The Role of Tissue Plasminogen Activator in a Mouse Spinal Cord Injury Model

TBI是一个重大的公共卫生问题。它是工业化国家45岁以下的人慢性残疾和丧失生产力的主要原因之一。TBI通常会导致数十年的认知，行为，情感和身体功能障碍。然而，TBI的治疗选择仍然有限，目前的疗法和药物几乎没有提供任何益处。TBI治疗缺乏疗效的部分原因是在TBI研究中仍然存在的理解上的差距。确定TBI慢性残疾的根本原因是确定治疗这种致残性疾病患者的潜在治疗靶点的第一步。这样做将减轻个人的痛苦和与数十年残疾相关的医疗费用。导致持续性功能障碍的一个潜在机制是神经递质、受体和细胞信号蛋白的改变。我们的研究集中在这样一个潜在的细胞蛋白，多巴胺和cAMP调节磷蛋白32（DARPP-32）。DARPP-32通过整合来自多巴胺和谷氨酸等神经递质系统的信号传导，并间接改变许多重要的细胞事件，包括ERK和CREB信号传导、NMDA受体和Na/K ATP酶，发挥着极其重要的作用。DARPP-32通过影响蛋白激酶a（PKA）和蛋白磷酸酶1（PP 1）的活性，间接改变ERK、CREB、NMDA受体和Na/K ATP酶的磷酸化。PKA或PP 1的抑制依赖于DARPP-32在Thr 34和Thr 75 DARPP-32的磷酸化状态。我们假设TBI导致DARPP-32在Thr 34磷酸化的减少。我们假设，这种TBI诱导的DARPP-32/Thr 34磷酸化的减少将消除其对PP 1的抑制并增加其对PKA的抑制。PP 1活性的增加将导致ERK和CREB的磷酸化降低，从而降低它们的活性。ERK和CREB活性的降低与重要的神经营养因子的转录减少有关。PKA活性的降低将降低其磷酸化活性，随后降低Na/K ATP酶磷酸化和NMDA受体磷酸化。

TBI is a significant public health concern. It represents one of the leading causes of chronic disability and lost productivity in individuals under the age of 45 in industrialized countries. TBI often leads to decades of cognitive, behavioral, emotional, and physical dysfunction. Yet treatment options for TBI remain limited and current therapies and Pharmaceuticals provide little benefit. Part of the reason for the lack of efficacy in TBI treatments is the gap in understanding that remains in the study of TBI. Identifying the underlying causes of chronic disability in TBI represents the first step in identifying potential therapeutic targets to treat patients with this disabling disease. Doing so would relieve both individual suffering and the healthcare costs associated with decades of disability. One potential mechanism that leads to persistant dysfunction is alterations in neurotransmitters, receptors, and cellular signaling proteins. Our research focuses on one such potential cellular protein, dopamine and cAMP regulated phosphoprotein 32 (DARPP-32). DARPP-32 plays an extremely important role by integrating signaling from dopamine and glutamate, among other neuretransmitter systems, and indirectly altering many important cellular events including ERK and CREB signaling, NMDA receptors, and the Na/K ATPase. DARPP-32 alters phosphorylation of ERK, CREB, NMDA receptors, and the Na/K ATPase indirectly by affecting the activity of protein kinase a (PKA) and protein phosphatase 1 (PP1). Inhibition of PKA or PP1 is dependent upon the phosphorylation state of DARPP-32 at Thr34 and Thr75 DARPP-32. We hypothesize that TBI causes a decrease in DARPP-32 phosphorylation at Thr34. We hypothesize that this TBI induced decrease in phosphorylation at DARPP-32/Thr34 will remove its inhibition upon PP1 and increase its inhibition of PKA. The increase in PP1 activity will cause decreased phosphorylation of ERK and CREB thereby reducing their activity. A reduction in ERK and CREB activity is associated with reduced transcription of important neurotrophic factors. The decrease in PKA activity will reduce its phosphorylation activity with subsequent decreases in Na/K ATPase phosphorylation and NMDA receptor phosphorylation.