Ischemic stroke is now the most frequent cause of persistent neurologic disability in the US. Despite considerable effort there are no therapies that can reduce injury or restore function once a stroke occurs. Over the past several years, our view of stroke as a "neuronal disease" has been transformed into the concept of stroke as a "neurovascular" disease, and more recently into the novel theory that stroke is truly a "systemic" disease in which peripheral inflammatory processes play a fundamental role. Secondary injury from the infiltration of peripheral immune cells is increasingly recognized as a major contributor to brain injury, edema and hemorrhagic transformation. These cells require proteases to transmigrate into the brain, a process mediated primarily by activation of matrix metalloproteinases (MMPs). Extracellular Matrix Metalloproteinase Inducer (EMMPRIN;CD 147) is a 58-kDa cell surface glycoprotein that regulates leukocyte trafficking into the brain. The proposed work will examine regulation of CD147 after stroke and determine if a function blocking antibody can reduce injury or blood brain barrier (BBB) breakdown. These effects will be confirmed in aged animals (Aim 1) and with chronic functional assessments (Aim 2). This preliminary work will set the stage for an investigation of the potential for other biologically based therapies to treat stroke. These exploratory studies will hopefully identify new biological targets for therapeutic intervention for patients with stroke.

Public Health Relevance

There is considerable evidence that inflammation plays a major role in outcomes from clinical and experimental stroke. Migration of immune cells from the periphery into the brain leads to enhanced injury. As stroke is now the number one cause of long-term disability, new treatments targeting the peripheral trafficking of immune cells should be explored.

National Institute of Health (NIH)
Exploratory/Developmental Grants (R21)
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Brain Injury and Neurovascular Pathologies Study Section (BINP)
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Bosetti, Francesca
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University of Connecticut
Schools of Medicine
United States
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Ritzel, Rodney M; Patel, Anita R; Grenier, Jeremy M et al. (2015) Functional differences between microglia and monocytes after ischemic stroke. J Neuroinflammation 12:106
Bushnell, Cheryl; McCullough, Louise (2014) Stroke prevention in women: synopsis of the 2014 American Heart Association/American Stroke Association guideline. Ann Intern Med 160:853-7