PKA-Hypothermia Bridge: A New Therapeutic Approach for Traumatic Brain Injury

PKA-低温桥：创伤性脑损伤的新治疗方法

基本信息

批准号：
7998177
负责人：
LARRY W JENKINS
金额：
$ 32.48万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-01-01 至 2012-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7998177
关键词：
A kinase anchoring protein AMPA Receptors Acute Adenylate Cyclase Adult Affect Aftercare Behavioral Binding Proteins Biological Assay Biological Preservation Brain Injuries Calcium Calcium/calmodulin-dependent protein kinase Calmodulin Calpain Caring Catheters Cessation of life Chronic Chronic Phase Clinical Clinical Treatment Cognitive Cyclic AMP Cyclic AMP-Dependent Protein Kinases Data Dose Down-Regulation Drug Kinetics Enzyme-Linked Immunosorbent Assay Enzymes Funding Future Glutamate Receptor Glutamates Grant Health Hippocampus (Brain)Hospitals Immunohistochemistry Impaired cognition Implant Injection of therapeutic agent Injury Label Laboratories Learning Measures Mediating Memory Memory impairment Modeling Modification Morbidity - disease rate Mus N-Methyl-D-Aspartate Receptors NMDA receptor A1 Neurons Nootropic Agents Outcome Pathway interactions Patients Peritoneal Pharmaceutical Preparations Pharmacotherapy Phase Phosphodiesterase Inhibitors Phosphorylation Phosphotransferases Process Protein Isoforms Protein Kinase Protein Kinase A Inhibitor Protein phosphatase Protein-Serine-Threonine Kinases Public Health Rattus Rehabilitation therapy Rodent Rodent Model Rolipram Secondary Prevention Signal Transduction System Testing Therapeutic Time Translating Translations Traumatic Brain Injury Tumor Necrosis Factor-alpha Ubiquitin-mediated Proteolysis Pathway Work base controlled cortical impact effective therapy excitotoxicity human TNF protein improved inhibitor/antagonist injured morris water maze mortality natural hypothermia neuroprotection novel therapeutic intervention phosphodiesterase IV prevent protein kinase C beta receptor function response therapeutic target treatment duration

项目摘要

DESCRIPTION (provided by applicant): Traumatic brain injury (TBI) is a leading cause of clinical mortality and morbidity and a major public health problem. Currently, there is no proven treatment for clinical TBI beyond the prevention of secondary insults; yet, evidence for rapid post-traumatic changes in multiple protein kinase and phosphatase enzymes is accumulating suggesting that therapeutic manipulations of protein phosphorylation status after TBI may represent an unexploited therapeutic target. Recent studies in our laboratories have unexpectedly shown dramatic and acute changes in protein kinase A (PKA) RIIb function after TBI in an adult murine model using controlled cortical impact (CCI) using hypothermia treatment. Although other serine/threonine protein kinases were also affected by hypothermia, the changes in PKA activation were more dramatic suggesting that PKA may be a key mechanism in hypothermia neuroprotection and a target for kinase manipulation after experimental TBI. To this end, we found that the activation of PKA activity with Rolipram, (a type IV phosphodiesterase inhibitor [PDE4] which increases cAMP levels and PKA activation) and reduced spatial memory deficits after TBI in adult rats. Based on these findings, we propose that enhancement of PKA activity; with low dose (15g/kg) daily rolipram, during the acute and chronic phases, following experimental TBI may be beneficial. We propose: 1) PKA activation by acute low dose (15g/kg) rolipram treatment alone may reduce behavioral morbidity after moderate and severe TBI; 2) PKA activation by chronic low dose (15g/kg) rolipram treatment alone will reduce behavioral morbidity after moderate and severe TBI; 3) PKA activation by continuous daily low dose (15g/kg) rolipram treatment alone will most effectively reduce behavioral but not structural morbidity after moderate and severe TBI; 4) Type II PKA regulatory subunits will be most affected by both injury and low dose (15g/kg) rolipram treatment after moderate and severe TBI; 5) PKA activation by low dose (15g/kg) rolipram treatment will inhibit calpain and ubiquitin-mediated proteolysis, preserving many important serine/threonine protein kinase levels after moderate and severe TBI; 6) PKA activation by low dose (15g/kg) will be associated with not only the preservation of general kinase levels, but will normalize glutamate NMDA and AMPA receptor levels, distribution, and PKA and PKC-dependent phosphorylation status. 7) Lastly, that low dose (15g/kg) rolipram provides behavioral efficacy after both moderate and severe TBI primarily via the cAMP-PKA pathway. PUBLIC HEALTH RELEVANCE: This project will evaluate a promising therapy (drugs that increase cAMP) for the treatment of experimental traumatic brain injury (TBI). This class of drug is already in clinical use for other purposes, and may bridge the time between injury and when patients arrive at the hospital. The drug may also be useful in the rehabilitation period after brain injury has occurred. Currently, there is no known effective treatment that has been translated to clinical TBI care.

描述（由申请人提供）：创伤性脑损伤（TBI）是临床死亡率和发病率和主要公共卫生问题的主要原因。目前，除了预防继发侮辱之外，尚无对临床TBI的可靠治疗。然而，多种蛋白激酶和磷酸酶酶快速创伤后变化的证据表明，TBI后蛋白质磷酸化状态的治疗操作可能代表未开发的治疗靶标。在我们实验室中的最新研究意外地表明，使用低温治疗使用受控皮质影响（CCI），在成人鼠模型中，TBI在TBI后的蛋白激酶A（PKA）RIIB功能发生了巨大变化和急性变化。尽管其他丝氨酸/苏氨酸蛋白激酶也受到低温影响，但PKA激活的变化更为戏剧性，表明PKA可能是神经抑制作用的关键机制，并且是实验性TBI后激酶操纵的靶标。为此，我们发现PKA活性用ROLIPRAM（IV型磷酸二酯酶抑制剂[PDE4）[PDE4]增加了cAMP水平和PKA激活），并减少了成年大鼠TBI后的空间记忆缺陷。基于这些发现，我们建议增强PKA活性。在实验性TBI之后，在急性和慢性相期间，在急性和慢性期间的每日低剂量（15g/kg）可能是有益的。我们提出：1）单独通过急性低剂量（15g/kg）ROLIPRAM治疗的PKA激活可能会降低中度和重度TBI后行为发病率； 2）仅慢性低剂量（15g/kg）ROLIPRAM治疗的PKA激活将降低中度和严重TBI后的行为发病率； 3）仅连续每日低剂量（15g/kg）ROLIPRAM治疗的PKA激活最有效地降低了中度和重度TBI后的行为发病率，而不能降低结构性发病率； 4）II型PKA调节亚基将受到损伤和低剂量（15g/kg）Rolipram治疗的影响最大； 5）低剂量（15g/kg）rolipram治疗的PKA激活将抑制钙蛋白酶和泛素介导的蛋白水解，并在中度和严重的TBI后保留许多重要的丝氨酸/苏氨酸蛋白激酶水平； 6）低剂量（15g/kg）的PKA激活不仅将与一般激酶水平的保存相关，而且还将使谷氨酸NMDA和AMPA受体水平，分布以及PKA和PKC依赖性磷酸化状态归一化。 7）最后，低剂量（15g/kg）rolipram主要通过CAMP-PKA途径在中度和重度TBI之后提供行为疗效。公共卫生相关性：该项目将评估一种有希望的疗法（增加营地的药物），以治疗实验性创伤性脑损伤（TBI）。这类药物已经用于其他目的的临床用途，可能会弥合受伤之间和患者到达医院的时间。该药物在发生脑损伤后的康复期内也可能有用。当前，尚无已知有效治疗方法已转化为临床TBI护理。