia; Modeling; Molecular Chaperones; Morphology; Multiple Sclerosis; Mus; Myeloid Cells; Nervous System Physiology; Nervous System Trauma; Neurologic; Obstruction; Oryctolagus cuniculus; Pathologic; Pathway interactions; Permeability; Pharmaceutical Preparations; Premature Infant; Production; Public Health; Receptor Signaling; Recovery; Research; Role; SHH gene; Sampling; Signal Transduction; Sphingosine-1-Phosphate Receptor; Stroke; Structure of choroid plexus; Survivors; Testing; Tight Junctions; Time Study; Tracer; Ventricular; antagonist; astrogliosis; blood-brain barrier function; blood-brain barrier permeabilization; brain parenchyma; contrast enhanced; effective therapy; intraventricular hemorrhage; lipid mediator; mRNA sequencing; migration; myelination; neonate; neurobehavior; neurobehavioral; neuroprotection; novel; novel therapeutics; oligodendrocyte progenitor; premature; prevent; receptor; restoration; rho; small hairpin RNA; smoothened signaling pathway; sphingosine 1-phosphate; stem cells; targeted treatment; trafficking; transcriptome; transcytosis; white matter; white matter injury

Abstract Intraventricular hemorrhage (IVH) remains a major neurological complication of prematurity that results in cerebral palsy, hydrocephalus, and cognitive deficits. No effective therapy exists to prevent these disorders in infants with IVH. IVH triggers inflammation in the periventricular germinal matrix and adjacent white matter, resulting in maturational arrest of oligodendrocyte progenitor cells (OPCs) and myelination failure. Moreover, there is increased CSF production and concurrent obstruction in CSF flow, which leads to hydrocephalus. IVH- induced injury may disrupt the integrity and function of the blood brain barrier (BBB) and blood-CSF barrier (BCB), allowing myeloid cells to infiltrate the brain, and fluids to exude from it, thus worsening the consequences of IVH. Sphingosine 1 phosphate (S1P) is a lipid mediator and a key regulator of BBB and BCB function. S1P binds and stimulates G-protein coupled receptors (S1PR1 through S1PR5). S1PR1 contributes to vessel maturation, regulates adherens and tight junction assembly and function, and limits trafficking of immune cells across the BBB. In contrast, S1PR2 promotes immune responses, increases BBB permeability, and facilitates leukocyte entry into the brain. Thus, constitutively-expressed S1PR1 antagonizes S1PR2, which is often induced under pathological conditions in the BBB. Both S1PR1 activation and S1PR2 inhibition offer neuroprotection in brain injury models. However, the role of S1PR1 and S1PR2 in BBB and BCB damage, hydrocephalus, and white matter injury is unclear in neonates with IVH. Our central hypotheses are: i) IVH will induce inflammation, disrupt the BBB and BCB, and alter S1PR1 and S1PR2 expressions in the BBB and BCB in both humans and rabbits and ii) modulation of S1PR1 and S1PR2 signaling by receptor subtype- specific agents will restore BBB and BCB integrity, minimize cerebral inflammation, and reverse white matter injury and hydrocephalus in preterm rabbits with IVH. We will test these hypotheses in a rabbit model of glycerol-induced IVH and autopsy samples from human premature infants. In Aim 1, we will determine the effect of IVH on a) BBB and BCB permeability and immune cell infiltration across the BBB and BCB, b) endothelial tight and adherens junction, endothelial transcytosis, and key transporters, and c) transcriptional changes in the capillary endothelium of the periventricular brain region and choroid plexus. The observations made in rabbit will be validated in autopsy samples from preterm infants with and without IVH. In Aim 2 and 3, we will evaluate the effect of S1PR1 and S1PR2 modulation on a) BBB and BCB permeability, endothelial tight and adherens junction assembly, endothelial transcytosis and transcriptome, b) immune cell infiltration, ventriculomegaly, and c) myelination and neurobehavior. We will also determine whether S1PR1 and S1PR2 signaling affect adherens and tight junction as well as myelination via sonic hedgehog and Rho-ROCK pathways, respectively. These studies will enhance our understanding of S1P biology in the maturing brain and hasten development of new therapies to minimize white matter injury and hydrocephalus in survivors of IVH.

抽象的 脑室内出血（IVH）仍然是早产儿的主要神经系统并发症，导致 脑瘫、脑积水和认知缺陷。目前尚无有效的疗法来预防这些疾病 患有脑室内出血的婴儿。 IVH 引发脑室周围生发基质和邻近白质的炎症， 导致少突胶质祖细胞 (OPC) 成熟停滞和髓鞘形成失败。而且， 脑脊液产生增加，同时脑脊液流动受阻，导致脑积水。脑室内出血- 诱发的损伤可能会破坏血脑屏障 (BBB) 和血脑脊液屏障的完整性和功能 (BCB)，允许骨髓细胞浸润大脑，液体从大脑中渗出，从而使病情恶化 IVH 的后果。磷酸鞘氨醇 (S1P) 是一种脂质介质，也是 BBB 和 BCB 的关键调节剂 功能。 S1P 结合并刺激 G 蛋白偶联受体（S1PR1 至 S1PR5）。 S1PR1 贡献 促进血管成熟，调节粘附和紧密连接组装和功能，并限制贩运 免疫细胞穿过血脑屏障。相反，S1PR2 促进免疫反应，增加 BBB 通透性， 并促进白细胞进入大脑。因此，组成型表达的 S1PR1 拮抗 S1PR2，从而 通常是在 BBB 病理条件下诱发的。 S1PR1 激活和 S1PR2 抑制均提供 脑损伤模型中的神经保护。然而，S1PR1和S1PR2在BBB和BCB损伤中的作用， IVH 新生儿中的脑积水和白质损伤尚不清楚。我们的中心假设是： i) IVH 会诱发炎症，破坏 BBB 和 BCB，并改变 BBB 和 BBB 中的 S1PR1 和 S1PR2 表达 人类和兔子中的 BCB 以及 ii) 通过受体亚型调节 S1PR1 和 S1PR2 信号传导 特定药物将恢复 BBB 和 BCB 完整性，最大限度地减少脑炎症并逆转白质 患有 IVH 的早产兔的损伤和脑积水。我们将在兔子模型中测试这些假设 甘油诱导的 IVH 和人类早产儿的尸检样本。在目标 1 中，我们将确定 IVH 对 a) BBB 和 BCB 通透性以及跨 BBB 和 BCB 的免疫细胞浸润的影响，b) 内皮紧密连接和粘附连接、内皮转胞吞作用和关键转运蛋白，以及 c) 转录 脑室周围区域和脉络丛毛细血管内皮的变化。观察结果 在兔子身上制造的产品将在患有或不患有 IVH 的早产儿的尸检样本中得到验证。在目标 2 和 3 中， 我们将评估 S1PR1 和 S1PR2 调节对 a) BBB 和 BCB 通透性、内皮致密性的影响 和粘附连接组装、内皮转胞吞作用和转录组，b) 免疫细胞浸润， 脑室扩大，c) 髓鞘形成和神经行为。我们还将确定 S1PR1 和 S1PR2 是否 信号转导通过 Sonic Hedgehog 和 Rho-ROCK 影响粘附和紧密连接以及髓鞘形成 路径，分别。这些研究将增强我们对成熟大脑中 S1P 生物学的理解 加快开发新疗法，以尽量减少脑室内出血幸存者的白质损伤和脑积水。