Prenatal blood-borne lipids in post-hemorrhagic hydrocephalus

描述（由申请人提供）：出血性脑积水（PHH）是一种影响新生儿和婴儿的常见神经系统疾病，其特征是头部增大、脑脊液（CSF）积聚和中枢神经系统残疾。神经外科切除脑脊液提供了姑息性治疗，但受影响的个体仍然遭受神经系统后遗症和a

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.