The vasculature in the central nervous system (CNS) is essential to support and maintain brain function throughout life. To do so, the brain vasculature acquires many unique cellular and molecular properties to make up the blood-brain barrier (BBB). Reduced vascular integrity, due to a loss of these properties, is a recognized consequence of many CNS diseases, like encephalitis. Even though altered vascular integrity is thought to exacerbate encephalitis, the underlying mechanisms are poorly understood. Addressing these gaps in our knowledge will provide insight into the underlying causes of vascular instability during encephalitis. Furthermore, understanding these mechanisms could provide a potential for developing therapeutics aimed at improving the cerebral vasculature as a means to protect the brain from further injury. During my thesis work, I have identified that the brain vasculature is undergoing endothelial- mesenchymal transition (EndoMT) in a mouse model of viral-induced encephalitis. EndoMT contributes to vascular malformations and loss of BBB properties in a congential vasculopathy called Cerebral Cavernous Malformations. Based on this, I hypothesize that EndoMT initiates vascular instability and this is mediated by TGF? signaling, an EndoMT effector pathway. I will test this hypothesis in two distinct aims.
In Aim 1, I will establish a timeline for EndoMT progression in the vasculature to understand how this relates to loss of vascular integrity and BBB properties during viral encephalitis.
In Aim 2, I will identify if TGF? signaling promotes EndoMT and vascular instability thereby exacerbating disease outcome. Completion of experiments in this proposal will provide new knowledge about the cellular and molecular properties that are affected within the vasculature during encephalitis.
Insufficient vascular function and integrity are a consequence of many central nervous system (CNS) disorders like encephalitis. Defects in vascular stability can affect oxygen supply, allow for leakage of otherwise restricted substances, and accelerate immune infiltration, thus exacerbating encephalitis. In this proposal I seek to identify the underlying mechanisms that result in vascular instability during encephalitis. Elucidating vascular instability during encephalitis is important for understanding how CNS vascular defects arise and provide a means in which they can be treated.
| Bonney, Stephanie; Dennison, Brenna J C; Wendlandt, Megan et al. (2018) Retinoic Acid Regulates Endothelial ?-catenin Expression and Pericyte Numbers in the Developing Brain Vasculature. Front Cell Neurosci 12:476 |
| Bonney, Stephanie; Siegenthaler, Julie A (2017) Differential Effects of Retinoic Acid Concentrations in Regulating Blood-Brain Barrier Properties. eNeuro 4: |
