Modulation of the Cyclic AMP Pathway after Traumatic Brain Injury in Aged Animals

老年动物脑外伤后环磷酸腺苷途径的调节

• 批准号: 7929020
• 负责人: COLEEN M. ATKINS
• 金额: $ 16.09万
• 依托单位: UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-15 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7929020
• 关键词: Acute; Affect; Aftercare; Age; Age-Years; Alzheimer' s Disease; Amyloid beta-Protein Precursor; Animals; Applications Grants; Attenuated; Back; Behavioral; Biochemical; Brain; Brain Injuries; Calcium; Cessation of life; Chronic; Cognition; Cognitive; Contusions; Cortical Contusions; Craniocerebral Trauma; Cues; Cyclic AMP; Cyclic AMP-Dependent Protein Kinases; Data; Deposition; Depressed mood; Dose; Elderly; Exhibits; External Capsule; Genes; Goals; Health; Hippocampus (Brain); Histopathology; Hospitalization; Impaired cognition; Individual; Inflammatory; Injury; Ischemia; Learning; Liquid substance; Memory; Modeling; Neurons; Outcome; Parkinson Disease; Pathology; Pathway interactions; Percussion; Performance; Pharmacodynamics; Phosphodiesterase Inhibitors; Population; Recovery; Research; Risk; Rolipram; Severities; Short-Term Memory; Signal Pathway; Signal Transduction; Slice; Spinal cord injury; Symptoms; Synaptic plasticity; Testing; Therapeutic Intervention; Trauma; Traumatic Brain Injury; United States; Water; aged; aging brain; central nervous system injury; clinically relevant; conditioned fear; cost; disability; excitotoxicity; functional outcomes; improved; mature animal; middle age; natural hypothermia; neuronal survival; older patient; phosphoric diester hydrolase; public health relevance; sham surgery; therapeutic target; young adult

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. The highest rates of hospitalization and death from TBI occur in the elderly ages 75 or older; and as our population ages, brain trauma in the elderly will become an even more significant health problem. Currently, there are no pharmacological therapies available to elderly people suffering from TBI because of the lack of studies identifying the biochemical changes that are misregulated after TBI. The overall goal of the current application is to elucidate the biochemical signaling pathways that are altered during TBI in the aged animal so that new potential therapeutic targets can be identified to improve functional outcome in aged individuals after brain trauma. Using the parasagittal fluid-percussion head injury (FPI) as a clinically relevant model of TBI, we have found that signaling through the cAMP-protein kinase A (PKA) pathway is impaired after TBI. In both young adult and aged animals, cAMP levels are decreased after TBI. Furthermore, in young adult animals, activation of cAMP-dependent signaling remains chronically impaired for up to 12 weeks after TBI. In Aim 1, we will determine if cAMP and PKA signaling is impaired after TBI in aged animals as compared to young adult animals. In uninjured aged animals, deficits exist already in the ability to increase cAMP levels and activate PKA during learning. Treatment with a phosphodiesterase (PDE) inhibitor, rolipram, to increase cAMP levels improves hippocampal synaptic plasticity and learning in the uninjured aged animal. Our preliminary data indicate that rolipram can rescue the decreases in cAMP levels in the aged animal after TBI. Thus, we hypothesize that treatment with rolipram after TBI will improve signaling through the cAMP-PKA pathway and improve outcome in aged animals. In Aim 2, we will determine if rolipram improves histopathological outcome after TBI in aged animals. A prominent disability after TBI is cognitive dysfunction and in particular, memory formation. The cortex and hippocampus are highly vulnerable during TBI which affects the ability to form and store memories. In Aim 3, we will determine if rolipram improves cAMP- dependent signaling in acute hippocampal slices and ameliorates hippocampal-dependent learning deficits after TBI in aged animals. These proposed studies will identify the biochemical mechanisms misregulated by trauma in the aged brain and expand the potential therapeutic interventions available to elderly patients suffering from brain trauma to improve cognition and facilitate recovery. PUBLIC HEALTH RELEVANCE: More than 1.4 million individuals per year are afflicted with a traumatic brain injury (TBI) and the ability to withstand brain injury diminishes with age. The research proposed in this grant application is to develop a therapy that reduces pathology in the brain after TBI and improves behavioral recovery in the aged population.

描述(申请人提供)：创伤性脑损伤(TBI)是一个重大的健康问题，每年在美国影响140万人，花费560亿美元。脑损伤的住院率和死亡率最高的是75岁或以上的老年人；随着我们人口的老龄化，老年人的脑损伤将成为一个更严重的健康问题。目前，由于缺乏研究确定脑外伤后的生化变化是错误的，因此没有可用于治疗脑外伤的老年人的药物治疗方法。目前应用的总体目标是阐明老年动物在脑外伤过程中发生变化的生化信号通路，以便找到新的潜在治疗靶点，以改善脑损伤后老年人的功能结局。以矢状旁液冲击性头部损伤(FPI)作为临床相关的脑损伤模型，我们发现脑外伤后cAMP-蛋白激酶A(PKA)通路的信号转导功能受损。无论是青壮年动物还是老年动物，脑损伤后cAMP水平均下降。此外，在年轻的成年动物中，cAMP依赖的信号激活在脑损伤后12周内仍处于慢性受损状态。在目标1中，我们将确定与年轻成年动物相比，老年动物在脑创伤后cAMP和PKA信号是否受损。在未受伤的老年动物中，在学习过程中增加cAMP水平和激活PKA的能力已经存在缺陷。使用磷酸二酯酶(PDE)抑制剂Rolipram提高cAMP水平可改善未受损伤的老年动物的海马突触可塑性和学习能力。我们的初步数据表明，罗利普兰可以挽救脑损伤后老龄动物cAMP水平的下降。因此，我们假设颅脑损伤后应用罗利普兰治疗将通过cAMP-PKA途径改善信号通路，并改善老年动物的预后。在目标2中，我们将确定罗利普兰是否能改善老年动物脑损伤后的组织病理学结果。脑外伤后一个突出的残疾是认知功能障碍，特别是记忆的形成。大脑皮层和海马体在脑外伤期间非常脆弱，这会影响记忆的形成和存储能力。在目标3中，我们将确定罗利普兰是否改善了急性海马片中cAMP依赖的信号转导，并改善了老年动物脑损伤后的海马区依赖学习缺陷。这些拟议的研究将确定老年脑创伤导致的生化机制失调，并扩大老年脑创伤患者可用的潜在治疗干预措施，以改善认知和促进康复。公共卫生相关性：每年有140多万人受到创伤性脑损伤(TBI)的困扰，承受脑损伤的能力随着年龄的增长而减弱。在这项拨款申请中提出的研究是为了开发一种治疗方法，减少脑外伤后大脑的病理变化，并改善老年人口的行为恢复。