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

项目总结 在美国，中风是第五大死亡原因，也是导致残疾的首要原因。那里有残骸 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。缺血性卒中再灌注损伤后线粒体生化功能障碍 导致显著的神经细胞丢失；然而，针对线粒体的治疗药物的发展 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中心作用 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 探索新的线粒体蛋白mitoNEET作为卒中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量学的蛋白质。我们开发了一款首开纪录的- NL-1类mitoNEET激动剂，在短暂性脑缺血后显示出显著的组织保护作用。 这项提案的目的是评估一种最近发现的线粒体蛋白mitoNEET作为一种 中风药物治疗的有效治疗途径。MitoNEET(Cisd1基因)调节 线粒体作为氧化还原感受器的生物能量学能力。我们的中心假设是配体 选择性地与mitoNEET结合将保护脑组织免受低氧诱导的再灌注损伤，这是通过减少 线粒体功能障碍和氧化应激。在我们的第一个目标中，我们将确定其药理作用 MITONEET配体在小鼠中脑缺血再灌注损伤模型中的表达及其作用时间的评估 MITONEET激动剂的治疗窗口，化合物仍将有效地预防 如果在再灌注损伤后给予神经细胞死亡。在第二个目标中，我们将发展强有力和有选择性的 具有血脑屏障通透性的mitoNEET配体。预测的结果是mitoNEet 激动剂在中风中将具有神经保护作用。这些发现将对发展产生深远的影响。 神经保护性药物作为限制线粒体对细胞丢失的作用的治疗策略 治疗中风患者的临床设置。

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.