Promoting vascular remodeling has emerged as a potential therapeutic approach for neurorestorative therapy. Cerebral vascular trauma leads to inadequate cerebral blood flow which potentiates neuronal cell loss resulting in motor and cognitive deficits in models of brain injury. Endothelial cells (ECs) lining the blood vessels actively respond to tissue trauma. Our novel findings demonstrate, cell-to-cell contact proteins called Eph receptor tyrosine kinases (EphR), and their ephrin ligand(s), are present on cerebral arteriole ECs and play a central role in limiting arteriogenesis in the murine brain following injury. The research objectives in this application focus on the novel growth suppressive mechanism(s) of EphR signaling on arteriole remodeling and neural recovery. Endothelial-specific deletion of EphR resulted in significant neuroprotection and restoration of blood flow which reflects a monumental change in arteriogenic growth and production of pro-arteriogenic factors. We hypothesize that activation of EphR signaling mediates neural tissue damage and dysfunction by suppressing the EC response during arteriole vascular remodeling. To test this, we will employ novel cell-specific and inducible knockout mice, double reporter labeling and adoptive transfer. We will also investigate the relevance and mechanisms of injury-induced arteriogenesis in neural recovery using gain- and reverse-of-function infusion approaches. These studies will reveal a novel therapeutic strategy to enhance this important adaptive process which will greatly impact treatment and management of acute and chronic head injuries.

Public Health Relevance

The proposed studies focus on an important, yet understudied area of brain research. Our overall goal is to greatly improve the research and medical communities understanding of vascular remodeling following brain injury and how this impacts the microenvironment in which neurons repair themselves. New insights into the novel mechanism(s) restricting cerebral arteriogenesis will advance treatment strategies for improving neurorestoration in the brain.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS096281-03
Application #
9456822
Study Section
Brain Injury and Neurovascular Pathologies Study Section (BINP)
Program Officer
Bellgowan, Patrick S F
Project Start
2016-03-01
Project End
2021-02-28
Budget Start
2018-03-01
Budget End
2019-02-28
Support Year
3
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Virginia Polytechnic Institute and State University
Department
Veterinary Sciences
Type
Schools of Veterinary Medicine
DUNS #
003137015
City
Blacksburg
State
VA
Country
United States
Zip Code
24061
Brickler, Thomas R; Hazy, Amanda; Guilhaume Correa, Fernanda et al. (2018) Angiopoietin/Tie2 Axis Regulates the Age-at-Injury Cerebrovascular Response to Traumatic Brain Injury. J Neurosci 38:9618-9634
Okyere, Benjamin; Creasey, Miranda; Lebovitz, Yeonwoo et al. (2018) Temporal remodeling of pial collaterals and functional deficits in a murine model of ischemic stroke. J Neurosci Methods 293:86-96
Theus, Michelle H; Sparks, Joshua B; Liao, Xiaofeng et al. (2017) All- Trans-Retinoic Acid Augments the Histopathological Outcome of Neuroinflammation and Neurodegeneration in Lupus-Prone MRL/lpr Mice. J Histochem Cytochem 65:69-81
Theus, Michelle H; Brickler, Thomas; Meza, Armand L et al. (2017) Loss of NLRX1 Exacerbates Neural Tissue Damage and NF-?B Signaling following Brain Injury. J Immunol 199:3547-3558
Greer, Kisha; Chen, Jiang; Brickler, Thomas et al. (2017) Modulation of gap junction-associated Cx43 in neural stem/progenitor cells following traumatic brain injury. Brain Res Bull 134:38-46
Powell, Chadwick R; Foster, Jeffrey C; Okyere, Benjamin et al. (2016) Therapeutic Delivery of H2S via COS: Small Molecule and Polymeric Donors with Benign Byproducts. J Am Chem Soc 138:13477-13480
Okyere, Benjamin; Giridhar, Kaavya; Hazy, Amanda et al. (2016) Endothelial-Specific EphA4 Negatively Regulates Native Pial Collateral Formation and Re-Perfusion following Hindlimb Ischemia. PLoS One 11:e0159930
Brickler, Thomas; Gresham, Kisha; Meza, Armand et al. (2016) Nonessential Role for the NLRP1 Inflammasome Complex in a Murine Model of Traumatic Brain Injury. Mediators Inflamm 2016:6373506