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（由申请人提供）：脑出血（ICH）是最致命的中风形式，经常发生早期神经功能恶化或死亡，因此，迫切需要对 ICH 进行全面的医疗治疗。Dore 博士和其他人已经成功地进行了治疗。证明了前列腺素受体在缺血性中风中的作用；然而，初步数据表明 FP 受体的激活在出血性中风中仍有待阐明。氟前列醇（FP 受体激动剂）会增加 WT 小鼠的缺血性中风脑损伤和神经功能缺损，但 FP-/- 小鼠则不会。此外，删除 FP 受体可以保护大脑。免受缺血性中风引起的损伤并增强 PGF2¿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，进而激活钙途径，这与短暂性局灶性脑缺血后的兴奋性毒性有关。为了研究 FP 受体在 ICH 中的作用，我建议在 WT 和 FP-/- 小鼠中使用自体血液注射 ICH 模型，在目标 1 中，我将进行测量。 PGF2?? ICH 后不同时间的 FP 受体表达水平，并研究 FP 缺失对 ICH 诱导的神经功能缺损评分、脑损伤、水肿和血脑屏障通透性的影响。将通过用 FP 后治疗 WT 小鼠来研究 ICH 的治疗范例。拮抗剂 AL8810，表明这种 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，使用这种药理学方法扩展了我们从基因敲除动物中得到的结果，以解决这一问题。我热切地希望阻断和删除 FP 受体将显着改善 ICH 后的结果，血红蛋白和血红素等有毒血液成分存在于血管外空间，并且在很大程度上导致发病。一种血液副产品，对初级皮质神经元具有神经毒性，因此，在目标 2 中，我将使用 ICH 体外模型来确定有或没有血红素和 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，我将重点关注血红素治疗后原代皮质纹状体神经元的存活，因为血红素主要来自 ICH 后的血红蛋白，我将确定是否可以在出生后挽救血红素和/或 Hgb 诱导的神经毒性。我对 WT 和 FP-/- 小鼠的神经元进行了研究，得出 FP 受体激活的神经元存活的结论，我认为 FP-/- 及其阻断将保护或拯救神经元。我预计 AL8810 在 WT 培养物中的使用将证实并扩展 FP-/- 研究的体内结果，该目标的第二部分是开始研究 FP 受体相关的 Ca2+ 信号传导机制。我预计[Ca2+]i 对血红素/Hgb 的反应会增加，并与自由基供体tBuOOH 毒性相比，我认为PGF2 会激活FP 受体。会影响 [Ca2+]i 的变化，并且 FP 受体阻断会减弱这些变化。