Traumatic brain injury (TBI) is the leading cause of death and disability in children in the USA. Despite intense research efforts to develop effective therapies, there is no specific treatment, and clinical care remains supportive. An emerging consensus is that effective therapies must target the different cell types that function in a coordinated fashion in the brain. This grouping of neurons, glia and endothelial cells is termed the neurovascular unit (NVU). Due to the essential role of the endothelial cell in the NVU, I have proposed to explore a neuroprotective strategy that targets the brain microvascular endothelial cell (BMEC). My preliminary data show that trophic support from the endothelium provides dramatic protection to neurons subjected to injury, and that Brain Dervied Neutrophic Factor (BDNF) is a factor that mediates this protection. We have found that neuregulin-1 (NRG1), an endogenous growth factor, enhances endothelial production of BDNF, promotes angiogenesis, and protects brain microvascular endothelial cells (BMECs) from oxidative stress. Additionally, mice treated with NRG1 perform better in tests of spatial memory and motor function after TBI. My overall hypothesis is that NRG1 provides neuroprotection by supporting endothelial function and BDNF expression, both of which protect neurons. I plan to test this hypothesis with the following aims:
Aim 1 : Evaluate the effect of NRG1 on cell death in in vitro models of metabolic stress and mechanical injury.
Aim 2 : Evaluate the effect of NRG1 on tight junction function, angiogenesis, and BDNF expression in BMECs in vitro under normal conditions and following cell injury.
Aim 3 : Investigate the protective effect of NRG1 in a model of TBI using immature mice. The concept that preserving the endothelium will also protect neurons and glia fits well with the current momentum to develop combination therapies for TBI by targeting different cell types. The approach proposed here is particularly significant because the timing and route of NRG1 administration, which are supported by preliminary findings, are attainable in translational settings. Our combination of molecular, cellular and in vivo studies will provide useful information on whether NRG1, and more broadly the concept of neurovascular targeting, can be translated into therapeutic approaches for TBI.

Public Health Relevance

Traumatic brain injury is the leading cause of death and disability in children and young adults in the U.S. Unfortunately currently there is no specific therapy. The experiments in this proposal investigate whether the actions of neuregulin-1, a growth factor in the body, can protect the brain after trauma by supporting the function of the microvessels in the brain. The ultimate goal is to identify new therapeutic strategies, which are urgently needed in treating brain trauma in children.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Clinical Investigator Award (CIA) (K08)
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NST-2 Subcommittee (NST)
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Hicks, Ramona R
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Massachusetts General Hospital
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Wu, Limin; Walas, Samantha; Leung, Wendy et al. (2015) Neuregulin1-? decreases IL-1?-induced neutrophil adhesion to human brain microvascular endothelial cells. Transl Stroke Res 6:116-24
Lok, Josephine; Leung, Wendy; Zhao, Song et al. (2011) ýý-glutamylcysteine ethyl ester protects cerebral endothelial cells during injury and decreases blood-brain barrier permeability after experimental brain trauma. J Neurochem 118:248-55
Lok, Josephine; Leung, Wendy; Murphy, Sarah et al. (2011) Intracranial hemorrhage: mechanisms of secondary brain injury. Acta Neurochir Suppl 111:63-9