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TRPM2 channels and synaptic dysfunction following ischemic injury in the developing brain.

发育中大脑缺血损伤后的 TRPM2 通道和突触功能障碍。

基本信息

批准号：
9386009
负责人：
Robert M Dietz
金额：
$ 19.33万
依托单位：
UNIVERSITY OF COLORADO DENVER
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-07-15 至 2022-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9386009
关键词：
Acute Adolescent Adult Behavior Biological Preservation Brain Brain Injuries Calcineurin Cell Death Cell model Cerebral Ischemia Child Clinical Research Cognitive deficits Communication Data Development Electrophysiology (science)Exhibits Face Functional disorder Genetic Heart Arrest Hippocampus (Brain)Impairment Infant Injury Innovative Therapy Intervention Ion Channel Ischemia Lead Learning Long-Term Potentiation Measures Memory Memory impairment Mentors Modeling Molecular Mus Neurologic Neuronal Dysfunction Neurons Oxidative Stress Pathologic Peptides Pharmacology Phenotype Physiological Physiology Play Puberty Recovery Reperfusion Injury Research Research Proposals Role Signal Transduction Stimulus Stress Subfamily lentivirinae Survivors Synapses Synaptic plasticity Techniques Testing Therapeutic Time Training Transfection Translating Work behavior test career design developmental plasticity experience experimental study fitness functional disability functional outcomes improved in vivo inhibitor/antagonist innovation juvenile animal knock-down mouse model neuron loss neuroprotection neurotoxicity new therapeutic target novel novel therapeutics preclinical study prepuberty prevent protein expression protein function receptor skills small hairpin RNA synaptic function young adult

项目摘要

Project Summary Global cerebral ischemia caused by cardiac arrest results in many neurological sequelae, including deficits in learning and memory. These deficits are as evident in children as they are in adults. The resulting neurological sequelae from cardiac arrest (CA) in children likely arise from both neuronal death and altered physiology in surviving neurons. TRPM2 channels are non-selective ion channels that are activated by hyperoxidative stress and are compelling targets in preventing neurotoxicity and cellular dysfunction. Our lab has recently designed a novel inhibitor of TRPM2 channels, known as tatM2NX, to better understand the role of TRPM2 in neuronal death and dysfunction. A useful measure to assess neuronal dysfunction is to investigate the level of synaptic function. The ability for neurons to undergo synaptic plasticity (long-term potentiation; LTP) in the hippocampus is recognized as an innate measure of function and is a widely accepted cellular model for learning and memory. This proposal makes use of a novel cardiac arrest model in juvenile mice (p21-25) to investigate the hypothesis that activation of TRPM2 channels contributes to impairment of synaptic function and cognitive deficits following global cerebral ischemia. We have found that inhibiting TRPM2 soon after juvenile CA leads to preservation of synaptic function, despite no significant change in neuronal death. We will further test the hypothesis by inhibiting TRPM2 at delayed time points (7-14 days after PCA). Inhibition of TRPM2 will be done with pharmacology (in vivo tatM2NX) or genetic modulation (TRPM2-/-, lentiviral shRNA TRPM2 knockdown) and function will be assessed by electrophysiology and behavior. Preliminary data suggest that delayed inhibition of TRPM2 reverses synaptic impairments after CA. We will use signal transduction techniques to identify the mechanism for synaptic impairment after ischemia-induced TRPM2 activation. We will focus on the hypothesis that activation of TRPM2 signals calcineurin, leading to decreased synaptic function. Finally, we have found that while ischemia in young animals results in impairment of synaptic function up to 14 days after CA, there is remarkable endogenous recovery to control levels. The final aim of the project will investigate the role of developmental changes in TRPM2 expression in neurons through puberty into adulthood that may account for endogenous recovery of impaired synaptic function. Overall, this project has high translational potential through the opportunity of redefining therapeutic windows after global cerebral ischemia in children. Experiments outlined in this proposal will provide important training for an independent research career. In this proposal, I will learn hippocampal lentivirus shRNA transfection, behavior testing, and signal transduction techniques to assess protein expression and function. The mentor team assembled has experience and expertise to assure completion of this project. Upon completion of this proposal, I will combine these skills with electrophysiology techniques that I am already familiar with and apply for an R01 to further characterize TRPM2 activity in the maturing juvenile mouse after cardiac arrest. The impact of this work will be in establishing a novel therapeutic strategy to improve neurological consequences of ischemia in the young brain.