Germinal matrix hemorrhage (GMH) is one of the leading causes of morbidity, mortality, and acquired infantile
hydrocephalus in preterm infants in the United States, with little progress made in its clinical management. Blood
clots have been shown to elicit secondary brain injury after GMH, by disrupting normal cerebrospinal fluid
circulation and absorption after germinal matrix hemorrhage causing post-hemorrhagic hydrocephalus
development. Current experimental evidence suggests that rapid hematoma resolution is necessary to quickly
ameliorate inflammation and improve neurological outcomes after hemorrhagic stroke. N-formyl peptide receptor
2 (FPR2), a G-protein-coupled receptor, has been shown to be neuroprotective after stroke. FPR2 activation has
been associated with the upregulation of phagocytic macrophage clearance, yet its mechanism has not been
fully explored. Recent literature suggests that FPR2 may play a role in the stimulation of scavenger receptor
CD36. Scavenger receptor CD36, a trans-membrane glycoprotein, plays a vital role in microglia phagocytic blood
clot clearance after GMH. FPR2 has been shown to activate extracellular-signal-regulated kinase 1/2 (ERK1/2),
which promotes the transcription of the dual-specificity protein phosphatase 1 (DUSP1) gene. Current literature
suggests that DUSP1 may act on CD36 receptor and may play a role in FPR2 induced phagocytosis. Our
preliminary suggests that FPR2 activation enhances hematoma resolution and improves neurological deficits.
Therefore, we seek to elucidate the underlying hematoma resolving mechanism of FPR2. We hypothesize that
FPR2 stimulation enhances microglia induced hematoma resolution through the activation of the ERK
(1/2)/DUSP1/CD36 signaling pathway, thereby improving short- and long-term neurological outcomes.
Aim 1 will investigate the role of FPR2 in enhancing hematoma resolution, thereby improving neurological
function following GMH. Aim 2 will investigate FPR2-induced activation of the ERK/DUSP1/CD36 signaling
pathway after GMH. The long-term goal of this proposal is to provide a basis for clinical translation of FPR2
stimulation as an effective non-invasive therapeutic strategy to protect against acute and chronic complications
in the GMH patient population.