This Program Project Grant (PPG) will address how an """"""""expanded neurovascular unit"""""""" responds to injury and putative therapeutic treatment in three major brain hemorrhagic disorders seen in neurosurgery service. The expanded neurovascular unit includes not only endothelial cells, pericytes, and astrocytes but also the feeding and upstream cerebral arteries of the neurovascular unit and arterial smooth muscle cells. The responses of the expanded neurovascular unit to hemorrhagic brain injury may not only demonstrate universal but also distinct pathophysiological features. In our PPG we propose a horizontal comparative study in rodent models o f t h e three major brain hemorrhage disorders, subarachnoid hemorrhage (SAH), intracerebral hemorrhage (ICH), and traumatic brain injury (TBI). Similarly we will compare three different treatment strategies such as osteopontin (OPN), anti-PDGF (Gleevec), and AP-Cav (caveolin) in all three distinct hemorrhagic brain injury models. Based upon existing literature combined with our own preliminary observations, our hypothesis is that there are universal but distinct features of injury encompassing the expanded neurovascular unit following brain hemorrhage in SAH/ICH/TBI models. We further hypothesize that three distinct neurovascular protection strategies targeting the matrix protein OPN, PDGF-receptors, and endothelial caveolin will prevent arterial smooth muscle phenotype changes, provide neurovascular protection to strengthen blood-brain barrier (BBB) integrity, improve vascular function and reduce brain edema via different mechanisms.

Public Health Relevance

This PPG will integrate expertise from cerebral hemorrhage, traumatic brain injury and vascular biology to study common features of an expanded neurovascular injury after subarachnoid hemorrhage, intracerebral hemorrhage and traumatic brain injury. Injuries will be mimicked in three rodent models while employing neuroimaging, neurobehavioral testing and vascular biology to compare common and distinct features. Using three treatment strategies in all models, our results have the potential to impact daily neurosurgery service.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Program Projects (P01)
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National Institute of Neurological Disorders and Stroke Initial Review Group (NSD)
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Koenig, James I
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Loma Linda University
Loma Linda
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Guo, Zongduo; Hu, Qin; Xu, Liang et al. (2016) Lipoxin A4 Reduces Inflammation Through Formyl Peptide Receptor 2/p38 MAPK Signaling Pathway in Subarachnoid Hemorrhage Rats. Stroke 47:490-7
Jullienne, Amandine; Obenaus, Andre; Ichkova, Aleksandra et al. (2016) Chronic cerebrovascular dysfunction after traumatic brain injury. J Neurosci Res 94:609-22
Yang, Peng; Manaenko, Anatol; Xu, Feng et al. (2016) Role of PDGF-D and PDGFR-β in neuroinflammation in experimental ICH mice model. Exp Neurol 283:157-64
Flores, Jerry J; Klebe, Damon; Rolland, William B et al. (2016) PPARγ-induced upregulation of CD36 enhances hematoma resolution and attenuates long-term neurological deficits after germinal matrix hemorrhage in neonatal rats. Neurobiol Dis 87:124-33
Wu, Jiang; Zhang, Yang; Yang, Peng et al. (2016) Recombinant Osteopontin Stabilizes Smooth Muscle Cell Phenotype via Integrin Receptor/Integrin-Linked Kinase/Rac-1 Pathway After Subarachnoid Hemorrhage in Rats. Stroke 47:1319-27
Yang, Peng; Wu, Jiang; Miao, Liyan et al. (2016) Platelet-Derived Growth Factor Receptor-β Regulates Vascular Smooth Muscle Cell Phenotypic Transformation and Neuroinflammation After Intracerebral Hemorrhage in Mice. Crit Care Med 44:e390-402
Yin, Cheng; Huang, Guang-Fu; Sun, Xiao-Chuan et al. (2016) Tozasertib attenuates neuronal apoptosis via DLK/JIP3/MA2K7/JNK pathway in early brain injury after SAH in rats. Neuropharmacology 108:316-23
Wang, Yuechun; Reis, Cesar; Applegate 2nd, Richard et al. (2015) Ischemic conditioning-induced endogenous brain protection: Applications pre-, per- or post-stroke. Exp Neurol 272:26-40
Chen, Yujie; Zhang, Yang; Tang, Junjia et al. (2015) Norrin protected blood-brain barrier via frizzled-4/β-catenin pathway after subarachnoid hemorrhage in rats. Stroke 46:529-36
Huang, Lei; Sherchan, Prativa; Wang, Yuechun et al. (2015) Phosphoinositide 3-Kinase Gamma Contributes to Neuroinflammation in a Rat Model of Surgical Brain Injury. J Neurosci 35:10390-401

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