Stroke is a leading cause of long-term disability worldwide. Multiple mechanisms are involved in the pathophysiology of ischemic stroke, including blood-brain barrier disruption, microglial activation, and infiltration of peripheral immune cells. A plethora of drugs showing neuroprotection in preclinical studies have failed to show efficacy in clinical trials. Multiple factors contribute to these disappointing failures, including study design, use of inappropriate animal models (i.e. exclusive use of young animals), impractical therapeutic windows (acute vs chronic), and poor target selection. Stroke results in biphasic injury: acute (minutes to hours) and chronic (weeks to months) injury. During the acute injury phase, the cross talk between intrinsic and infiltrating peripheral immune cells lead to neuroinflammation. However, restorative processes are stimulated during the chronic phase of stroke. Inhibition of circulating leukocyte transmigration, especially monocytes and neutrophils at early time points will reduce neuroinflammation. Additionally, invigorating restorative processes including angiogenesis will benefit long-term functional outcomes post stroke. CD13 is a membrane-bound metalloprotease, shown to upregulate monocytes and neutrophils and promote their transmigration. On the other hand, CD13 upregulation on angiogenic vessels plays a role in repair after injury. The proposed work will examine the effects of CD13 in post stroke inflammation and recovery. Mechanistic studies will be performed in CD13 knockout animals; CD13 deletion in myeloid cells and endothelial cells will allow us to study its role in acute injury and recovery post stroke respectively (Aim 1). We will then determine the pharmacological efficacy of CD13 inhibition (acute Vs chronic phase) using a specific inhibitor, Ubenimex, in a clinically relevant aged stroke model (Aim 2).
Preclinical and clinical studies demonstrate considerable differences in functional outcomes after stroke with age. Emerging data from experimental studies have identified CD13 as a novel pathway involved in transmigration of circulating immune cells and stimulation of reparative processes involved in tissue injury progression. We will explore the role of CD13 using cell specific knockout animals and test if pharmacological inhibition of CD13 is effective in aged animals after experimental ischemic stroke.
