Neonatal stroke is an important cause of morbidity and mortality;however there are currently no treatments available for the newborn. One of the mechanisms which contributes to brain injury is overactivation of the NMDA receptor (NMDAR). This leads to an influx of calcium ions and recruitment of several classes of molecules to the NMDAR. One such class is the Src family kinases (SFK). They are recruited to the NMDAR in response to ischemia in both the adult and developing brain. SFKs have emerged as critical mediators of brain injury via NMDAR dependent and independent cell death pathways. However, very little is known about the mechanisms by which Src kinases enhance brain injury in the immature brain. Our lab recently reported that SFKs Src and Fyn are recruited to the NMDAR after neonatal hypoxia-ischemia (HI) and SFK inhibition is protective. Preliminary data demonstrate that mice with neuron-specific Fyn overexpression have increased brain injury, mortality, and activation of the MAPK pathway. We hypothesize that Fyn enhances cell death after neonatal HI through modification of the NMDAR and activation of the MAPK pathway.
Aim 1 will determine whether Fyn acts upstream of the p38 pathway to promote cell death in an in vivo model of hypoxia- ischemia.
In Aim 2 we will purify the NR2B complex in wild type and Fyn-transgenic mice after HI or sham operation. In addition to identifying novel proteins recruited to the NMDAR, this approach will allow us to determine whether Fyn plays a role in remodeling the NMDAR complex in response to HI.
This proposal investigates the molecular mechanisms by which Fyn contributes to brain injury in an experimental model of focal ischemia in the neonate. An understanding of the specific pathways by which Fyn activates injury pathways will inform the development of novel therapeutics.
|Knox, Renatta; Jiang, Xiangning (2015) Fyn in Neurodevelopment and Ischemic Brain Injury. Dev Neurosci 37:311-20|
|Knox, Renatta; Brennan-Minnella, Angela M; Lu, Fuxin et al. (2014) NR2B phosphorylation at tyrosine 1472 contributes to brain injury in a rodent model of neonatal hypoxia-ischemia. Stroke 45:3040-7|
|Knox, Renatta; Zhao, Chong; Miguel-Perez, Dario et al. (2013) Enhanced NMDA receptor tyrosine phosphorylation and increased brain injury following neonatal hypoxia-ischemia in mice with neuronal Fyn overexpression. Neurobiol Dis 51:113-9|
|Jiang, Xiangning; Knox, Renatta; Pathipati, Praneeti et al. (2011) Developmental localization of NMDA receptors, Src and MAP kinases in mouse brain. Neurosci Lett 503:215-9|