Shannon E. G. Hamrick, MD

Neonatologist

Under the mentorship of Dr. Donna Ferriero in the Neonatal Brain Disorders Laboratory at UCSF I focused the research component of my neonatal fellowship on understanding the mechanism of neuronal injury and neuroprotection in an in vitro model of birth asphyxia. The immature brain has an increased vulnerability to hypoxia-ischemia. Reasons for this increased susceptibility include immaturity of vascular regulation and maturational differences in both metabolic function and free radical generation and management. Designing an appropriate therapeutic agent following injury is difficult due to concerns over disrupting the normal developmental process. One treatment strategy is to inhibit free radical production via Fenton chemistry, a process that is dependent on iron. The iron chelator desferoxamine (DFO) has been shown in this lab and others to ameliorate neuronal death after in vitro hypoxia-ischemia. DFO is also known to upregulate hypoxia-inducible factor-1a (HIF-1a), a nuclear protein induced during hypoxia that is essential for transcriptional activation of hypoxia-inducible genes whose protein product would confer an adaptive advantage during states of hypoxia. To investigate the mechanism of neuroprotection by DFO: iron chelation or HIF-1a induction, we transfected primary neurons with antisense oligonucleotides to HIF-1a to see if desferoxamine’s protective effects were diminished. We found that that the protective effects of DFO were reduced upon inhibition of HIF-1a.
Iron chelators, and specifically desferoxamine with its dual role, may provide a unique method of neuroprotection. However, determining which infant to potentially treat, and specifically when to treat the infant, has remained a difficulty. Through an ongoing NIH-funded MRI study (BAMRI – Birth Asphyxia Magnetic Resonance Imaging) we have been able to better predict neurodevelopmental outcome using novel imaging modalities such as MR spectroscopy and diffusion tensor imaging. Currently we are expanding these modalities to other at-risk neonatal populations, including infants with congenital heart disease, to look at the timing of brain injury.
Finally, the UCSF Intensive Care Nursery (ICN) has maintained a thorough database of all patients admitted for over 20 years, and all patients seen in the ICN Follow-Up clinic. We have been able to evaluate the neurodevelopmental outcome of select populations of at-risk infants, such as infants with congenital heart disease who are supported with ECMO post-operatively, and we have defined characteristics that may predict both survival and outcome. Through both retrospective database analysis and prospective clinical studies, particularly in infants with congenital heart disease, my ultimate goal is to identify neurologically at-risk neonates during a window in which therapeutic options may be beneficial.



contact: segh@itsa.ucsf.edu