Neuroinflammation in an Optimized Model of Lysophosphatidic Acid (LPA)-Induced Post-hemorrhagic Hydrocephalus

IF 3.8 3区 医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY
Paloma Sánchez-Pavón, Carter R. Palmer, Christine S. Liu, Valerie P. Tan, Victoria A. Blaho, Jerold Chun
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引用次数: 0

Abstract

Post-hemorrhagic hydrocephalus (PHH) is a neurological disease that primarily affects premature infants and involves infiltration of blood into the brain’s ventricles followed by excessive accumulation of cerebrospinal fluid (CSF), leading to ventricular enlargement and increased intracranial pressure. The precise mechanisms driving PHH development and persistence are incompletely understood and lack disease-modifying treatments. Using a mouse model of PHH, we have identified transcriptomic, proteomic, and cellular features of PHH involving neuroimmune and neurovascular alterations recapitulating those reported in human disease. Improvement upon a lysophosphatidic acid (LPA)-induced PHH mouse model was combined with unbiased proteomic and single-nucleus transcriptomics that identified microglial molecular pathways propagating PHH. Pharmacological depletion of microglia in vivo significantly reduced PHH-associated ventriculomegaly. These data identify microglial and neurovascular elements in the development of PHH, implicating them as other potentially tractable therapeutic targets beyond LPA receptors, towards developing medical treatments for PHH.

溶血磷脂酸(LPA)诱导出血性脑积水优化模型中的神经炎症
出血性脑积水(PHH)是一种主要影响早产儿的神经系统疾病,涉及血液渗入脑室,随后脑脊液(CSF)过度积聚,导致脑室增大和颅内压升高。驱动PHH发展和持续的确切机制尚不完全清楚,并且缺乏改善疾病的治疗方法。使用小鼠PHH模型,我们已经确定了PHH涉及神经免疫和神经血管改变的转录组学、蛋白质组学和细胞特征,这些特征在人类疾病中得到了概括。在溶血磷脂酸(LPA)诱导的PHH小鼠模型的基础上,结合无偏倚的蛋白质组学和单核转录组学,确定了传播PHH的小胶质分子途径。体内小胶质细胞的药理学耗竭可显著降低phh相关的脑室肥大。这些数据确定了PHH发展中的小胶质细胞和神经血管因子,暗示它们是LPA受体之外的其他潜在可处理的治疗靶点,有助于开发PHH的医学治疗方法。
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来源期刊
Neurochemical Research
Neurochemical Research 医学-神经科学
CiteScore
7.70
自引率
2.30%
发文量
320
审稿时长
6 months
期刊介绍: Neurochemical Research is devoted to the rapid publication of studies that use neurochemical methodology in research on nervous system structure and function. The journal publishes original reports of experimental and clinical research results, perceptive reviews of significant problem areas in the neurosciences, brief comments of a methodological or interpretive nature, and research summaries conducted by leading scientists whose works are not readily available in English.
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