The goal of this project is to test the hypothesis that the microvascular effects of neuregulin-1 (NRG1) contribute to neuroprotection after brain trauma. My hypothesis is that through its interactions with the RhoA pathway, NRG1 signaling in the microvascular endothelial cell prevents cytokine-induced endothelial hyper-permeability and decreases microthrombi formation. These beneficial actions on the microvasculature further provide support for the other types of cells in the brain - including the neurons, astrocytes, oligodendrocytes, and pericytes.
The specific aims of the project are:
Aim 1 : Test the hypothesis that NRG1- inhibits cytokine-induced endothelial RhoA activation, decreasing dysfunctional cytoskeletal contraction, tight junction phosphorylation and re-distribution, endothelial hyper-permeability, and neutrophil transmigration.
Aim 2 : Test the hypothesis that NRG1- decreases microthrombi formation.
Aim 3 : Test the hypothesis that microvascular actions of NRG1- contribute to improved cognitive outcome after traumatic brain injury. The research design includes in-vitro experiments in which NRG1- mediated pathways related to these processes are studied in the endothelial cell, and in-vivo experiments in which the effect of exogenous NRG1 is investigated in a mouse model of brain trauma. Delineating these signaling pathways will add to the understanding of NRG1 actions in the brain, a relevant topic since NRG1 is now known to have extensive functions within the nervous system, has the potential to be neuroprotective after brain trauma, and is currently being investigated in clinical trials for the treatment of heart failure.
The overall hypothesis of this proposal is that the microvascular effects of neuregulin-1 (NRG1) contribute to neuroprotection after brain trauma. My hypothesis is that through its interactions with the RhoA pathway, NRG1 signaling in the microvascular endothelial cell prevents cytokine-induced endothelial hyper-permeability and decreases microthrombi formation. Delineating these signaling pathways will add to the understanding of NRG1 functions in the brain, a relevant topic since NRG1 is now known to have extensive functions within the nervous system and is being investigated in clinical trials for the treatment of heart failure.
| Chung, Joon Yong; Krapp, Nicolas; Wu, Limin et al. (2018) Interleukin-1 Receptor 1 Deletion in Focal and Diffuse Experimental Traumatic Brain Injury in Mice. J Neurotrauma : |
| Wu, Limin; Ramirez, Servio H; Andrews, Allison M et al. (2016) Neuregulin1-? decreases interleukin-1?-induced RhoA activation, myosin light chain phosphorylation, and endothelial hyperpermeability. J Neurochem 136:250-7 |
