DESCRIPTION (provided by applicant): This Mentored Patient-Oriented Research Career Development Award (K23) application outlines the candidate's 3-year plan to establish her future scientific career as an independent NIH-funded clinical investigator in neonatal hypoxic-ischemic encephalopathy (HIE). Birth asphyxia constitutes a major global public health burden for millions of infants. Hypothermia remains the sole neuroprotective therapy available, yet as many as half of treated infants have poor outcomes. There is a huge knowledge gap relative to vascular mechanisms underlying the severity of injury and responses to therapy. Understanding the control and modulation of the neurovascular unit in HIE and how it is affected by hypothermia is a novel and fundamental concept that forms the focus of both the candidate's research plan and career development. The overarching goal of the research project is to assess cerebrovascular function in a spectrum of mild, moderate and severe HIE to determine how changes in cerebrovascular function reflect the extent of cerebral injury as detected by MRI and occurrence of seizures. Dysfunctional autoregulation will be further examined in newborns with moderate to severe HIE undergoing hypothermia therapy to test how it is modulated with a deeper/longer hypothermia regimen and during the rewarming process. Ultimately, the candidate will determine if assessment of cerebrovascular function can be used as a reliable biomarker of injury severity and a correlate of outcome following hypothermia therapy in HIE infants. To achieve this goal, state-of-the-art noninvasive near infrared spectroscopy (NIRS) and transcranial Doppler will be used to measure cerebral autoregulation and cerebral tissue oxygenation for the first 5 days of age; MRI will be done at 10-14 days to evaluate severity of brain injury in newborns with HIE. An experienced multidisciplinary mentoring team of leaders in their field of academic research will ensure the candidate's successful transition to independence. Her specific career development objectives are: 1) to develop new expertise in cerebrovascular autoregulation and neurophysiology, and 2) to learn advanced spectral statistical analysis, multicenter clinical protocol development, and leadership skills. The first gal is pivotal for utilizing and interpreting new cerebral autoregulation monitoring technology in orde to unravel the mechanisms of injury and responses to therapy. The second goal is essential to remain focused, acquire deliverables and move to independence by becoming competitive for RO1 funding. Building expertise in understanding cerebrovascular responses as biomarkers of severity of brain injury as well as their modulation with neuroprotective therapy, along with competence in leadership and the conduct of clinical trials, will allow the candidate to become an independent clinical investigator. This knowledge will be crucial for the procurement of R01 funding by serving as a necessary groundwork for assessment of new neuroprotective modalities to optimize neurodevelopmental outcomes following HIE.

Despite hypothermia therapy, birth asphyxia remains a major public health burden for millions of infants worldwide and a major cause of death and neurodevelopmental impairment with as many as half of treated infants having poor outcomes. This proposal addresses gap of knowledge of dysfunctional autoregulation as a manifestation of severity of insult and a key modulator for success of neuroprotection and can be further applied to new therapies beyond hypothermia. Defining new biomarkers of cerebrovascular integrity will help refine delivery of hypothermia therapy and enhance neuroprotection, thus leading to improved outcomes and decreased burden of chronic illness in society by improving the health and quality of life in keeping with the mission of the NIH and objectives of the Healthy People 2010 Initiative.