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）：创伤性脑损伤 (TBI) 是退伍军人群体中的一个主要问题，目前尚无有效的治疗方法被证明可以改善长期康复。在新的初步数据中，我们发现 TBI 后大鼠脑中环戊烯酮前列腺素 (CyPG) D12-前列腺素 J2 (D12-PGJ2) 的浓度增加。 CyPG（例如 D12-PGJ2）是 PPARg 核受体的有效配体，并且已被认为在炎症消退和损伤和感染后伤口愈合中发挥重要作用。 CyPG 还可能通过非 PPAR3 介导的作用损伤神经元，包括破坏泛素蛋白酶体途径 (UPP)。在额外的初步数据中，我们发现 CyPG 与神经元中关键的 UPP 酶、泛素羧基末端水解酶-L1 (UCH-L1) 结合并抑制其作用，导致泛素化蛋白的积累和神经元细胞死亡。在这些拟议的研究中，我们将进一步描述 TBI 后 CyPG 的产生和代谢特征。我们还将确定 PPARg 激活和 UCH-L1 活性恢复在确定 TBI 后恢复和长期行为结果中的作用。提出以下具体目标： 1. 表征大鼠受控皮质损伤（CCI）后环戊烯酮前列腺素及其代谢物产生的时间过程。 2. 测试 PPAR3 受体的激活是否可以减少继发性损伤并改善 TBI 后的行为恢复。 3. 测试通过 TAT-UCH-L1 融合蛋白全身治疗恢复 UCH-L1 活性是否可以防止 Ub 蛋白的积累并改善 TBI 后的行为结果。将使用大鼠和小鼠的受控皮质冲击损伤模型诱导 TBI。 TBI 后，将通过四极杆 LC MS/MS 使用 CyPG 母体质量的子离子碎片的选择性反应监测来测量脑中 CyPG 的浓度。通过测量脑组织中的髓过氧化物酶活性来量化中性粒细胞迁移。已知受 PPARg 调节的蛋白质 iNOS、TNFa 和 MMP-9 将通过 ELISA 进行测量，并用作 PPARg 激活的下游监测器。 TBI 后大脑中 UPP 的破坏将通过监测 UCH-L1 活性并通过免疫印迹和免疫组织化学检测泛素化蛋白的积累来确定。将使用在创伤后第 14 天至 20 天评估的莫里斯水迷宫程序的工作记忆变化来评估行为结果。这些初步数据代表了 TBI 后大脑中存在 CyPG 的第一份报告。 PPARg 的激活和失去的 UCH-L1 活性的恢复是 TBI 的新治疗方法，可能会产生新的疗法，从而改善 TBI 后的长期恢复和功能恢复。

项目成果

期刊论文数量（2）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Abolishing UCHL1's hydrolase activity exacerbates TBI-induced axonal injury and neuronal death in mice.

消除 UCHL1 的水解酶活性会加剧 TBI 诱导的小鼠轴突损伤和神经元死亡。

DOI：
发表时间：
2021
期刊：
影响因子：
5.3
作者：
Mi, Zhiping;Liu, Hao;Rose, Marie E;Ma, Xiecheng;Reay, Daniel P;Ma, Jie;Henchir, Jeremy;Dixon, C Edward;Graham, Steven H
通讯作者：
Graham, Steven H

Rosiglitazone attenuates inflammation and CA3 neuronal loss following traumatic brain injury in rats.

Rosiglitazone 可减轻大鼠脑外伤后的炎症和 CA3 神经元损失。