The blood brain barrier in neuroinflammation

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DESCRIPTION (provided by applicant): Blood-brain barrier (BBB) disruption represents a classic hallmark of central nervous system inflammation and it occurs in a variety of neuropathological conditions. BBB disruption involves remodeling of the brain endothelial cell surface, altered distribution of endothelial intercellular junction proteins and increased BBB permeability. These changes lead to abnormal extravasation of leukocytes and other blood components and vasogenic edema. Leukocyte extravasation is a crucial event in the development of inflammatory injury and their migration across the cerebral endothelium is regulated by an orchestrated interplay of molecular signals provided by diversity of cytokines, adhesion molecules and chemokines on both brain endothelial cells and leukocytes. Junction adhesion molecules (JAMs; JAM-A, JAM-B, JAM-C) are transmembrane tight junction proteins and while they are involved in maintaining tight endothelial:endothelial cell interactions, recent evidence has suggested that they are also critical players in regulating and directing leukocyte transmigration. During inflammatory processes they can act as adhesion molecules and directly interact with the invading leukocytes, facilitating their movement through a formed brain endothelial paracellular cleft. This proposal is designed to investigate whether during ischemic reperfusion injury JAMs contributed to progression of injury and inflammatory response (Specific Aim 1), whether and how inflammatory stimulus expressed during ischemia/reperfusion injury regulated JAMs expression and function (Specific Aim 2), what is the molecular mechanisms of JAMs redistribution and conversion of JAMs to leukocytes adhesion molecules (Specific Aim 3) and whether inhibiting JAMs or their redistribution can ameliorate brain ischemia/reperfusion injury (Specific Aim 4). Collectively, these studies will provide new information related to the mechanisms of BBB disruption and leukocyte extravasation that is relevant to multiple disease states and will, hopefully, elucidate methods of preventing such disruption. PUBLIC HEALTH RELEVANCE: Inflammation and white blood cell recruitment are critical events in the brain damage and brain swelling that follows a stroke. The purpose of this study is to highlight the molecular mechanisms underlying white blood cell trafficking under inflammatory conditions. This may provide a foundation for developing novel therapeutic strategies to lessen the ravages of stroke as well as other inflammatory processes affecting the central nervous system.