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Role of the LRRC8A-containing volume-regulated anion channel in intraischemic glutamate release and animal stroke outcomes

含有 LRRC8A 的容量调节阴离子通道在缺血内谷氨酸释放和动物中风结果中的作用

基本信息

批准号：
9909654
负责人：
Corinne Sage Wilson
金额：
$ 4.5万
依托单位：
ALBANY MEDICAL COLLEGE
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-09-11 至 2021-09-10
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9909654
关键词：
Adult Alteplase Animal Disease Models Animal Model Animals Anions Astrocytes Back Behavioral Blood Vessels Blood flow Brain Brain Injuries Calcium Cause of Death Cells Chloride Channels Clinical Clinical Trials Complex Data Development Distal Exclusion Criteria FDA approved Family Fellowship Future Glial Fibrillary Acidic Protein Glutamate Receptor Glutamates Glycolysis Goals Hour Human Immunohistochemistry Impairment In Vitro Individual National Research Service Award Injury Ischemic Brain Injury Ischemic Penumbra Ischemic Stroke Knock-out Knockout Mice Knowledge Learning Leucine-Rich Repeat Link LoxP-flanked allele Measures Mediating Messenger RNA Metabolic Microdialysis Middle Cerebral Artery Occlusion Modeling Modernization Molecular Molecular Biology Motor Mus Neurodegenerative Disorders Neuroglia Neurons Neurotransmitters Pathologic Pathway interactions Patients Permeability Pharmacologic Substance Pharmacology Pharmacotherapy Play Population Process Property Proteins Publishing Reporting Research Rodent Model Role Route Scientist Sensory Specificity Stains Stroke Stroke Volume Swelling Tamoxifen Techniques Testing Therapeutic Time Tissues Training Transgenic Organisms United States Western Blotting Work acute stroke behavioral outcome channel blockers clinical practice design disability excitotoxicity experimental study glutamatergic signaling improved outcome in vivo inhibitor/antagonist knockout animal leucine-rich repeat protein member middle cerebral artery mouse model new therapeutic target post stroke pre-doctoral prevent sex side effect skills stroke model stroke outcome stroke patient stroke therapy theories tool translational scientist treatment strategy

项目摘要

PROJECT SUMMARY (30 LINES) Ischemic stroke is the fifth leading cause of death in the United States, and one of the leading causes of long- term disability in adults. One of the hallmarks of ischemic stroke is cell swelling, which occurs primarily in astrocytes. In order to regulate their volume, cells engage volume regulated anion channels (VRAC), which are chloride channels that are permeable to a number of organic osmolytes, including glutamate. Overactivation of glutamate receptors causes an excitotoxic cascade that culminates in calcium-mediated neuronal damage. This theory of swelling-activated glutamate release in the ischemic brain has been around for several decades, as inhibitors of VRAC (tamoxifen and DCPIB) reduce stroke volumes and intraischemic glutamate release. However, the lack of both knowledge on the molecular identity of VRAC and specificity of VRAC inhibitors prevented further research in this field. The recent discovery that VRAC is composed of proteins from the LRRC8 family, with subunits LRRC8A-E, has opened the doors for new studies using molecular biology tools to specifically target VRAC and the essential LRRC8A subunit. In the following work, we plan to establish LRRC8- containing VRAC as a primary contributor to intraischemic glutamate release and provide a mechanism for the neuroprotective effects of nonspecific VRAC inhibitors. In preliminary studies, we have shown in vitro that heterogenous populations of VRAC are preferentially permeable to glutamate, and that VRAC channels are likely active in the ischemic penumbra and possibly even the ischemic core. For the proposed in vivo experiments, we will use transgenic floxed LRRC8A mice to develop an astrocyte-specific LRRC8A knockout (KO) mouse model. First, we will determine if the neuroprotective properties of VRAC inhibitors are due to their inhibition of VRAC activity by measuring stroke volumes and behavior outcomes in astrocytic LRRC8A KO mice following permanent distal occlusion of the middle cerebral artery, a mouse model of stroke. We will also test whether LRRC8-containing VRAC is a major pathway for intraischemic glutamate release, using microdialysis techniques to measure cortical glutamate from astrocytic LRRC8A KO animals. This work will help us to understand more about the complex mechanisms of damage in the ischemic brain, and someday allow for the development of better therapeutics for ischemic stroke. Through the proposed work and training over the next two years, I will hone my knowledge and skills in animal models of disease and prepare myself to become a successful, independent scientist in the field of pharmaceutical research. With the help of the Ruth L. Kirschstein National Research Service Award (NRSA) Individual Predoctoral Fellowship, I will be able to design and perform research establishing a new target for ischemic stroke treatment, and will be ideally suited for future work with clinical trial development for patients suffering from neurodegenerative diseases.

项目总结（30行）