UNIVERSITY OF LOUISVILLE

Endothelial cells (ECs) are among the first cells to die acutely after contusive spinal cord injury (SCI), triggering secondary degeneration, including axon and myelin loss. We showed that i.v. treatments with the Tie2 ligand angiopoietin-1 (Ang1) plus the ?v?3/?5?1 integrin agonist C16 provide high levels of functional recovery, vascular and tissue protection, and reduced inflammation. However, it is essential that we find additional therapeutic methods or targets as we rescue less than half of the blood vessels and white matter and no long-projecting descending pathways. We suggest that this is possible by adding the neuroprotective effects of protein tyrosine phosphatase (PTP) inhibition, which rescues axons projecting through the injury site. To identify additional opportunities for neuroprotective treatments Aim 1 will determine whether PTP inhibition can further enhance the effect of C16+Ang1 on EC survival and tissue sparing and whether EC sparing mediates rescue of long-projecting axons, and whether this involves VE-PTP, which normally inactivates Tie2. We will also determine whether C16+Ang1 is superior because of Tie2 and ?v?3/?5?1 integrin cooperation or whether additional mechanisms are involved. We have also found new avenues to study and modulate angiogenesis, which we now recognize as one of the critical and beneficial EC response to SCI. Thrombospondin-1 (TSP-1), a potent anti-angiogenic factor which also induces EC apoptosis, was identified using a novel microvascular purification method and EC arrays. Aim 2 will determine which domains mediate CNS microvasculature responses in culture and the role of CD36 and CD47, two domain-specific TSP-1 EC receptors, in mediating vascular responses after SCI. Our data also indicate that enhanced angiogenesis in the absence of vessel maturation will not enhance functional recovery and that providing Ang-1 to mature those nacent angiogenic vessels further reduced functional loss. Therefore, aim 3 will utilize the best angiogenic treatments from aims 1 and 2 and test the maturation effects of prolonged Ang1 on neurological function and tissue sparing. These 3 aims will identify additional molecular targets and much better EC-targeted intravenous treatments for improved tissue locomotor function following traumatic spinal cord injury.FINAL ARRA REPORT SUBMISSION

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