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
Schools of Medicine
Loma Linda
United States
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Zhou, Keren; Enkhjargal, Budbazar; Xie, Zhiyi et al. (2018) Dihydrolipoic Acid Inhibits Lysosomal Rupture and NLRP3 Through Lysosome-Associated Membrane Protein-1/Calcium/Calmodulin-Dependent Protein Kinase II/TAK1 Pathways After Subarachnoid Hemorrhage in Rat. Stroke 49:175-183
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