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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.

项目总结