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cardiopulmonary resuscitation (CPR) after cardiac arrest in mice or after ventricular fibrillations in pig (unpublished).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

项目摘要/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-的中心介体受体（NMDAR）依赖性突触可塑性：长期增强（LTP）和抑郁（LTD）。脑缺血期间NMDAR的病理过度刺激导致兴奋性神经元细胞死亡，并我们最近表明，CAMKII在全球脑缺血（GCI）后也介导神经元损伤。重要的是，在体内注射我们优化的CAMKII抑制剂（TATCN19O）提供了重要的神经保护作用在密切模仿最相关的人类条件的GCI模型之后：心肺复苏（CPR）在小鼠心脏骤停或猪心室纤颤后（未发表）。 CAMKII抑制（i）是在对于这些条件的高度相关时间点（CPR后30分钟）；（ii）也有效具有当前的护理标准（治疗性体温过低）；（iii）不仅免受神经元细胞死亡的保护同样来自LTP中持续的功能障碍，这些功能障碍在幸存的神经元中看到。在这里，三个相关但独立的目标将直接促进，我们对Camkii的机械理解介导的神经元细胞死亡和LTP损伤的调节。具体而言，该项目将调查（1） CAMKII自治机制的串扰介导缺血引起的神经元损伤，（2）可能 CaMKII在神经元细胞死亡与生存中的双重作用，以及（3）CAMKII-的机制缺血后生存的神经元的依赖性长期LTP损害。在一起的结果研究将大大提高我们对缺血神经元下分子机制的理解细胞死亡。此外，他们将为未来的人类疗法发展提供信息。