Cyclic Nucleotide Regulation in Traumatic Brain Injury

创伤性脑损伤中的环核苷酸调节

• 批准号: 7264918
• 负责人: W Dalton Dietrich
• 金额: $ 33.23万
• 依托单位: UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-03-01 至 2012-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7264918
• 关键词: Active Sites; Acute; Adenylate Cyclase; Affect; Apoptosis; Apoptotic; Behavioral; Binding; Binding Sites; Biochemical; Brain; Brain Injuries; Brain Pathology; Calcium; Cells; Cessation of life; Clinical Research; Cognitive; Contusions; Cortical Contusions; Craniocerebral Trauma; Cyclic AMP; Cyclic AMP-Dependent Protein Kinases; Cyclic Nucleotides; Data; Depressed mood; Diffuse; Diffuse Axonal Injury; Edema; Enzymes; Future; Genetic Transcription; Goals; Health; Hippocampus (Brain); Histopathology; Hour; Human; Hydrolysis; Impaired cognition; Impairment; Inflammation; Inflammatory; Inflammatory Response; Injury; Interleukin-1 alpha; Ischemia; Laboratories; Learning; Liquid substance; Locomotor Recovery; Memory; Microglia; Modeling; Neurons; Outcome; Pathway interactions; Patients; Percussion; Personal Satisfaction; Phase; Phosphodiesterase Inhibitors; Protein Isoforms; Proteins; Recovery; Regulation; Research Personnel; Rolipram; Signal Pathway; Signal Transduction; Signaling Molecule; Site; Spinal cord injury; Swelling; Therapeutic; Time; Traumatic Brain Injury; United States; Water; Work; axon regeneration; cell type; clinically relevant; cost; cytokine; day; design; disability; extracellular; functional outcomes; improved; inhibitor/antagonist; injured; neuron apoptosis; neuronal survival; neurotoxic; neutrophil; novel therapeutics; phosphodiesterase IV; phosphoric diester hydrolase; preclinical study; prevent; programs; research study; therapeutic target; transcription factor

DESCRIPTION (provided by applicant): Traumatic brain injury (TBI) is a significant health concern, affecting 1.4 million people in the United States each year at a cost of $56 billion. Both focal and diffuse brain pathologies result from TBI and are exacerbated by the inflammatory response that continues from hours to days after the initial TBI. Unfortunately, there are still no pharmacological therapies available to victims suffering from TBI. The objective of this application is to identify the biochemical signaling pathways affected by TBI so that potential new therapeutic targets can be identified to improve histopatholoqical and functional outcome in people suffering from TBI. Recent work in our laboratory has found that signaling through the cAMP-protein kinase A (PKA) pathway is impaired after TBI. cAMP levels are depressed in the injured cortex and hippocampus as is its downstream target, PKA. In other models of CMS injury, the phosphodiesterase (PDE) IV inhibitor rolipram, which prevents the degradation of cAMP, improves neuronal survival, axonal regeneration, and decreases inflammation. cAMP primarily exerts its actions through PKA and is well known to reduce inflammation by inhibiting the expression and secretion of pro-inflammatory cytokines from the inflammatory cells in the brain, microglia. Thus, we hypothesize that treatment with the PDE IV inhibitor, rolipram, after TBI will improve signaling through the cAMP-PKA pathway and improve histopathological and functional outcome by decreasing the inflammatory response. In Aim 1, we will determine if the cAMP-PKA pathway is chronically depressed after TBI, what cell types are involved, and whether this can be rescued with rolipram treatment. A clinically relevant model of head injury, parasagittal moderate fluid-percussion brain injury (FPI), will be utilized. In our preliminary experiments, we observed a significant improvement in cortical contusion volume with rolipram treatment given prior to or after FPI. Furthermore, rolipram treatment improved both cortical and hippocampal CAS neuronal survival. These exciting findings have propelled us to assess further in Aim 2 the therapeutic time window for post-injury treatment of rolipram to improve histopathology. Whether these improvements in histopathology are accompanied by an improvement in memory and sensorimotor deficits will also be assessed. In Aim 3, we will determine the mechanism of how rolipram leads to an improvement in functional outcome, possibly by decreasing the inflammatory response. The following experiments are designed to determine if treatment with a PDE IV inhibitor after TBI will improve signaling through the cAMP-PKA pathway, improve histopathological and cognitive outcome, decrease inflammation in the brain, and hopefully expand our repertoire of therapies available to patients suffering from TBI. These preclinical studies could provide necessary data to initiate Phase I clinical studies in the near future, targeting acute TBI in humans.

描述（由申请人提供）：创伤性脑损伤 (TBI) 是一个重大的健康问题，每年影响美国 140 万人，造成 560 亿美元的损失。局灶性和弥漫性脑部病变均由 TBI 引起，并因初始 TBI 后持续数小时至数天的炎症反应而加剧。不幸的是，对于 TBI 患者来说，仍然没有可用的药物治疗方法。该应用的目的是确定受 TBI 影响的生化信号通路，以便确定潜在的新治疗靶点，以改善 TBI 患者的组织病理学和功能结果。我们实验室最近的工作发现，TBI 后通过 cAMP-蛋白激酶 A (PKA) 通路的信号传导受损。受伤的皮层和海马体中的 cAMP 水平及其下游靶标 PKA 均降低。在其他 CMS 损伤模型中，磷酸二酯酶 (PDE) IV 抑制剂咯利普兰可防止 cAMP 降解，改善神经元存活、轴突再生并减少炎症。 cAMP 主要通过 PKA 发挥作用，众所周知，它可以通过抑制大脑炎症细胞小胶质细胞促炎细胞因子的表达和分泌来减轻炎症。因此，我们假设 TBI 后使用 PDE IV 抑制剂咯利普兰治疗将改善 cAMP-PKA 通路的信号传导，并通过减少炎症反应来改善组织病理学和功能结果。在目标 1 中，我们将确定 TBI 后 cAMP-PKA 通路是否长期受到抑制、涉及哪些细胞类型以及是否可以通过咯利普兰治疗来挽救。将使用临床相关的头部损伤模型，即矢状旁中度流体冲击性脑损伤（FPI）。在我们的初步实验中，我们观察到在 FPI 之前或之后给予咯利普兰治疗后，皮质挫伤体积显着改善。此外，咯利普兰治疗改善了皮质和海马 CAS 神经元的存活率。这些令人兴奋的发现促使我们在目标 2 中进一步评估咯利普兰损伤后治疗的治疗时间窗，以改善组织病理学。还将评估组织病理学的这些改善是否伴随着记忆和感觉运动缺陷的改善。在目标 3 中，我们将确定咯利普兰如何可能通过减少炎症反应来改善功能结果的机制。以下实验旨在确定 TBI 后使用 PDE IV 抑制剂治疗是否会改善 cAMP-PKA 通路的信号传导，改善组织病理学和认知结果，减少大脑炎症，并有望扩大我们对 TBI 患者可用的治疗方案。这些临床前研究可以为在不久的将来启动针对人类急性 TBI 的 I 期临床研究提供必要的数据。