Investigating the role of lysophosphatidic acid (LPA) in pediatric brain injury

Project: Research project

Project Details

Description

? DESCRIPTION (provided by applicant): In children, traumatic brain injury (TBI) is the leading cause of mortality and morbidity representing a major health burden for affected individuals, their parents and the society at large with more than $1 billion in healthcare. Sadly, despite high
incidence and decades of research, to date no new treatments improve outcome in children with TBI. Further understanding of the pathophysiology leading to secondary brain damage is required to develop new therapies. Our research has demonstrated that lysophosphatidic acid (LPA) is a proinflammatory lipid, highly produced after CNS injury, and contributes to tissue and neurological damage. Compelling data showed that LPA was markedly increased in adult patients' cerebrospinal fluid (CSF) after severe TBI, with specific LPA isoforms serving as potential signatures of brain damage. In postmortem human brain, the LPA receptors were upregulated by glial and ependymal cells after TBI implying enhanced LPA signaling. Therapeutic inhibition of LPA signaling in animal models of neurotrauma with a specific anti-LPA monoclonal antibody (mAb), Lpathomab(tm), delayed pathological processes, including neuroinflammation. Thus, LPA is a driving force for secondary injury processes associated with CNS inflammation and neurodegeneration after neurotrauma. To extend our results in adult human and rodent studies, here we investigate the involvement of LPA in pediatric TBI with a specific focus on diffuse brain injury. These preliminary data are essential to understand the similarities and differences between adult and pediatric TBI, in order to develop targeted interventions. We will use a dual clinical and experimental research approach following the aims below: 1) To determine time profiles of LPA isoforms in CSF and plasma of children with severe TBI, and validate the presence of higher levels of LPA in CSF compared to plasma; 2) To determine whether changes of LPA observed in children's samples are modeled effectively as an elevation of LPA in juvenile rat CSF and plasma after diffuse brain injury; 3) To identify the
brain regions producing LPA in the injured rat brain, and assess the relationship of LPA with neuroinflammation (astrocytosis, activation of microglia, and cytokine production). By defining the CSF and plasma LPA pulse in response to pediatric TBI, this study will complement our recent findings in adult TBI. The experimental data will (1) demonstrate LPA production in juvenile TBI; (2) reveal potential associations between LPA that are specific to diffuse brain injury, the most frequent type of TBI in children; and (3) corroborate the link of increased LPA with cellular and humoral neuroinflammation. If our preliminary results are encouraging in both childhood TBI and juvenile diffuse TBI model, we will embark on a study to determine the efficacy of blocking LPA signaling in reducing secondary brain damage. In future, LPA may become a therapeutic target to reduce secondary brain damage in children suffering from TBI.
StatusFinished
Effective start/end date5/15/154/30/17

Funding

  • National Institutes of Health: $76,708.00
  • National Institutes of Health: $76,459.00

ASJC

  • Medicine(all)
  • Neuroscience(all)

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