Targeting Novel Neurotrophin Effectors for Treating Posttraumatic Epilepsy
Abstract
Post-traumatic epilepsy (PTE) is a recurrent seizure disorder due to brain trauma. The incidence of PTE is highest in adolescents and young adults partly due to their susceptibility to brain trauma in sports, motor vehicle, and military-related incidents. The still-developing brains of adolescents also present a unique challenge for therapeutic interventions as the developing brain exhibits a distinctive injury response than the adult brain. Thus, there is an urgent need for research into adolescent PTE and potential remediation. Neurotrophins are secreted proteins that are important for early brain development and are known to be neuroprotective after injury. However their short biological half-life and poor blood-brain barrier permeability have made it difficult to use neurotrophins in clinical settings. One promising strategy is to target cellular effector proteins of neurotrophins that can be manipulated pharmacologically. Recently, we identified two novel effector proteins within the neurotrophic pathways named Par1 and HuD. These two proteins remain unexplored in PTE research. We found that the levels of these two proteins decrease significantly after pediatric traumatic brain injury (TBI). We also found that both Par1 and HuD are important for brain development and disruption of either protein leads to poor cognitive functions and increased seizure susceptibility, which are symptoms often observed after pediatric TBI. Thus, in this proposal, we will test the molecular and cellular mechanisms by which Par1 and HuD are involved in the pediatric brain injury response, using multifaceted approaches including laser capture and quantitative real-time PCR, 3D serial reconstruction, live two-photon in vivo imaging, biochemical and behavioral analyses. We will also use genetic and pharmacological approaches to stimulate the Par1-HuD pathway to determine whether we can promote regeneration and reduce PTE.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 29, 2018
- Source ID
- W81XWH1810388
Entities
People
- Huaye Zhang
Organizations
- Rutgers University
- United States Army