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 evidence suggests that rapid hematoma resolution is necessary to quickly 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 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. Our data suggests that FPR2 activation enhances hematoma resolution and improves neurological deficits. Our central hypothesis is that FPR2 stimulation enhances microglia induced hematoma resolution through the activation of the p-ERK(1/2)/DUSP1/CD36 signaling pathway, thereby improving short- and long-term neurological outcomes. Aim 1 investigated the role of FPR2 in enhancing hematoma resolution, thereby improving neurological function following GMH. Aim 2 investigated FPR2-induced activation of the p-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. FPR2 stimulation improved short-term hematoma resolution and motor coordination, which was reversed by FPR2 antagonist Boc2 and FPR2 CRISPR. FPR2 stimulation attenuated long-term neurocognitive deficits and post-hemorrhagic hydrocephalus, which was reversed by pharmacological inhibition. Furthermore, FPR2 stimulation increased the expression of the proposed signaling pathway, which was then inhibited by pharmacological inhibition and gene knock-down of FPR2. Thus, our study presents a non-invasive therapeutic target for the treatment of GMH.

LLU Discipline





School of Medicine

First Advisor

John H. Zhang

Second Advisor

Marino DeLeon

Third Advisor

Johnny Figueroa

Fourth Advisor

Lubo Zhang

Fifth Advisor

Jiping Tang

Degree Name

Doctor of Philosophy (PhD)

Degree Level


Year Degree Awarded


Date (Title Page)




Library of Congress/MESH Subject Headings

Cerebral Hemorrhage -- therapy; Receptors, Formyl Peptide



Page Count

xii, 123 p.

Digital Format


Digital Publisher

Loma Linda University Libraries

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This title appears here courtesy of the author, who has granted Loma Linda University a limited, non-exclusive right to make this publication available to the public. The author retains all other copyrights.


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Loma Linda University. Del E. Webb Memorial Library. University Archives

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