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.
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.
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