In our previous grant period (Neurovascular Protection for Subarachnoid Hemorrhage, NIH/NS053407 2007- 2011) we have studied endothelial protective mechanisms against cerebral vasospasm and brain edema. Our studies were the pioneering observations that early brain injury which is featured by an elevated intracranial pressure, reduced cerebral blood flow, decreased cerebral perfusion pressure, disrupted blood-brain barrier, increased brain edema, sporadically distributed neuronal cell death/apoptosis, and therefore resulted poor neurological functional evaluations within 72 hrs after SAH, is a determination factor, rather than cerebral vasospasm as we believed previously, for clinical outcome. Our observations lead the changes of the directions of SAH research, and most labs in the world are now studying early brain injury management to improve outcomes. During our previous studies, we have identified several promising candidates for neurovascular protection after subarachnoid hemorrhage (SAH) and one of them is osteopontin (OPN). OPN is an extracellular matrix protein that can interact with cell surface integrin receptors through its arginine-glycine- aspartate (RGD) sequence and has been implicated in promoting cell survival, proliferation and reducing 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. However, the mechanism by which rOPN elicits neurovascular protection has not been evaluated. Elucidating the molecular mechanisms by which OPN exerts its effects would facilitate the development of a novel therapy to protect against SAH. Furthermore, we propose to administer rOPN intranasally, which is an established, safe, and non-invasive method to bypass the blood-brain barrier. The specific objective of this proposal is to determine the neurovascular protective potential of rOPN administered intranasally as a novel treatment strategy to reduce early brain injury after SAH, and to determine the mechanism of neurovascular protection conferred by rOPN through anti-apoptotic signaling and BBB stabilization. Our central hypothesis is that intranasal administration of rOPN provides protection against early brain injury after SAH by reducing neuronal apoptosis and stabilization of the BBB via integrin receptor signaling pathway. The following three specific aims are proposed to address our hypothesis.
Aim 1 will determine the neurovascular protective effect of intranasal rOPN administration after SAH. Our specific hypothesis is (1) that OPN concentration in CSF/brain will be increased after intranasal rOPN administration. (2) intranasal rOPN will improve neurological outcomes and reduce mortality after SAH via integrin receptor signaling.
Aim 2 will determine the mechanism of anti-apoptotic effect of rOPN after SAH. Our specific hypothesis is that (1) rOPN performs anti-apoptotic signaling mediated by FAK signaling and (2) via PI3K/ Akt pathways.
Aim 3 will determine the mechanism of blood brain barrier protection by rOPN after SAH. Our specific hypothesis is that rOPN protects BBB via ILK and Rac-1 pathways. The long-term goal of this proposal is to provide a basis for clinical translation of rOPN as an effective therapeutic option o protect against complications in patients after SAH and to improve overall patient outcomes in the long-term.
Osteopontin is a protein that its level increased upon brain injury and protects brain cells. This project intends to establish a clinical relevant intranasal-dop in the nose-application of osteopontin and test its brain protective effect and mechanisms.
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