The blood brain barrier in neuroinflammation

描述（由申请人提供）：血脑屏障（BBB）破坏代表中枢神经系统炎症的典型标志，并且其发生在各种神经病理学病症中。BBB破坏涉及脑内皮细胞表面的重塑、内皮细胞间连接蛋白的分布改变和BBB通透性增加。这些变化导致白细胞和其他血液成分的异常外渗和血管源性水肿。白细胞外渗是炎性损伤发展中的关键事件，并且它们穿过脑内皮的迁移受到脑内皮细胞和白细胞上的细胞因子、粘附分子和趋化因子的多样性提供的分子信号的协调相互作用的调节。连接粘附分子（JAM; JAM-A、JAM-B、JAM-C）是跨膜紧密连接蛋白，并且虽然它们参与维持紧密的内皮细胞：内皮细胞相互作用，但最近的证据表明它们也是调节和指导白细胞迁移的关键参与者。在炎症过程中，它们可以作为粘附分子，直接与入侵的白细胞相互作用，促进它们通过形成的脑内皮细胞旁间隙的运动。本研究旨在探讨在缺血再灌注损伤过程中，JAM是否参与了损伤和炎症反应的进展（具体目的1）缺血/再灌注损伤过程中表达的炎性刺激是否以及如何调节JAMs的表达和功能（具体目标2），JAM重新分布和转化为白细胞粘附分子的分子机制是什么（具体目标3）以及抑制JAM或其再分布是否可以改善脑缺血/再灌注损伤（具体目标4）。总的来说，这些研究将提供与多种疾病状态相关的BBB破坏和白细胞外渗机制相关的新信息，并有望阐明预防此类破坏的方法。 公共卫生相关性：炎症和白色血细胞的募集是中风后脑损伤和脑肿胀的关键事件。本研究的目的是强调炎症条件下白色血细胞运输的分子机制。这可能为开发新的治疗策略提供基础，以减轻中风以及影响中枢神经系统的其他炎症过程的破坏。

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.