Targeting the mitochondrial protein mitoNEET for the treatment of reperfusion-injury after stroke

靶向线粒体蛋白 mitoNEET 治疗中风后再灌注损伤

基本信息

批准号：
10217166
负责人：
Werner Geldenhuys
金额：
$ 30.07万
依托单位：
WEST VIRGINIA UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-09-08 至 2025-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10217166
关键词：
Affinity Agonist Attenuated Binding Biochemistry Bioenergetics Biophysics Blood - brain barrier anatomy Brain Brain Edema Brain Infarction Brain Injuries Cause of Death Cells Centers of Research Excellence Cerebrum Clinic Clinical Clinical Trials Coagulation Process Computer Models Crystallization Data Drug Targeting Ensure Evaluation Future Genes Goals Hypoxia Ischemia Ischemic Stroke Lead Ligands Lysine Middle Cerebral Artery Occlusion Mitochondria Mitochondrial Proteins Modeling Mus Neuroprotective Agents Outer Mitochondrial Membrane Oxidation-Reduction Oxidative Phosphorylation Oxidative Stress Patient-Focused Outcomes Pharmaceutical Preparations Pharmacological Treatment Pharmacology Pilot Projects Play Program Development Property Protein Family Proteins Quality of life Reperfusion Injury Reperfusion Therapy Research Role Stroke Structure Structure-Activity Relationship Testing Therapeutic Time Tissues Translating United States Universities West Virginia Zinc Fingers base blood-brain barrier permeabilization brain tissue design disability drug development drug discovery gene function improved improved outcome innovation mitochondrial dysfunction mitochondrial oxidative dysfunction mouse model neuron loss neuroprotection new therapeutic target novel novel therapeutic intervention novel therapeutics outcome prediction post stroke prevent programs prototype sensor stroke model stroke outcome stroke patient stroke therapy therapeutic development therapeutic target therapeutically effective treatment strategy

项目摘要

PROJECT SUMMARY Stroke is the fifth leading cause of death and the leading cause of disability in the United States. There remains a critical need for innovative therapeutic approaches that can successfully prevent or reverse brain injury following stroke. Dysfunction of the mitochondrial biochemistry following ischemic stroke and reperfusion injury contributes to significant neuronal cell loss; however, the development of therapeutics targeting mitochondrial function for stroke patients are lacking. Mitochondrial dysfunction plays a central role in the neuronal cell death seen in ischemia-reperfusion injury, but has not yet been fully investigated as drug target. In this project, we are investigating novel mitochondrial protein mitoNEET as therapeutic drug target of mitochondrial function in stroke. MitoNEET is a newly discovered protein that regulates mitochondrial bioenergetics. We developed a first-in- class mitoNEET agonist NL-1 which showed significant tissue protection after transient ischemia in the brain. The objectives of this proposal are to evaluate a recently discovered mitochondrial protein, mitoNEET, as an effective therapeutic approach for the pharmacological treatment of stroke. MitoNEET (CISD1 gene) regulates mitochondrial bioenergetics capacity where it functions as redox sensor. Our central hypothesize is that ligands selectively binding to mitoNEET will protect brain tissue from hypoxia-induced reperfusion injury, by reducing mitochondrial dysfunction and oxidative stress. In our first aim, we will determine the pharmacological effect of the mitoNEET ligands in a mouse model of middle cerebral ischemic reperfusion injury, and evaluate the duration of the therapeutic window of the mitoNEET agonists where compounds will still be effective in preventing neuronal cell death if given after a reperfusion injury. In the second aim, we will develop potent and selective mitoNEET ligands with blood-brain barrier permeability properties. Predicted outcomes are that mitoNEET agonists will be neuroprotective in stroke. These findings will have far-reaching implication for developing neuroprotective medications as a treatment strategy for limiting the mitochondrial contribution to cell loss in the clinical setting in the treatment of stroke patients.

项目概要中风是美国第五大死亡原因和导致残疾的主要原因。还剩下迫切需要能够成功预防或逆转脑损伤的创新治疗方法中风后。缺血性中风和再灌注损伤后线粒体生化功能障碍导致显着的神经元细胞损失；然而，针对线粒体的治疗方法的开发中风患者的功能缺乏。线粒体功能障碍在神经细胞死亡中起着核心作用见于缺血再灌注损伤，但尚未作为药物靶点进行充分研究。在这个项目中，我们是研究新型线粒体蛋白 mitoNEET 作为中风线粒体功能的治疗药物靶点。 MitoNEET 是一种新发现的调节线粒体生物能的蛋白质。我们开发了首创的 mitoNEET 类激动剂 NL-1 在大脑短暂缺血后表现出显着的组织保护作用。该提案的目的是评估最近发现的线粒体蛋白 mitoNEET 作为一种药物治疗中风的有效治疗方法。 MitoNEET（CISD1基因）调节线粒体生物能量学能力，其功能为氧化还原传感器。我们的中心假设是配体选择性结合 mitoNEET 将通过减少缺氧诱导的再灌注损伤来保护脑组织线粒体功能障碍和氧化应激。在我们的第一个目标中，我们将确定药理作用小鼠中脑缺血再灌注损伤模型中的mitoNEET配体，并评估持续时间 mitoNEET 激动剂的治疗窗，其中化合物仍能有效预防如果在再灌注损伤后给予神经元细胞死亡。在第二个目标中，我们将开发有效且有选择性的 mitoNEET 配体具有血脑屏障渗透特性。预测结果是 mitoNEET 激动剂对中风具有神经保护作用。这些发现将对发展产生深远影响神经保护药物作为限制线粒体对细胞损失的贡献的治疗策略治疗中风患者的临床环境。