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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
3R01NS084398-02S1
Application #
9170532
Study Section
Program Officer
Morris, Jill A
Project Start
2016-01-01
Project End
2018-06-30
Budget Start
2016-01-01
Budget End
2016-06-30
Support Year
2
Fiscal Year
2016
Total Cost
$53,900
Indirect Cost
$25,900
Name
Scripps Research Institute
Department
Type
DUNS #
781613492
City
La Jolla
State
CA
Country
United States
Zip Code
92037
Groves, Aran; Kihara, Yasuyuki; Jonnalagadda, Deepa et al. (2018) A Functionally Defined In Vivo Astrocyte Population Identified by c-Fos Activation in a Mouse Model of Multiple Sclerosis Modulated by S1P Signaling: Immediate-Early Astrocytes (ieAstrocytes). eNeuro 5:
Rohrback, Suzanne; Siddoway, Benjamin; Liu, Christine S et al. (2018) Genomic mosaicism in the developing and adult brain. Dev Neurobiol 78:1026-1048
López-Serrano, Clara; Santos-Nogueira, Eva; Francos-Quijorna, Isaac et al. (2018) Lysophosphatidic acid receptor type 2 activation contributes to secondary damage after spinal cord injury in mice. Brain Behav Immun :
Blaho, Victoria A; Chun, Jerold (2018) 'Crystal' Clear? Lysophospholipid Receptor Structure Insights and Controversies. Trends Pharmacol Sci 39:953-966
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
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
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
Fan, Jean; Salathia, Neeraj; Liu, Rui et al. (2016) Characterizing transcriptional heterogeneity through pathway and gene set overdispersion analysis. Nat Methods 13:241-4
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

Showing the most recent 10 out of 15 publications