Background: 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 key regulators of 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 downstream effectors of neurotrophins that can be manipulated pharmacologically. Recently, we identified two novel effectors within the neurotrophic pathways, the Ser/Thr kinase partitioning-defective 1 (Par1) and its downstream target RNA-binding protein Hu antigen D (HuD). These two proteins remain unexplored in PTE research. Our preliminary studies show that Par1 and HuD are downregulated during early traumatic brain injury (TBI). In addition, Par1 and HuD can be induced by trophic factors, such as Neurotrophin-3 (NT-3). We also found that both Par1 and HuD are key regulators of neurocircuitry and disruption of either protein leads to poor cognitive functions and increased seizure susceptibility, which are phenotypes often observed after TBI. Finally, we found that loss of Par1 increases neuroinflammation.Hypothesis: Based on our preliminary data, our central hypothesis is that TBI-induced loss of Par1 and HuD disrupts postnatal brain development, leading to impaired cognition and post-traumatic seizures. Further, we propose that stimulating the Par1 pathway will enhance regeneration of disrupted neurocircuits and reduce neuroinflammation, both of which would reduce PTE and improve TBI outcomes.Specific Aims and Research Strategy: We will test our hypothesis through three specific aims. Aim 1 will determine Par1 and HuD-dependent molecular, cellular, and circuit changes after pediatric TBI, using laser capture and quantitative real-time PCR, 3D serial reconstruction, and live two-photon in vivo imaging. In Aim 2, we will determine if acutely inducing Par1 and HuD promotes regeneration and improve behavioral outcomes after pediatric TBI. We will genetically induce Par1 or HuD through in utero electroporation of tamoxifen-inducible conditional expression constructs or through virus-mediated expression. In addition, we will pharmacologically increase Par1 activity using a diabetes drug metformin. Molecular programs and neocortical circuits will be tested as in Aim 1. Finally, we will test whether acutely inducing Par1 and HuD improves cognitive functions and reduces seizure susceptibilities after pediatric TBI. In Aim 3, we will determine the role of Par1 in neuroinflammation after pediatric TBI and examine whether stimulating Par1 activity can reduce neuroinflammation and improve TBI outcomes, using confocal imaging and biochemical analyses. Together, our studies may lead to novel therapeutic strategies for adolescent PTE.
|Effective start/end date||9/30/18 → 9/29/21|
- Congressionally Directed Medical Research Programs (CDMRP)