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Change in NSF ATPase activity Leads to Brain Ischemia Reperfusion Injury

NSF ATP酶活性变化导致脑缺血再灌注损伤

基本信息

批准号：
10748602
负责人：
Bingren Hu
金额：
$ 31.11万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
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：
2022-12-06 至 2024-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10748602
关键词：
ATP phosphohydrolase Abbreviations Affect American Bax protein Brain Injuries Brain Ischemia Cathepsins B Cause of Death Cell Death Cell Membrane Permeability Characteristics Comparative Study Deposition Electrons Endosomes Ethylmaleimide Event Glutamates Glutamine Golgi Apparatus Heart Arrest Ischemia Ischemic Stroke Knockout Mice Lead Lysosomes Mediator Membrane Microscopic Mitochondria Modeling Molecular Mus N-ethylmaleimide-sensitive protein Neurons Outer Mitochondrial Membrane Pathologic Pathway interactions Peptide Hydrolases Phase Phenotype Play Process Proteins Reperfusion Injury Reperfusion Therapy Stroke Structure System Technology Testing Therapeutic Agents Time Transgenes Transgenic Mice Transgenic Organisms Vesicle Wild Type Mouse apoptosis inducing factor cytochrome c disability endonuclease G inducible gene expression insight late endosome mouse model mutant nervous system disorder neuron loss neuroprotection new therapeutic target novel therapeutic target therapeutically effective trafficking transgene expression vesicle transport virtual

项目摘要

Project Summary: Both focal (stroke) and global (cardiac arrest) brain ischemia are major causes of death and long-term disability, but the underlying mechanisms are still not completely understood. The objective of this proposal is to study a novel hypothesis that both focal and global brain ischemia lead to a cascade of events of inactivation of N-ethylmaleimide sensitive factor (NSF), massive buildup of damaged Golgi-endosomal structures, fatal cathepsin B (CTSB) release, induction of mitochondrial outer membrane permeabilization (MOMP), and brain ischemia-reperfusion injury (IRI). NSF is the sole ATPase for controlling membrane trafficking from Golgi apparatus to the endosome- lysosome system. Our recent studies show that NSF is trapped into inactive aggregates during the early period of reperfusion in neurons destined to die after both focal and global brain ischemia. EM studies further show extensive buildup of damaged Golgi/transport vesicles (Vs) and late endosomes (LEs) in postischemic neurons. Consequently, CTSB is significantly accumulated over time in and eventually released from damaged Golgi/Vs/LEs, which is followed by induction of MOMP and neuronal death after ischemia. To study whether NSF inactivation after brain ischemia leads to massive buildup of damaged Golgi/Vs/LEs and CTSB release, we generated a new neuron-specific NSF activity-deficient transgenic (tg) mouse line. The most prominent pathological phenotype of this NSF activity-deficient tg mouse line is massive buildup of damaged Golgi/Vs/LEs and CTSB release, followed by neuronal death, virtually identical to the events observed in wildtype (wt) neurons destined to die after both focal and global brain ischemia. Moreover, induced NSF expression in tg mice protects neurons from IRI. Based on these new discoveries, we propose to test the novel hypothesis strongly supported by preliminary studies, i.e., brain ischemia leads to NSF inactivation, massive buildup of Golgi/Vs/LEs, fatal CTSB release, induction of MOMP, and eventually IRI. We will use both focal and global brain ischemia models, two new tg and one knockout (KO) mouse models, and several cutting-edge technologies to study the molecular processes. Aim 1 will test the novel hypothesis that the NSF inactivation-induced cascade of events of massive buildup of damaged Golgi/Vs/LEs and fatal CTSB release is a common pathway of neuronal death after both focal and global ischemia. Aim 2 will use a translational focal ischemia model and CTSB KO mice to test the novel hypothesis that CTSB release plays a key role in execution of neuronal death via induction of mitochondrial outer membrane permeabilization (MOMP). Aim 3 will use inducible NSF expression tg mice to test the hypothesis that postischemic expression of (active) NSF alleviates NSF inactivation-induced damaging events after focal brain ischemia. These studies will provide novel insights into the neuronal death mechanisms of focal brain IRI and identify new therapeutic targets for its treatment.

项目总结：局灶性脑缺血（中风）和全局性脑缺血（心脏骤停）是脑缺血的主要原因