Prenatal blood-borne lipids in post-hemorrhagic hydrocephalus

描述（由申请方提供）：出血后脑积水（PHH）是一种常见的影响新生儿和婴儿的神经系统疾病，其特征为头部增大、脑脊液（CSF）蓄积和CNS残疾。神经外科切除CSF提供了姑息治疗，但受影响的个体仍然患有神经系统后遗症， 需要持续的CSF移除和分流翻修。目前还没有真正的疾病缓解疗法。我们的建议探索了一种新的机制，在PHH的病因，特别是发生在产前或早产，通过溶血磷脂（LP）的行动。这些小的膜衍生脂质包括称为溶血磷脂酸（LPA）的甘油磷脂，其可以高水平存在于血液或出血性流体中。LPA激活LPA受体家族，并且初步数据证明至少一种受体LPA 1参与介导动物模型中出血性流体和LPA促进PHH的作用。该模型还概括了与人类产前PHH相关的脑内共病变化。将在5年内追求三个具体目标，以测试PHH的启动和进展涉及LPA信号传导的假设，这进一步为开发新的治疗方法提供基础。目标1.评估产前LPA暴露对PHH相关神经解剖学变化的影响。目标2.评估PHH小鼠模型中的颅内液组成和隔室。目标3。确定LPA依赖性PHH发展时间并评估治疗易处理性。

DESCRIPTION (provided by applicant): Post-hemorrhagic hydrocephalus (PHH) is a common neurological disorder affecting neonates and infants, characterized by increased head size, cerebrospinal fluid (CSF) accumulation, and CNS disability. Neurosurgical removal of CSF offers palliative treatment, yet affected individuals still suffer from neurological sequelae and a need for continual CSF removal and shunt revisions. No truly disease-modifying therapies are currently available. Our proposal explores a new mechanism in the etiology of PHH, particularly occurring during prenatal or premature life, through the actions of lysophospholipids (LPs). These small, membrane- derived lipids include the glycerophospholipid known as lysophosphatidic acid (LPA) that can be present at high levels in blood or hemorrhagic fluids. LPA activates a family of LPA receptors, and preliminary data demonstrate the involvement of at least one receptor, LPA1, in mediating the actions of hemorrhagic fluids and LPA in promoting PHH in an animal model. This model also recapitulates comorbid changes within the brain that have been associated with prenatal PHH in humans. Three specific aims will be pursued over a 5-year period to test the hypothesis that the initiation and progression of PHH involves LPA signaling that further provides a foundation for developing new, therapeutic approaches. Aim 1. Assess effects of prenatal LPA exposure on neuroanatomical changes associated with PHH. Aim 2. Assess intracranial fluid composition and compartments in the PHH mouse model. Aim 3. Determine LPA-dependent PHH developmental timing and assess therapeutic tractability.