The concept of the neurovascular unit suggests that, to be successful, stroke therapy must target both vascular and neuronal compartments. Here, we propose that the transmembrane receptor CD47 (also known as integrin associated protein) may be an ideal neurovascular target for stroke therapy. Pilot data suggest that (i) the major CD47 ligand thrombospondin-1 (TSP-1) is elevated in plasma of acute stroke patients within 8 hrs, (ii) CD47 and its ligands signal regulatory protein (SIRP-a) and TSP-1 are upregulated in cerebral endothelial cells and neurons after injury, (iii) activation of CD47 in cerebral endothelial cells upregulates inflammatory adhesion molecules (ICAM-1, VCAM-1), (iv) activation of CD47 induces cell death in both neurons and cerebral endothelial cells, and (v) CD47 is upregulated in brain after focal cerebral ischemia, and CD47 knockout mice may have smaller infarcts and reduced neutrophil infiltration compared to wildtype mice. Therefore, we propose the overall hypothesis that CD47 mediates inflammation and cell death in both vascular and neuronal compartments after stroke.
In Aim 1, we will use cerebral endothelial cell cultures to show that activation of CD47 upregulates inflammatory mediators (MMP-9, ICAM-1, VCAM-1) and induces cell death. Oxidative stress via AP-1 and NFkB responses will be assessed as a trigger for CD47 upregulation. Interactions with the two major CD47 ligands TSP-1 and SIRP-a will be examined. Signaling specificity will be assessed using cells derived from knockout mice lacking either CD47 or the related receptor CD36.
In Aim 2, we will use neuronal cultures to show that CD47 mediates cell death by triggering stress activated protein kinase cascades of p38 and JNK leading to caspase-dependent and/or caspase-independent cell death. Once again, we examine interactions between TSP-1 and SIRP-a, and use neurons from knockout mice to examine specific roles of CD47 versus CD36.
In Aim 3, we will use a mouse model of focal cerebral ischemia to document the role of CD47 in neurovascular injury in vivo. Knockout mice lacking eitherTSP-1, CD47 or CD36 will be compared against wildtype mice. To distinguish blood versus tissue CD47 responses, we will also use bone marrow transplants to create chimeric mice.
We aim to show that CD47 mediates neurovascular inflammation, blood-brain barrier leakage, and infarction after stroke. Proof-of-concept data collected here may lead to the development of CD47 as a novel neurovascular target for stroke therapy. ? ?
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