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.
Post-hemorrhagic hydrocephalus (PHH) affects premature and newborn infants and young children, representing a common neurological disorder that lacks understanding and medicinal therapies. Lysophosphatidic acid (LPA) signaling through defined receptors represents a new approach to understanding PHH mechanisms and potentially treating PHH that will be approached here by employing molecular, cellular, and pharmacological tools to study LPA signaling in combination with a newly developed mouse model and a range of germane mutants. This proposal could lead to actual medicinal therapies to treat forms of PHH, particularly those occurring during prenatal or premature life.
|Dancs, Péter Tibor; Ruisanchez, Éva; Balogh, Andrea et al. (2017) LPA1 receptor-mediated thromboxane A2 release is responsible for lysophosphatidic acid-induced vascular smooth muscle contraction. FASEB J 31:1547-1555|
|Fang, Victoria; Chaluvadi, V Sai; Ramos-Perez, Willy D et al. (2017) Gradients of the signaling lipid S1P in lymph nodes position natural killer cells and regulate their interferon-? response. Nat Immunol 18:15-25|
|Alfonzo-Méndez, Marco A; Castillo-Badillo, Jean A; Romero-Ávila, M Teresa et al. (2016) Carboxyl terminus-truncated ?1D-adrenoceptors inhibit the ERK pathway. Naunyn Schmiedebergs Arch Pharmacol 389:911-20|
|Funke, Manuela; Knudsen, Lars; Lagares, David et al. (2016) Lysophosphatidic Acid Signaling through the Lysophosphatidic Acid-1 Receptor Is Required for Alveolarization. Am J Respir Cell Mol Biol 55:105-16|
|Fan, Jean; Salathia, Neeraj; Liu, Rui et al. (2016) Characterizing transcriptional heterogeneity through pathway and gene set overdispersion analysis. Nat Methods 13:241-4|
|González de San Román, Estibaliz; Manuel, Iván; Giralt, María Teresa et al. (2015) Anatomical location of LPA1 activation and LPA phospholipid precursors in rodent and human brain. J Neurochem 134:471-85|
|Santos-Nogueira, Eva; López-Serrano, Clara; Hernández, Joaquim et al. (2015) Activation of Lysophosphatidic Acid Receptor Type 1 Contributes to Pathophysiology of Spinal Cord Injury. J Neurosci 35:10224-35|
|Chrencik, Jill E; Roth, Christopher B; Terakado, Masahiko et al. (2015) Crystal Structure of Antagonist Bound Human Lysophosphatidic Acid Receptor 1. Cell 161:1633-43|
|Sheng, Xiaoyan; Yung, Yun C; Chen, Allison et al. (2015) Lysophosphatidic acid signalling in development. Development 142:1390-5|
|Mirendil, H; Thomas, E A; De Loera, C et al. (2015) LPA signaling initiates schizophrenia-like brain and behavioral changes in a mouse model of prenatal brain hemorrhage. Transl Psychiatry 5:e541|
Showing the most recent 10 out of 11 publications