Protective Prostaglandin Receptors in Cerebral Ischemia

脑缺血中的保护性前列腺素受体

• 批准号: 8820292
• 负责人: Katrin I. Andreasson
• 金额: $ 35.98万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-01-01 至 2017-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8820292
• 关键词: Adverse effects; Affect; Agonist; Animal Model; Anti-Inflammatory Agents; Anti-inflammatory; Attenuated; Autoradiography; Binding; Brain; Cardiovascular system; Cell Adhesion Molecules; Cells; Cerebral Ischemia; Cerebrovascular Circulation; Cerebrum; Chronic; Clinic; Cytoprotection; Dinoprostone; Disease; Disease model; EP4 receptor; Endothelial Cells; Female; G-Protein-Coupled Receptors; Genetic; Goals; Immune response; Industry; Infarction; Inflammation; Inflammatory Response; Injury; Investigation; Ischemia; Knock-out; Lipopolysaccharides; Literature; Mediating; Membrane; Microglia; Middle Cerebral Artery Occlusion; Misoprostol; Modeling; Molecular; Morbidity - disease rate; Mus; Natural regeneration; Neurons; Neutrophil Infiltration; Outcome Measure; PTGS2 gene; Pathway interactions; Patients; Perfusion; Peripheral; Process; Property; Prostaglandin Receptor; Prostaglandin-Endoperoxide Synthase; Prostaglandins; Receptor Signaling; Recovery of Function; Relative (related person); Reperfusion Therapy; Research; Rodent Model; Role; Signal Pathway; Signal Transduction; Stroke; Testing; Therapeutic Intervention; Time; Toll-like receptors; Toxic effect; Translating; Translations; angiogenesis; attenuation; base; cell type; cerebrovascular; cytokine; functional outcomes; genetic approach; human WFDC2 protein; improved; in vivo; macrophage; male; mortality; nervous system disorder; neurogenesis; neuroprotection; neurotoxicity; neurovascular unit; neutrophil; post stroke; programs; protective effect; protein expression; receptor; receptor function; repaired; stroke recovery; therapeutic target

DESCRIPTION (provided by applicant): Activation of the inducible cyclooxygenase COX-2 generates significant toxicity in wide range of neurological disease models, in particular cerebral ischemia. However, sustained COX-2 inhibition exerts cardiovascular and cerebrovascular side effects, suggesting that selected downstream prostaglandin receptor signaling pathways may be beneficial. Our previous studies have focused on identifying which prostaglandin receptors mediate COX-2 neurotoxicity and we have determined that although several receptors do promote toxicity, a major finding has been that a larger group of prostaglandin receptors mediates an unexpected and significant protective effect in models of ischemia. Thus, the investigation of prostaglandin receptor pathways downstream of COX-2 has uncovered toxic as well as paradoxically protective signaling pathways, both of which are amenable to therapeutic targeting in models of ischemia. The research objective of this proposal is to expand our investigation of the mechanisms of protection of the PGE2 EP4 receptor, which we have found is significantly cerebroprotective in rodent models of stroke. In this proposal, the cellular substrates and molecular mechanisms that mediate EP4 cerebroprotection with regard to cerebral perfusion and the inflammatory response will be investigated in the murine model of transient focal cerebral ischemia. Genetic strategies using conditional knockout models and pharmacological strategies will be used to identify the cellular substrate(s) mediating protection by this receptor in ischemia and evaluate effects on long term functional outcome measures. Successful completion of these studies will broaden our understanding of endogenous mechanisms of cerebrovascular protection in stroke, and establish the rationale for subsequent investigations in larger animal models of cerebral ischemia to promote accelerated functional recovery, with the long term goal of therapeutic intervention in patients affected by stroke.

描述（由申请人提供）：诱导型环氧酶COX-2的激活在广泛的神经系统疾病模型，尤其是脑缺血的广泛毒性中产生显着毒性。然而，持续的COX-2抑制作用会发挥心血管和脑血管副作用，表明选定的下游前列腺素受体信号传导途径可能是有益的。我们以前的研究集中在鉴定哪些前列腺素受体介导了COX-2神经毒性，我们确定，尽管几种受体确实促进了毒性，但主要的发现是，一组较大的前列腺素受体介导了在缺血模型中的意外和显着的保护作用。因此，对COX-2下游前列腺素受体途径的研究已经发现了毒性和矛盾的保护性信号传导途径，这两种途径都可以在缺血模型中适合治疗靶向。该提案的研究目标是扩大我们对PGE2 EP4受体保护机制的研究，我们发现，在啮齿动物的啮齿动物模型中，我们发现这具有显着的脑保护性。在此提案中，将在瞬时局灶性脑缺血的鼠模型中研究介导EP4脑灌注和炎症反应的细胞底物和分子机制。使用条件基因敲除模型和药理学策略的遗传策略将用于确定该受体在缺血中介导保护的细胞底物，并评估对长期功能结果指标的影响。这些研究的成功完成将扩大我们对中风中脑血管保护的内源性机制的理解，并为在较大的大脑缺血模型中建立了随后研究的基本原理，以促进受势力患者的长期治疗干预措施加速功能恢复。

项目成果

Protection by vascular prostaglandin E2 signaling in hypoxic-ischemic encephalopathy.

• DOI: 10.1016/j.expneurol.2014.02.012
• 发表时间: 2014-05
• 期刊: EXPERIMENTAL NEUROLOGY
• 影响因子: 5.3
• 作者: Taniguchi, Hidetoshi;Anacker, Christoph;Wang, Qian;Andreasson, Katrin
• 通讯作者: Andreasson, Katrin

Impaired cognition, sensorimotor gating, and hippocampal long-term depression in mice lacking the prostaglandin E2 EP2 receptor.

• DOI: 10.1016/j.expneurol.2009.01.016
• 发表时间: 2009-05
• 期刊: EXPERIMENTAL NEUROLOGY
• 影响因子: 5.3
• 作者: Savonenko, A.;Munoz, P.;Melnikova, T.;Wang, Q.;Liang, X.;Breyer, R. M.;Montine, T. J.;Kirkwood, A.;Andreasson, K.
• 通讯作者: Andreasson, K.

Divergent effects of prostaglandin receptor signaling on neuronal survival.

前列腺素受体信号传导对神经元存活的不同影响。

• DOI: 10.1016/j.neulet.2007.05.055
• 发表时间: 2007
• 期刊: Neuroscience letters
• 影响因子: 2.5
• 作者: Wu,Liejun;Wang,Qian;Liang,Xibin;Andreasson,Katrin
• 通讯作者: Andreasson,Katrin