Subarachnoid hemorrhage (SAH), which occurs due to rupture of an intracranial aneurysm, is associated with significant mortality and long-term morbidity among survivors. SAH leads to early brain injury, especially neurovascular injuries, within the first 72 hours after SAH. Osteopontin (OPN) is an extracellular matrix protein that can interact with cell surface integrin receptors especially avP3 through its arginine-glycineaspartate (RGD) sequence and has been implicated in promoting cell survival, proliferation and reductions in cellular apoptosis. Recent studies from our laboratory and others have demonstrated the neurovascular protective effects of intracerebroventricular administration of recombinant osteopontin (rOPN) in various preclinical stroke models, which makes rOPN an attractive candidate for neurovascular protection. However, intracerebroventricular route is not translational;therefore, we propose to administer rOPN intranasally, which is an established, safe, and non-invasive method. Our central hypothesis is that intranasal administration of rOPN will provide neurovascular protection against early brain injury after SAH by preservation of smooth muscle phenotypes and stabilization of the BBB via integrin receptor signaling pathways. In addition, we propose that ICH and TBI cause similar expanded neurovascular injury, and rOPN will provide similar neurovascular protection to ICH and TBI. We propose three specific aims to address our hypothesis.
Aim 1 will determine the neurovascular protective effect of intranasal rOPN administration after SAH.
Aim 2 will determine the mechanisms of neurovascular protection by rOPN after SAH.
Aim 3 will determine a broad neurovascular protection of intranasal application of rOPN after ICH and TBI. Our specific hypothesis is that rOPN will offer similar neurovascular protection by preserving smooth muscle phenotypes, stabilizing BBB and reducing brain edema, to improve long term neurological and neurobehavioral functional outcomes. The long-term goal of this proposal is to provide a basis for clinical translation of rOPN as an effective therapeutic option to protect against the expanded neurovascular injuries in patients after SAH and to improve overall patient outcomes in the long-term.

Public Health Relevance

Osteopontin is a protein whose level increases upon brain injury and protects brain cells. This project intends to establish a clinically relevant intranasal-drop application of osteopontin and test its brain protective effect and mechanisms.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Program Projects (P01)
Project #
1P01NS082184-01A1
Application #
8661423
Study Section
National Institute of Neurological Disorders and Stroke Initial Review Group (NSD)
Project Start
Project End
Budget Start
2014-01-01
Budget End
2014-12-31
Support Year
1
Fiscal Year
2014
Total Cost
$183,943
Indirect Cost
$66,720
Name
Loma Linda University
Department
Type
DUNS #
009656273
City
Loma Linda
State
CA
Country
United States
Zip Code
92350
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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