PGE2 EP1 and EP3 receptors as therapeutic targets in intracerebral hemorrhage

PGE2 EP1和EP3受体作为脑出血的治疗靶点

基本信息

批准号：
8546456
负责人：
Jian Wang
金额：
$ 34.2万
依托单位：
JOHNS HOPKINS UNIVERSITY
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：
2012-09-30 至 2017-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8546456
关键词：
Adverse effects Affect Animal Model Attention Autologous Biological Assay Blood Blood Vessels Brain Brain Edema Brain Injuries Cerebral Ischemia Cerebral hemisphere hemorrhage Clinical Data Dinoprostone Dose Enzymes Event Female Functional disorder G-Protein-Coupled Receptors Gelatinase B Genetic Hemoglobin Histologic Human Image In Vitro Inflammatory Inflammatory Response Injury Investigation Ischemic Brain Injury Ischemic Stroke Knockout Mice Magnetic Resonance Imaging Matrix Metalloproteinase Inhibitor Matrix Metalloproteinases Mediating Modeling Molecular Morbidity - disease rate Mus Na(+)-K(+)-Exchanging ATPase Neurologic Deficit Outcome Outcomes Research Pathologic Phosphorylation Physiological Production Prostaglandin E Receptor Prostaglandin-Endoperoxide Synthase Prostaglandins Receptor Inhibition Research Rho-associated kinase Role Sex Characteristics Signal Pathway Signal Transduction Stroke Testing Therapeutic Thrombin Toxic effect Whole Blood Wild Type Mouse Work age difference age related aged cerebral atrophy clinically relevant collagenase design drug efficacy effective therapy efficacy testing functional outcomes gray matter human WFDC2 protein improved in vivo inhibitor/antagonist insight kinase inhibitor male mortality neurobehavioral neuroprotection novel novel therapeutic intervention pre-clinical preclinical efficacy prostaglandin EP3 receptor prostanoid receptor EP1 receptor src-Family Kinases therapeutic target white matter injury

项目摘要

DESCRIPTION (provided by applicant): PGE2 EP1 and EP3 receptors as therapeutic targets in intracerebral hemorrhage Intracerebral hemorrhage (ICH) is the stroke subtype with the highest mortality and morbidity; unfortunately, this condition has received far less research attention than has ischemic stroke. Inflammatory mechanisms, including those mediated by certain prostaglandins (PGs), have been suggested to contribute to the progression of ICH injury. In particular, PGE2, which is predominant in the brain, is produced and accumulates in the perihematomal region. PGE2 acts through four G-protein-coupled receptor subtypes known as EP1- EP4. Each of these receptors has distinct signaling cascades in animal models of cerebral ischemia. Genetic deletion or selective inhibition of the EP1 and EP3 receptors has been shown to reduce ischemic brain injury both in vivo and in vitro. The overall objective of this R01 is to investigate whether inhibition of PGE2 EP1 and EP3 receptors can be used as neuroprotective therapy in ICH, and if so, to generate preclinical efficacy data and elucidate the underlying mechanisms. We have been investigating the specific roles of PGE2 receptors in ICH injury and have preliminary data showing that deletion or inhibition of the EP1 or EP3 receptor reduces ICH injury and improves functional outcomes. Our data also indicate that Src kinase mediates EP1 toxicity and Rho kinase (ROCK) mediates EP3 toxicity after ICH. Consequently, we will test the hypothesis that PGE2 EP1 receptor blockade reduces ICH injury through the Src kinase signaling pathway, whereas EP3 receptor blockade reduces ICH injury through the ROCK signaling pathway. We have designed three specific aims that utilize the autologous blood ICH model and collagenase-induced ICH model. Considering that an increase in PGE2 production contributes to age-related dysfunction of the inflammatory responses and that aging and sex differences affect ICH outcomes, this research will be carried out in young male and female and aged male mice to enhance the clinical relevance. Aim 1 will determine whether inhibition of EP1 or EP3 receptors improves ICH outcomes; Aim 2 will determine whether inhibition of Src kinase signaling contributes to the neuroprotection afforded by EP1 receptor blockade after ICH and whether EP1 receptor inhibition decreases thrombin-induced brain damage; and Aim 3 will determine whether inhibition of ROCK signaling contributes to the neuroprotection afforded by EP3 receptor blockade after ICH and whether EP3 receptor inhibition decreases thrombin-induced brain damage. Through pharmacologic, genetic, imaging, histologic, molecular, and cellular biologic approaches, this work will provide novel information about the efficacy of selective PGE2 EP1 and EP3 receptor inhibition to protect against ICH-induced brain injury and the mechanisms by which such protection occurs. This proof-of-concept information is required to plan more detailed preclinical assessment of selective EP1 and EP3 receptor antagonists in ICH.

描述（由申请人提供）：PGE2 EP1和EP3受体作为脑出血性脑出血（ICH）的治疗靶标的是中风亚型，其死亡率和发病率最高；不幸的是，这种情况比缺血性中风所获得的研究关注要少得多。炎症机制，包括由某些前列腺素（PG）介导的机制，提出有助于ICH损伤的进展。特别是，在大脑中主要是在大脑中产生的PGE2，并在近日围栏区域积累。 PGE2通过四个G蛋白偶联受体亚型作用，称为EP1- EP4。这些受体中的每一个在脑缺血动物模型中都有不同的信号级联反应。遗传缺失或对EP1受体的选择性抑制已被证明可减少体内和体外缺血性脑损伤。总体目标 R01是为了研究PGE2 EP1和EP3受体的抑制是否可以用作ICH中的神经保护疗法，如果是的，则可以产生临床前疗效数据并阐明基本机制。我们一直在研究PGE2受体在ICH损伤中的特定作用，并具有初步数据，表明对EP1或EP3受体的缺失或抑制可减少ICH损伤并改善功能结果。我们的数据还表明，SRC激酶介导EP1毒性，Rho激酶（ROCK）介导ICH后EP3毒性。因此，我们将检验以下假设：PGE2 EP1受体阻断通过SRC激酶信号通路减少ICH损伤，而EP3受体阻断可通过岩石信号通路减少ICH损伤。我们设计了三个使用自体血液ICH模型和胶原酶诱导的ICH模型的特定目标。考虑到PGE2产生的增加会导致炎症反应与年龄相关的功能障碍，并且衰老和性别差异会影响ICH结果，因此这项研究将在年轻的男性和女性和老年男性小鼠中进行，以增强临床相关性。 AIM 1将确定抑制EP1或EP3受体是否可以改善ICH结果； AIM 2将确定抑制SRC激酶信号传导是否有助于ICH后EP1受体阻滞提供的神经保护以及EP1受体抑制是否会降低凝血酶诱导的脑损伤； AIM 3将确定对岩石信号传导的抑制是否有助于ICH后EP3受体阻滞提供的神经保护作用，以及EP3受体抑制是否会降低凝血酶诱导的脑损伤。通过药理学，遗传，成像，组织学，分子和细胞生物学方法，这项工作将提供有关选择性PGE2 EP1和EP3受体抑制的功效的新颖信息，以防止ICH诱导的脑损伤以及发生这种保护的机制。需要此概念证明信息来计划ICH中选择性EP1和EP3受体拮抗剂的更详细的临床前评估。