Platelets and Microvascular Dysfunction in Traumatic Brain Injury

Platelets are increasingly recognized to be essential mediators of inflammation, independent of their role in thrombosis and hemostasis. Platelet recruitment to microvascular endothelium is a critical initial step in the inflammatory response. Although platelets have been shown to contribute to vascular dysfunction in the acute

phase of traumatic brain injury (TBI), the role platelets play in persistent TBI symptomology is incompletely understood. TBI affects a large portion of Veterans, and Veterans who experienced TBI are at increased risk for

chronic neurological impairment with great detriment to quality of life. Currently, there is a distinct lack of effective therapeutics aimed at preventing these long-term TBI complications. The mechanisms by which acute injury transitions to persistent symptomology are not well understood. To address this knowledge gap, the proposed

studies will use an innovative strategy combining real-time high-resolution intravital microscopy and a controlled cortical impact (CCI) model of injury in a repeated-measures study of TBI. The CCI model is a well-established models for replicating the neuronal cell death and overt vascular breakdown

which results from TBI and highlights the diffuse systemic coagulation which can result from brain injury. TBI results in platelet activation and an acute disruption in the blood brain barrier (BBB) which may predispose individuals to the development of long-term complications including neurodegenerative disorders. Despite this,

very little research has been conducted investigating the platelet-dependent changes that occur during the transition from the acute phase of TBI to the chronic phase of injury. The mentor's laboratory has significant expertise with platelet-microvessel interactions in systemic vascular beds and various models of inflammation.

The applicant recently developed a chronic cranial window model of repeated-measures imaging of the cortical vasculature combined with a CCI model of TBI. Preliminary data generated in this model provide evidence of pathological platelet-microvessel interaction and platelet extravasation into cortical tissue, concomitant with

disruption of the BBB, in the uninjured cortex contralateral to the site of injury. We will use this novel approach to examine the longitudinal profile of platelet-endothelial interaction and BBB disruption that occurs over the development of chronic TBI. The overall objective of this application is to determine the contribution of

platelets to the longitudinal cerebrovascular changes following TBI, and to determine the molecular mechanisms responsible for platelet-microvessel interactions and cerebrovascular dysfunction following TBI. Our central hypothesis is that platelet-microvessel interaction contributes to the cerebrovascular dysfunction, BBB

disruption and functional deficits found in the acute and chronic phases of TBI. This hypothesis was formed based on the current literature in conjunction with our own published and preliminary data demonstrating the contribution of platelets in vascular pathology and the development of hyperreactive and damaged vascular

endothelium in other vascular beds. This research will drastically improve our understanding of the role platelets play in the cerebrovascular alterations that occur in the chronic phase of TBI and help inform therapeutic strategies for this disorder. The proposed mentorship and career plans will develop the applicant into an

independent VA investigator dedicated to the study of neurodegeneration and microvascular pathology with the goal of improving the lives of our Veteran population. In addition, the applicant is committed to mentoring future VA investigators and helping to foster a vibrant and collaborative research environment at the VA. The applicant's

expertise and VA-based imaging and neurobehavioral program, distinct from that of his mentor, will enhance the pre-clinical capacity of the Houston VA and foster further collaboration with the Texas Medical Center.