Role of prostaglandin F2a receptor (FP receptor) in hemorrhagic stroke.

前列腺素 F2a 受体（FP 受体）在出血性中风中的作用。

基本信息

批准号：
8660101
负责人：
Shekher Mohan
金额：
$ 0.54万
依托单位：
UNIVERSITY OF FLORIDA
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-07-06 至 2014-07-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8660101
关键词：
1,2-diacylglycerol Address Affect Agonist Animals Arachidonic Acids Attenuated Autologous Behavioral Binding Blinded Blood Blood - brain barrier anatomy Brain Brain Edema Brain Injuries Brain Ischemia Brain hemorrhage C57BL/6 Mouse Calcium Cells Cerebral Infarction Cerebral Ischemia Cerebral hemisphere hemorrhage Cerebrum Cessation of life Clinical Trials Coupled Data Data Analyses Deterioration Diglycerides Dinoprost Edema Epilepsy Event Exposure to Extravasation Free Radicals Funding GTP-Binding Proteins Goals Heme Hemoglobin Hemorrhage Human Image Immunologic Techniques In Vitro Infarction Inflammation Mediators Injection of therapeutic agent Injury Inositol Ischemic Stroke Knowledge Link Measures Mediating Medical Meningitis Mentors Methods Modeling Molecular Analysis Morbidity - disease rate Mus Neurologic Neurologic Deficit Neurological outcome Neuronal Injury Neurons Outcome PGF receptor Paper Pathogenesis Pathology Pathway interactions Permeability Pharmaceutical Preparations Physiological Play Predisposition Property Prostaglandin Receptor Prostaglandins Public Health Randomized Receptor Activation Receptor Signaling Recovery Regulation Research Research Personnel Research Proposals Role Saline Signal Transduction Stroke Subarachnoid Hemorrhage Testing Therapeutic Therapeutic Effect Time Toxic effect Training Translational Research Work blood product design disability excitotoxicity fluprostenol heme a improved in vitro Model in vivo interest knockout animal neuronal survival neuroprotection neurotoxic neurotoxicity novel postnatal pre-clinical receptor receptor expression response therapeutic target tripolyphosphate

项目摘要

DESCRIPTION (provided by applicant): Intracerebral hemorrhage (ICH) is the deadliest form of stroke with frequent early neurological deterioration or death. Therefore, there is a desperate need for a medical treatment of ICH across the board. Dr. Dore and others have successfully demonstrated the role of prostaglandin receptors in ischemic stroke; however this remains to be elucidated in hemorrhagic stroke. Preliminary data have shown that activation of FP receptor with fluprostenol (FP receptor agonist) increased ischemic stroke brain damage and neurological deficit in WT but not in FP-/- mice. Also, deletion of FP receptors protects the brain from ischemic stroke-induced damage and enhances behavioral recovery. PGF2¿ when bound to its FP receptors, initiates a signaling cascade that results in the release of inositol-1,4,5-triphosphate and diacylglycerol and in turn activation of the calcium pathway, which has been associated with excitotoxicity following transient focal brain ischemia. To study the role of FP receptors in ICH, I propose to use the autologous blood injection ICH model in WT and FP-/- mice. In Aim 1, I will measure PGF2¿ and FP receptor expression levels at different times after ICH and investigate the effect of FP deletion on ICH-induced neurological deficit score, brain injury, edema and blood brain barrier permeability. Therapeutic paradigms in ICH will be studied by post-treating WT mice with FP antagonist AL8810, suggesting potential drug treatment. The outcome and selectivity of this FP receptor antagonist drug will be further tested in the FP-/- mice. Using such pharmacological approaches extends our results from knockout animals to address potential compensatory effects. I hypothesize that blockade and deletion of FP receptor will significantly improve post-ICH outcomes. Following ICH, toxic blood components such as hemoglobin and heme are present in extravascular space and substantially contribute to morbidity. Preliminary data has shown that heme, a blood by-product, is neurotoxic to primary cortical neurons. Thus, in Aim 2, using an ICH-in vitro model, I will determine the cellular mechanism involved in FP receptor activation with and without heme and hemoglobin treatment. To elucidate FP receptor mediated neuroprotection I will focus on the survival of primary corticostriatal neurons after heme treatment because heme is derived mainly from hemoglobin after ICH. I will determine if heme- and/or Hgb- induced neurotoxicity can be rescued in postnatal neurons from WT and FP-/- mice and conclude FP receptor activated neuronal survival. I hypothesize that FP-/- and its blockade will protect or rescue neurons from heme/Hgb-induced toxicity. I anticipate that the use of AL8810 in WT cultures will corroborate and extend our in vivo results from the FP-/- studies. The second part of this aim is to begin investigating mechanisms of FP receptor related Ca2+ signaling. I expect increased [Ca2+]i response to heme/Hgb and compare with the free radical donor, tBuOOH toxicity. I hypothesize that FP receptor activation by PGF2¿ will affect changes in [Ca2+]i and that FP receptor blockade will attenuate those changes.

描述（由适用提供）：脑内出血（ICH）是中风的最致命形式，经常具有早期神经系统检测或死亡。因此，迫切需要全面对ICH进行医学治疗。多尔博士和其他人成功证明了前列腺素受体在缺血性中风中的作用。但是，这尚待阐明出血性中风。初步数据表明，用Fluprostenol（FP受体激动剂）激活FP受体会增加缺血性中风脑损伤和WT中的神经系统防御，但在FP - / - 小鼠中不增加。此外，删除FP受体可以保护大脑从缺血性中风引起的损害并增强行为恢复。当与其FP受体结合时，启动信号级联反应，导致肌醇1,4,5-三磷酸和二酰基甘油的释放，然后又激活了钙途径，该校准途径与临时局部性局灶性局灶性大脑后的兴奋性毒性相关。为了研究FP受体在ICH中的作用，我建议在WT和FP - / - 小鼠中使用自体注射ICH模型。在AIM 1中，我将在ICH之后的不同时间测量PGF2缺和FP受体表达水平，并研究FP缺失对ICH诱导的神经功能缺陷评分，脑损伤，水肿和血液脑屏障的渗透性的影响。 ICH中的治疗范例将通过使用FP拮抗剂AL8810进行治疗后的WT小鼠进行研究，这表明潜在的药物治疗。该FP受体拮抗剂药物的结果和选择性将在FP - / - 小鼠中进一步测试。使用这种药理方法，我们从敲除动物扩展了我们的结果，以解决潜在的补偿效果。我假设FP受体的封锁和缺失将显着改善近美化后的结果。在ICH之后，血管外空间中存在毒性血成分，例如血红蛋白和血红素，并实质上有助于发病率。初步数据表明，血红素是血液副产品，对原发性皮质神经元具有神经毒性。在AIM 2中，使用ICH-IN体外模型，我将确定有或没有血红素和血红蛋白处理的FP受体激活所涉及的细胞机制。为了阐明FP受体介导的神经保护作用，我将重点放在血红素治疗后原代皮质神经元的存活上，因为血红素主要来自ICH后血红蛋白。我将确定是否可以从WT和FP - / - 小鼠中挽救血红素和/或HGB诱导的神经毒性，并包含FP受体激活的神经元存活。我假设FP - / - 及其封锁将保护或挽救神经元免受血红素/HGB诱导的毒性的影响。我预计在WT培养物中使用AL8810将证实并从FP - / - 研究中扩展我们的体内结果。该目的的第二部分是开始研究与FP受体相关的CA2+信号传导的机制。我预计[Ca2+]对血红素/HGB的反应增加，并与自由基供体TBUOOH毒性进行比较。我假设PGF2 fp受体激活将影响[Ca2+] i的变化，而FP接收器阻断会减弱这些变化。