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CaMKII in global cerebral ischemia: mechanisms and therapeutic intervention

CaMKII 在全脑缺血中的作用：机制和治疗干预

基本信息

批准号：
10328983
负责人：
K. Ulrich Bayer
金额：
$ 38.88万
依托单位：
UNIVERSITY OF COLORADO DENVER
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-01-15 至 2025-11-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10328983
关键词：
Ablation Affect Aftercare Alzheimer&apos s Disease Amyloid beta-Protein Binding Brain Cardiopulmonary Resuscitation Cell Death Cell Survival Cerebral Ischemia Clinical Trials Cognition Conflict (Psychology)Data Development Family suidae Future Genetic Glucose Heart Arrest Human Impairment Individual Informed Consent Injections Intervention Ischemia Knockout Mice Learning Literature Long-Term Potentiation Mediating Mediator of activation protein Memory Mental Depression Modeling Molecular Movement Mus Mutant Strains Mice N-Methyl-D-Aspartate Receptors Neurons Nitric Oxide Synthase Type I Outcome Oxygen Pathologic Pathway interactions Pharmacological Treatment Phosphoric Monoester Hydrolases Phosphorylation Phosphotransferases Preparation Publishing Regulation Risk Factors Role Synaptic plasticity Testing Therapeutic Therapeutic Intervention Time Validation Ventricular Fibrillation Work base calmodulin-dependent protein kinase II clinically relevant deprivation excitotoxicity experimental study functional disability in vivo inhibitor motor impairment natural hypothermia neuron loss neuroprotection novel therapeutic intervention optimal treatments prevent restoration standard of care

项目摘要

Project Summary/Abstract The Ca2+/calmodulin-dependent protein kinase II (CaMKII) is a central mediator of two opposing forms of NMDA- receptor (NMDAR)-dependent synaptic plasticity: long-term potentiation (LTP) and depression (LTD). Pathological overstimulation of NMDARs during cerebral ischemia causes excitotoxic neuronal cell death, and we have recently shown that CaMKII mediates also the neuronal damage after global cerebral ischemia (GCI). Importantly, in vivo injection of our optimized CaMKII inhibitor (tatCN19o) provided significant neuroprotection after GCI models that closely mimic the most relevant human conditions: cardiopulmonary resuscitation (CPR) after cardiac arrest in mice or after ventricular fibrillations in pig (unpublished). CaMKII inhibition (i) was done at a highly clinically relevant timepoint for these conditions (30 min after CPR); (ii) was effective also in conjunction with current standard of care (therapeutic hypothermia); and (iii) protected not only from neuronal cell death but also from the long-lasting functional impairments in LTP that are seen in the surviving neurons. Here, three connected but independent aims will directly promote, our mechanistic understanding of CaMKII- mediated regulation of neuronal cell death and LTP impairment. Specifically, the project will investigate (1) the cross-talk of CaMKII autonomy mechanisms in mediating ischemia-induced neuronal damage, (2) a possible dual role of CaMKII in neuronal cell death versus survival, and (3) mechanisms that underly the CaMKII- dependent long-term LTP impairment of the neurons that survive after ischemia. Together, the results of this study will significantly advance our understanding of the molecular mechanisms underlying ischemic neuronal cell death. Additionally, they will inform future development of a therapy in humans.

项目总结/文摘