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Role of Cyclopentenone prostaglandins in promoting recovery after TBI

环戊烯酮前列腺素在促进 TBI 后恢复中的作用

基本信息

批准号：
8898730
负责人：
STEVEN H GRAHAM
金额：
--
依托单位：
VETERANS HEALTH ADMINISTRATION
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-01-01 至 2013-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8898730
关键词：
9-deoxy-delta-9-prostaglandin D2 Acute Agonist Amyloid beta-Protein Precursor Antidiabetic Drugs Behavior Behavioral Binding Brain Capsid Proteins Cell Death Chimeric Proteins Clinical Clinical Trials Cysteine Data Daughter Dose Enzyme-Linked Immunosorbent Assay Enzymes FDA approved Fatty Acids Functional disorder Gelatinase B Glutathione HIV Healed Hydrolase Hypoxia Immunoblotting Immunohistochemistry In Situ Nick-End Labeling Infection Inflammation Injury Ions Lead Ligands Measures Mediating Metabolism Modeling Monitor Mus Mutation Neurons Nuclear Receptors Outcome Parents Pathway interactions Patients Peroxidases Peroxisome Proliferator-Activated Receptors Play Population Procedures Production Prostaglandin-Endoperoxide Synthase Prostaglandins Proteins Prothrombin Rattus Reaction Recombinants Recovery Reporting Resolution Rodent Model Role Short-Term Memory TBI Patients Testing Time Toxic effect Translating Trauma Traumatic Brain Injury UCHL1 gene Ubiquitin Variant Veterans Wound Healing brain tissue controlled cortical impact cyclopentenone effective therapy enzyme activity enzyme pathway healing improved in vivo injured insight migration morris water maze multicatalytic endopeptidase complex neuron loss neutrophil novel novel strategies novel therapeutic intervention prevent receptor research study restoration rosiglitazone ubiquitin C-terminal hydrolase

项目摘要

DESCRIPTION (provided by applicant): Traumatic brain injury (TBI) is a major problem in the veteran population and there are no effective treatments proven to improve long-term recovery. In new preliminary data, we have found that the concentration of the cyclopentenone prostaglandin (CyPG) D12-prostaglandin J2 (D12-PGJ2) is increased in rat brain after TBI. CyPGs such as D12-PGJ2 are potent ligands of the PPARg nuclear receptor, and have been proposed to play an important role in resolution of inflammation and wound healing after injury and infection. CyPGs may also injure neurons by non-PPAR3-mediated effects including disruption of the ubiquitin proteasome pathway (UPP). In additional preliminary data, we have found that CyPGs bind to and inhibit the action of the key neuronal UPP enzyme, ubiquitin carboxy-terminal hydrolase-L1 (UCH-L1) in neurons resulting in accumulation of ubiquitinated proteins and neuronal cell death. In these proposed studies, we will further characterize the production of and metabolism of CyPGs after TBI. We will also determine the role of PPARg activation and restoration of UCH-L1 activity in determining recovery after TBI and long term behavioral outcome. The following specific aims are proposed: 1. Characterize the time course of production of cyclopentenone prostaglandins and their metabolites after controlled cortical injury (CCI) in rats. 2. Test whether activation of the PPAR3 receptors reduces secondary injury and improves behavioral recovery after TBI. 3. Test whether restoring UCH-L1 activity by systemic treatment with a TAT-UCH-L1 fusion protein can prevent accumulation of Ub-proteins and improve behavioral outcome after TBI. TBI will be induced using the controlled cortical impact injury model in rats and mice. Concentrations of CyPGs will be measured in brain after TBI by quadrupole LC MS/MS using selective reaction monitoring of daughter ion fragments of the CyPG parent masses. Neutrophil migration will be quantified by measuring myleoperoxidase activity in brain tissue. The proteins, iNOS, TNFa, and MMP-9, which are known to be regulated by PPARg, will be measured by ELISA and used as downstream monitors of PPARg activation. Disruption of the UPP in brain after TBI will be determined by monitoring UCH-L1 activity and detecting accumulation of ubquitinated proteins by immunoblotting and immunohistochemistry. Behavioral outcome will be assessed using a working memory variation of the Morris Water Maze procedure assessed on post trauma days 14 through 20. These preliminary data represent the first report that CyPGs are present in brain after TBI. Activation of PPARg and restoration of lost UCH-L1 activity are new therapeutic approaches to TBI that could lead to novel therapies that could improve long term recovery and restoration of function after TBI.

描述（由申请人提供）：