Platelets as regulator of non-neurological complications of ischemic stroke - PROJECT SUMMARY/ABSTRACT Cerebrovascular diseases, including stroke, are the leading cause of death globally. In the United States, stroke is the number one cause of preventable disability. The majority of strokes are ischemic, resulting from blood clots that block blood flow and prevent the delivery of vital nutrients and oxygen to brain tissue. The current clinical approach to managing ischemic stroke involves removing the blockage using either pharmacological or surgical methods. However, reperfusion, which restores blood flow, can lead to ischemia/reperfusion (I/R) injury, causing increased tissue death and additional complications such as remote organ injury (ROI) and infection. In fact, stroke-associated infection, particularly pneumonia, is the most common cause of death during the post- acute recovery phase for stroke victims. Surprisingly, administering prophylactic antibiotics to prevent stroke- associated infections has not been effective in reducing mortality among stroke patients. Therefore, it is crucial to gain a deeper understanding of ROI and develop therapies to alleviate the burden of this disease. Platelets, the second most abundant type of blood cell, play a significant role in ischemic stroke/reperfusion. In addition to their impact on the brain, these activated platelets can circulate throughout the body and cause secondary damage to other organs, such as the intestine and lungs. Consequently, targeting platelet activity could serve as a novel therapeutic approach to address ROI. Our laboratory has discovered that depleting platelets after stroke protects mice from gut permeability and subsequent bacterial presence in the lungs, even in mice with large brain infarcts. However, no studies have demonstrated how platelets contribute to the worsening of ROI and infection following stroke. Our hypothesis is that platelet activation after ischemic stroke/reperfusion leads to vascular/gut permeability, facilitating the translocation of gut microbes, ultimately resulting in increased inflammation and death. The aims of the proposal are: (1) Elucidate the role of activated platelets in ROI and infection after I/R; (2) Determine which platelet component is responsible for regulating endothelial activation and gut/vascular permeability after I/R; and (3) Evaluate potential pharmacological intervention after I/R. We will utilize both genetic and pharmacology-based methods to define the role of platelets and their products such as cytokines, microparticles and miRNAs in ROI and infection in a variety of in vivo models and assess their potential as therapeutic targets. Thus, these studies will add a new dimension to the paradigms underlying platelet mediated ROI and offer a tractable clinical approach for the treatment of ROI and infection after stroke.
