Mechanisms of G-CSF-Induced Neuroprotection

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DESCRIPTION (provided by applicant): No effective treatment strategies have yet been developed to prevent or reduce neonatal hypoxic/ischemic (HI) brain damage. Granulocyte-colony stimulating factor (G-CSF), a member of growth factor family, mainly stimulates the proliferation and differentiation of neutrophilic progenitor cells in the hematopoietic system. It has been widely used in clinical practice for the treatment of neutropenia associated with cytotoxic therapy. Recent studies have shown that systemic administration of G-CSF in adult animal models has mediated noteworthy neuroprotective effects in traumatic brain injury, focal transient cerebral ischemia, and intracerebral hemorrhage but its mechanism(s) are not fully elucidated. Whether G-CSF has neuroprotective effects following neonatal hypoxia-ischemia is not known. As a medical scientist and new investigator to the NIH, I have focused on this important question because of its health relevance, nationally and locally. Loma Linda University Medical Center has the largest Neonatal Intensive Care Unit (NICU) in the Western United States. I have bridged basic and clinical science disciplines to assemble an outstanding research team for this project. Our preliminary studies reveal a significant reduction in brain atrophy following systemic administration of G- CSF to an established rat model of neonatal HI and offer insight into mechanism of action. They support our central hypothesis that systemic G-CSF treatment protects the brain against HI-induced apoptosis. To test our main hypothesis, this project is designated to elucidate the impact of G-CSF-mediated neuroprotection on neurobehavioral outcomes, and thereby define its therapeutic potential. Equally important, this project is designed to determine the suppression of cell death mechanisms especially the mitochondrial apoptotic pathways that mediates the protective effects of G-CSF. The neuroprotective effects of G-CSF on neuronal death and brain atrophy will be related to neurobehavioral outcomes (Specific Aim 1). Brain damage will be measured by brain tissue loss, edema formation, blood-brain barrier disruption, brain infarction, and cellular morphological changes. To strengthen the clinical relevance of this project, the long-term effect and mechanisms of G-CSF treatment on sensorimotor functions, memory and learning abilities will be evaluated by a battery of neurological tests. Then G-CSF's underlying mechanism will be investigated in greater depth by measuring its effect on HI-induced activation of signaling pathways especially mitochondrial apoptotic pathways (Specific Aim 2). The apoptotic changes will be studied using biochemical and molecular approaches. Achieving our project goal through these specific aims will lay the foundation for clinical evaluation of systemic G-CSF in NICU neonates for prevention and treatment of brain damage from HI. PUBLIC HEALTH RELEVANCE: No effective treatment strategies have yet been developed to prevent or reduce neonatal hypoxic/ischemic brain damage. Our project goal is to relate G-CSF's protection of neonates from hypoxia/ischemia-induced brain damage to both neurological function and underlying mechanism. Achieving our goal will lay the foundation for clinical evaluation of systemic administration of G-CSF in human neonates for prevention and treatment of brain damage from hypoxia/ischemia.