CD38 activation of TRPM2 in hippocampal neurons contributes to stroke-induced cognitive dysfunction

海马神经元中 TRPM2 的 CD38 激活导致中风引起的认知功能障碍

基本信息

批准号：
10536591
负责人：
Amelia Burch
金额：
$ 3.99万
依托单位：
UNIVERSITY OF COLORADO DENVER
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-01-15 至 2025-01-14
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10536591
关键词：
Acute Address Adenosine Diphosphate Ribose Affect Animal Model Astrocytes Attention Behavioral Assay Biological Assay Brain Brain region Cations Cause of Death Cell model Cells Central Nervous System Cerebral Ischemia Chronic Clinical Trials Cognitive Cognitive deficits Country Data Dementia Electrophysiology (science)Endothelium Ensure Exhibits Family Health Healthcare Systems Hippocampus Human Image Immunofluorescence Immunologic Impaired cognition Impairment In Vitro Infarction Injections Intervention Ion Channel Ischemia Ischemic Stroke Knock-out Knockout Mice Language Learning Ligands Long-Term Potentiation Measures Memory Memory impairment Microglia Middle Cerebral Artery Occlusion Modeling Molecular Molecular Target Mus Neural Pathways Neurologic Neurons Oxidative Stress Pathology Pathway interactions Patients Pharmacotherapy Phenocopy Procedures Recovery of Function Reperfusion Therapy Research Role Short-Term Memory Signal Transduction Slice Source Stroke Survivors Symptoms Synapses Synaptic plasticity Therapeutic Intervention Thrombolytic Therapy United States Up-Regulation calmodulin-dependent protein kinase II cell type cognitive disability cognitive load cognitive process disability executive function experience functional improvement improved in vivo inhibitor ischemic injury middle cerebral artery mild cognitive impairment molecular targeted therapies mortality risk mouse model neural network neurobehavioral neuroprotection neurorestoration novel novel therapeutic intervention patient population pharmacologic post intervention post stroke preservation receptor restoration sex synaptic function treatment strategy

项目摘要

PROJECT SUMMARY Stroke is one of the leading causes of death and disability in the United States. Though the risk of mortality from stroke has declined with advances in reperfusion therapies, the number of survivors developing long-term cognitive impairment has increased with patients experiencing deficits across multiple cognitive domains including short-term memory, executive function and language. While significant research efforts have focused on neuroprotective strategies to reduce infarct volume following ischemic insult, numerous clinical trials showed no improvements functional outcome, despite effective reduction in infarct volume. For this proposal, I consider potential molecular targets for neurorestorative strategies, which aim to restore neural networks perturbed by ischemic injury. I specifically investigate molecular targets which improve Schaffer-CA1 hippocampal long-term potentiation (LTP), one of the mechanisms thought to underlie learning and memory, at both acute and delayed timepoints following stroke. By targeting hippocampal pathways, we aim to reduce the burden of cognitive deficits experienced by numerous patients following ischemic stroke. The transient receptor potential melastatin-related 2 channel (TRPM2) ion channel serves as a promising candidate for pharmacologic intervention post-stroke. TRPM2 is a nonselective cation channel, well-studied due to its sensitivity to oxidative stress and its implication in various central nervous system pathologies. Here, we demonstrate TRPM2 global knockout or pharmacologic inhibition restores hippocampal LTP and hippocampal- dependent learning and memory in a model of transient middle cerebral artery occlusion (MCAO). However, the cell-type specific role of TRPM2 and its mechanism of activation remain largely unknown. In this proposal, I examine the neuronal contribution of TRPM2 to hippocampal synaptic and cognitive impairment in a mouse model of MCAO. I also provide compelling preliminary evidence the ectoenzyme, CD38, is upregulated in astrocytes following MCAO, generating ligand necessary for TRPM2 activation, thereby producing cognitive deficits in both sexes. To further elucidate the cell-specific role of TRPM2 and its mechanism of activation, I propose to employ in vitro and in vivo electrophysiologic, molecular and neurobehavioral approaches. In this proposal, I investigate a novel neuroglial mechanism to uncover potential molecular targets for acute and chronic pharmacologic intervention to reduce the burden of cognitive disability following ischemic stroke.

项目摘要中风是美国死亡和残疾的主要原因之一。虽然来自随着再灌注疗法的进步，中风已经下降，幸存者的数量长期发展认知障碍随着多个认知领域的缺陷而增加包括短期记忆，执行功能和语言。虽然重大的研究工作集中关于减少缺血性损伤后减少梗死体积的神经保护策略，许多临床试验表明尽管有效减少了梗塞量，但仍未改善功能结果。对于这个建议，我考虑神经训练策略的潜在分子靶标，旨在恢复受扰动的神经网络缺血性损伤。我特别研究了改善Schaffer-CA1海马长期的分子靶标增强（LTP），这是一种被认为是学习和记忆的机制之一，急性和延迟中风后的时间点。通过针对海马途径，我们旨在减轻认知的负担缺血性中风后许多患者遇到的缺陷。瞬态受体电位梅拉望汀相关2通道（TRPM2）离子通道作为有希望的中风后药理干预候选人。 TRPM2是一个非选择性阳离子通道它对氧化应激的敏感性及其对各种中枢神经系统病理的影响。在这里，我们演示TRPM2全球敲除或药物抑制作用恢复海马LTP和海马 - 在瞬时脑动脉闭塞模型（MCAO）模型中的依赖学习和记忆。但是， TRPM2的细胞类型特异性作用及其激活机理在很大程度上未知。在这个建议中，我检查TRPM2对小鼠海马突触和认知障碍的神经元贡献 MCAO的模型。我还提供了引人注目的初步证据。 MCAO之后的星形胶质细胞，生成TRPM2激活所需的配体，从而产生认知性别的缺陷。为了进一步阐明TRPM2的细胞特异性作用及其激活机理，I 提议采用体外和体内电生理，分子和神经行为方法。在这个提案，我研究了一种新型的神经机制，以发现急性和慢性的潜在分子靶标缺血性中风后认知障碍的负担减轻了药理学干预措施。