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

组织纤溶酶原激活剂在小鼠脊髓损伤模型中的作用

• 批准号: 8005539
• 负责人: Noreen Bukhari-Parlakturk
• 金额: $ 3.04万
• 依托单位: STATE UNIVERSITY NEW YORK STONY BROOK
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-01-15 至 2013-07-15
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8005539
• 关键词: Actins; Affect; Age; Alteplase; Attenuated; Axon; Behavioral; Brain; CREB1 gene; CSPG3 gene; CSPG4 gene; Chondroitin ABC Lyase; Chondroitin Sulfate Proteoglycan; Chronic; Cicatrix; Cognitive; Contusions; Cues; DARPP 32; Databases; Developed Countries; Dopamine; Dyes; Emotional; Environment; Enzymes; Event; Extracellular Matrix; Flow Cytometry; Functional disorder; Genetic Transcription; Glutamates; Health Care Costs; Immunohistochemistry; In Vitro; Individual; Injection of therapeutic agent; Injury; Knock-out; Knockout Mice; Label; Measures; Mediating; Modeling; Motor; Mus; N-Methyl-D-Aspartate Receptors; Na(+)-K(+)-Exchanging ATPase; Neurites; Neurons; Neurotransmitter Receptor; Patients; Pharmacia brand of estropipate; Pharmacologic Substance; Phosphorylation; Plasmin; Play; Process; Productivity; Propidium Diiodide; Protein Kinase; Protein phosphatase; Proteins; Public Health; Publishing; Research; Role; Seizures; Sensory; Serine Protease; Signal Transduction; Signaling Protein; Spinal cord injury; System; Testing; Therapeutic; Time; United States; Wild Type Mouse; disability; disabling disease; extracellular; in vivo; in vivo Model; neuronal survival; neurotrophic factor; overexpression; phosphacan; phosphoprotein 32; repaired; spinal cord regeneration; sugar; therapeutic target

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.

脑外伤是一个重大的公共卫生问题。它是工业化国家45岁以下个人慢性残疾和丧失生产力的主要原因之一。创伤性脑损伤通常会导致数十年的认知、行为、情感和身体功能障碍。然而，创伤性脑损伤的治疗选择仍然有限，目前的治疗方法和药物几乎没有效果。创伤性脑损伤治疗缺乏疗效的部分原因是在创伤性脑损伤研究中仍然存在认识上的差距。确定TBI慢性残疾的潜在原因是确定治疗这种致残疾病患者的潜在治疗靶点的第一步。这样做既可以减轻个人痛苦，也可以减轻与数十年残疾相关的医疗费用。导致持续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。我们的研究重点是一种潜在的细胞蛋白，多巴胺和cAMP调节的磷酸化蛋白32 （DARPP-32）。DARPP-32通过整合来自多巴胺和谷氨酸以及其他神经递质系统的信号，并间接改变许多重要的细胞事件，包括ERK和CREB信号，NMDA受体和Na/K atp酶，起着极其重要的作用。DARPP-32通过影响蛋白激酶a （PKA）和蛋白磷酸酶1 （PP1）的活性，间接改变ERK、CREB、NMDA受体和Na/K atp酶的磷酸化。PKA或PP1的抑制依赖于DARPP-32在Thr34和Thr75位点的磷酸化状态。我们假设TBI导致DARPP-32 Thr34位点磷酸化降低。我们假设，这种TBI诱导的DARPP-32/Thr34磷酸化降低将消除其对PP1的抑制作用，并增加其对PKA的抑制作用。PP1活性的增加会导致ERK和CREB磷酸化降低，从而降低其活性。ERK和CREB活性的降低与重要神经营养因子转录的减少有关。PKA活性的降低会降低其磷酸化活性，进而降低Na/K atp酶磷酸化和NMDA受体磷酸化。