This K08 proposal describes a 5-year training program for Dr. Jennifer Lee. In this program, Dr. Lee will acquire laboratory and research skills that are essential for her success in academic medicine to enable her to obtain independent NIH funding in pediatric neuroprotection research. Candidate and Career Development Plan: Dr. Jennifer Lee, a pediatric anesthesiologist and pediatrician with formal training in pediatric critial care medicine, has studied cerebrovascular autoregulation in experimental neonatal models under the mentorship of Dr. Raymond Koehler since 2006. More recently, she extended her work to evaluate autoregulation in a model of pediatric hypoxic-asphyxic (HA) cardiac arrest, therapeutic hypothermia, and rewarming. She has translated her laboratory work to patient care by leading several clinical studies involving autoregulation monitoring and neurologic outcomes in neonates with hypoxic-ischemic encephalopathy (HIE), children resuscitated from cardiac arrest, and children undergoing neurosurgery. Thus far, her laboratory research has focused primarily on physiologic experiments of vascular reactivity. However, she has not had the opportunity to take formal coursework or study the biochemical, cellular, and mechanistic effects of therapeutic hypothermia and rewarming after HA brain injury. To continue her development as a clinician-scientist, Dr. Lee intends to study neuronal and oligodendrocyte cell death pathways, the unfolded protein response (UPR) that occurs with endoplasmic reticulum stress, oxidative stress, inflammation, and cortical injury after delayed hypothermia and different rates of rewarming in a clinically relevant model of HA cardiac arrest. This work will enable her to obtain more advanced technical skills that will make her more competitive in basic science research. Her coursework is timed to parallel her laboratory skill development and to address each Aim in her proposal. With the proposed career development and research plans, Dr. Lee will learn the skills necessary to become a successful clinician-scientist with independent NIH funding. Environment: The Johns Hopkins University (JHU) Department of Anesthesiology and Critical Care Medicine is well equipped to support Dr. Lee's research and career development with the K08 award. The Department is currently supporting her with 75% protected, non-clinical time for research. With the K08 award, she will continue to have this protected time. Her co-mentors, Dr. Raymond Koehler and Dr. Lee Martin, are world- renowned experts in cerebrovascular physiology, neuroprotection after hypoxic-ischemic injury, cell death mechanisms, and cellular neuroscience; they have long histories of NIH funding and successful mentoring of clinician-scientists. Dr. Lee also has an experienced, multidisciplinary advisory committee of experts in neuronal cell death mechanisms, hypoxic brain injuries, therapeutic hypothermia/rewarming, and pediatric resuscitation medicine to guide and support her research and career development. All equipment necessary to carry out the proposed experiments is accessible within her department. She will have the full support of her mentors, laboratory manager, and technicians to learn and perform the laboratory techniques outlined in the research plan. JHU has provided Dr. Lee with an environment that will ensure her success in the K08 program. Research Project: Despite the use of therapeutic hypothermia, neurologic morbidity remains high in neonatal HIE and after pediatric cardiac arrest. Experimental models of HA cardiac arrest have shown that therapeutic hypothermia decreases neuronal death from necrosis. However, preliminary laboratory data and clinical studies suggest that rewarming from hypothermia may shift neuronal and oligodendrocyte cell death from necrotic to apoptotic pathways and increase oxidative stress and inflammation, thus raising the risk of secondary brain injury. Moreover, preliminary data indicate that activation of the UPR from endoplasmic reticulum stress after a hypoxic insult may promote apoptosis in the white matter yet be neuroprotective in other regions of the brain.
Aim 1 will determine whether rewarming and different rates of rewarming increase cortical neuroapoptosis, oligodendrocyte apoptosis, oxidative stress, inflammatory markers, seizures, and cortical injury after HA injury.
Aim 2 will determine if caspase-3 inhibition prevents neuronal and oligodendrocyte cell death during rewarming, thus providing an adjuvant neuroprotective therapy.
Aim 3 will determine if UPR activation from rewarming after HA injury induces white matter apoptosis but is neuroprotective in other anatomic regions; and whether modulation of the UPR response influences neuroprotection. Findings from this project will have important implications for pediatric and neonatal resuscitation guidelines. They will also provide a basis for further investigations of adjunct therapies to reduce the adverse effects of rewarming after pediatric cardiac arrest and HIE.
Despite the use of therapeutic hypothermia, infants and children suffer severe and permanent neurologic disabilities after cardiac arrest or birth injuries This project will determine whether rewarming from hypothermia causes brain injury. We will also explore additional therapies to prevent cell death in the brain to eventually improve neurologic outcomes in this vulnerable population.
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