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conditions: cardiopulmonary resuscitation (CPR) after cardiac arrest in mice or after ventricular fibrillations in pig (unpublished).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.

项目概要/摘要 Ca2+/钙调蛋白依赖性蛋白激酶 II (CaMKII) 是两种相反形式的 NMDA 的中心介质受体（NMDAR）依赖性突触可塑性：长时程增强（LTP）和抑制（LTD）。脑缺血期间 NMDAR 的病理性过度刺激会导致兴奋性毒性神经元细胞死亡，并且我们最近发现 CaMKII 还介导全脑缺血 (GCI) 后的神经元损伤。重要的是，体内注射我们优化的 CaMKII 抑制剂 (tatCN19o) 提供了显着的神经保护作用在密切模仿最相关的人类状况的 GCI 模型之后：心肺复苏 (CPR) 小鼠心脏骤停后或猪心室颤动后（未发表）。 CaMKII 抑制 (i) 进行于这些情况的临床高度相关时间点（心肺复苏后 30 分钟）； (ii) 结合使用也有效按照当前的护理标准（低温治疗）； (iii) 不仅防止神经元细胞死亡，而且还来自于在存活的神经元中观察到的长期持续性功能损伤。在这里，三个相互联系但独立的目标将直接促进我们对 CaMKII 的机制理解—— 介导神经元细胞死亡和 LTP 损伤的调节。具体来说，该项目将调查 (1) CaMKII 自主机制在介导缺血引起的神经元损伤中的串扰，(2) 可能的 CaMKII 在神经元细胞死亡与存活中的双重作用，以及 (3) CaMKII 的机制缺血后存活神经元的依赖性长期 LTP 损伤。综合起来，这次的结果研究将显着增进我们对缺血性神经元潜在分子机制的理解细胞死亡。此外，它们还将为人类疗法的未来发展提供信息。