Candidate: My overall career goal is to become a leader in the field of developmental brain injury research. As a clinician-scientist in pediatric critical care, I have found the treatment of children after brain injury to be particularly challenging. Despite decades of research into the pathophysiology of brain injury and neuroprotection, effective therapy remains elusive and our clinical role after such an injury is largely supportive. The overarching goal of my work is to develop novel neuroprotective treatments to improve outcomes after brain injury in neonates and children. Sex differences play an important and under-recognized role in developmental brain injury and recovery. I believe that understanding the mechanisms underlying these differences will facilitate development of sex-specific treatments and identify new targets for neuroprotective strategies following cerebral ischemia, a defined mission of NINDS. The overall goal of this K08 career development proposal is to provide me with the research experience and training needed to become a leader in the field of developmental brain injury research. My training will be targeted to three key areas: 1) sex steroid receptor and 2) neurotrophin signaling in the sexually differential developing brain, 3) translational methods for studying developmental brain injury and will consist of coursework combined with mentoring from experts at University of Wisconsin and other institutions. This proposed research and training will provide me with the expertise necessary to develop a translational R01 proposal focused on designing new neuroprotective therapies targeting estrogen receptor ??(ER?) and nerve growth factor signaling pathways. Finally, this research experience in sex-specific neurotrophin signaling, in combination with my clinical expertise in pediatric brain injury, will uniquely position me for a successful independen research career in developmental brain injury. Environment: Mentoring committee for this proposed K08 Award was structured to support a novel direction focusing on the role of sex steroid receptors in neurotrophin signaling after neonatal hypoxia-ischemia (HI). Each mentor has extensive mentoring experience and expertise in the critical aspects of the research proposal and my career development. The Department of Pediatrics has provided me with start-up funds, laboratory space, and 9 months of protected research time each year. In addition, the University of Wisconsin is one of the premier research institutions in the US. The Waisman Center, where my laboratory is located, provides an ideal environment for conducting translational research in developmental brain injuries. Waisman Center houses the laboratory of many experts in developmental brain injuries including one of my mentors (Dr. Svaren). The center also provides core facility resources for animal surgeries, behavioral testing, microscopy, and RT-PCR. My primary mentor (Dr. Levine) is the director of Wisconsin National Primate Research Center, providing an ideal path for translation of my small animal model studies into larger animal models. This optimal research environment will ensure that my transition into an independent physician scientist is successful. Research: Cerebral ischemia resulting from perinatal asphyxia affects over 20,000 neonates every year in the US, and treatment options are limited. Female neonates are more resistant to the effects of perinatal asphyxia than males, a phenomenon that is poorly understood. The neurotrophin receptor, tyrosine kinase B (Trk beta), plays an important role in neuroprotection and improving the long-term functional recovery following cerebral ischemia by increasing neuronal survival. I recently showed that administration of 7,8 dihydroxyflavone (7,8-DHF; selective Trk beta agonist) increases Trk beta phosphorylation and hippocampal neuronal survival following HI in female, but not in male neonate mice. However, the cellular mechanisms of the female-specific responsiveness to Trk beta agonist and their roles in improving long-term neurological functional outcome post-HI are unknown. Thus, I hypothesize that: 1) ER alpha?mediates sex-specific Trk beta phosphorylation and enhanced neuroprotection in neonates post-HI, 2) ER alpha signals through Src-family kinases to enhance phosphorylation of Trk beta receptors and improve long-term functional outcomes post-HI. The critical elements of this hypothesis will be tested in the following specific aims:
Aim 1 : To determine if ER??mediates sex-specific Trk beta phosphorylation and improvement in long-term functional outcome post-HI.
Aim 2 : To determine if ER alpha?mediates cell autonomous Trk beta phosphorylation post-HI.
Aim 3 : To determine if ER alpha?enhances Trk beta phosphorylation via activation of Src-family kinases resulting in decreased neuronal apoptosis and improvement in long-term functional outcome post-HI. The work proposed in these aims is designed to test the role of ER beta in enhancing Trk beta phoshorylation and long-term functional outcome in male and female neonates post-HI. Establishing the role of ER alpha-Trk beta interactions in neuronal survival post-HI will provide a new target for preventive and therapeutic interventions, significantly advancing the developmental brain injury field.

Public Health Relevance

This project will investigate the role of a sex steroid receptor (estrogen receptor alpha-ERa) in activating nerve growth factor receptor (tyrosine kinase B receptor- TrkB) in a sexually different way in neonatal mice following cerebral ischemia. Identifying the role of ERa-TrkB interaction in neuroprotection will provide a new target for preventive and therapeutic interventions and significantly advance the developmental brain injury field, a defined mission of NINDS.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Clinical Investigator Award (CIA) (K08)
Project #
5K08NS088563-03
Application #
9301066
Study Section
NST-2 Subcommittee (NST)
Program Officer
Koenig, James I
Project Start
2015-07-01
Project End
2020-06-30
Budget Start
2017-07-01
Budget End
2018-06-30
Support Year
3
Fiscal Year
2017
Total Cost
Indirect Cost
Name
University of Wisconsin Madison
Department
Pediatrics
Type
Schools of Medicine
DUNS #
161202122
City
Madison
State
WI
Country
United States
Zip Code
53715
Cikla, Ulas; Chanana, Vishal; Kintner, Douglas B et al. (2016) Suppression of microglia activation after hypoxia-ischemia results in age-dependent improvements in neurologic injury. J Neuroimmunol 291:18-27
Chanana, Vishal; Tumturk, Abdulfettah; Kintner, Douglas et al. (2016) Sex Differences in Mouse Hippocampal Astrocytes after In-Vitro Ischemia. J Vis Exp :
Cikla, Ulas; Chanana, Vishal; Kintner, Douglas B et al. (2016) ER? Signaling Is Required for TrkB-Mediated Hippocampal Neuroprotection in Female Neonatal Mice after Hypoxic Ischemic Encephalopathy(1,2,3). eNeuro 3: