Modulation of BBB TJ proteins with chronic inflammation

在美国，超过7000万人患有慢性疼痛，这导致每年花费数十亿美元用于医疗和生产力损失。我们实验室的初步研究已经描述了与急性炎性疼痛相关的血脑屏障（BBB）受损。生理上，BBB是渗透脑的内皮血管系统。BBB对于维持大脑的调节环境至关重要。BBB的紧密连接（TJ）的蛋白质细胞结构负责控制BBB处的细胞旁通透性。已经确定的是，BBB在与TJ失调相关的各种疾病状态中受损。该提议的假设是慢性炎性疼痛导致功能性BBB完整性的变化，这与跨膜TJ蛋白封闭蛋白、封闭蛋白-3和封闭蛋白-5的改变相关。这些研究将为慢性炎症性疼痛对血脑屏障完整性的影响以及特定TJ蛋白功能改变的机制提供新的信息。最终，这项资助可能会为炎症介导的疾病状态的治疗干预确定新的途径。

DESCRIPTION (provided by applicant): In the United States, more than 70 million people are afflicted with chronic pain, which leads to billions of dollars spent for medical treatments and lost productivity yearly. Initial studies in our laboratory have described a compromised blood-brain barrier (BBB) associated with acute inflammatory pain. Physiologically, the BBB is the endothelial vasculature which permeates the brain. The BBB is critical to maintaining the regulated environment of the brain. The protein cytoarchitecture of the tight junctions (TJs) of the BBB are responsible for controlling paracellular permeability at the BBB. It has been well-established that the BBB is compromised in various disease states associated with TJ disregulation. The hypothesis of this proposal is that chronic inflammatory pain leads to a change in functional BBB integrity, which correlates with alterations in the transmembrane TJ proteins occludin, claudin-3 and claudin-5. These studies will provide new information related to the effect of chronic inflammatory pain on BBB integrity and the mechanisms underlying functional alterations in specific TJ proteins. Ultimately this grant may identify novel avenues for therapeutic intervention of inflammatory mediated disease states.