mitoNEET as a therapeutic target for mitigating ischemic brain injury following MCAO

mitoNEET 作为减轻 MCAO 后缺血性脑损伤的治疗靶点

• 批准号: 10735923
• 负责人: Werner Geldenhuys
• 金额: $ 54.95万
• 依托单位: WEST VIRGINIA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-01 至 2028-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10735923
• 关键词: Acute; Address; Advanced Development; Apoproteins; Apoptosis; Area; Attenuated; Basic Science; Bioenergetics; Blood - brain barrier anatomy; Blood brain barrier dysfunction; Brain; Brain Injuries; Cardiovascular system; Cause of Death; Cell Respiration; Cells; Cellular Stress; Clinical Research; Communication; Consumption; Data; Disabled Persons; Disease; Endothelial Cells; Female; Foundations; Generations; Glucose; Goals; Health; In Vitro; Infarction; Iron; Ischemia; Ischemic Brain Injury; Ischemic Stroke; Knowledge; Libraries; Ligands; Link; Lipid Peroxidation; Literature; Mediating; Medical; Metabolic; Middle Cerebral Artery Occlusion; Mission; Mitochondria; Mitochondrial Proteins; Modeling; Mus; National Institute of Neurological Disorders and Stroke; Nervous System Trauma; Neurologic; Neurons; Oncogenic; Outer Mitochondrial Membrane; Oxidation-Reduction; Oxidative Stress; Oxygen; Parents; Pathway interactions; Phase; Pioglitazone; Play; Pre-Clinical Model; Proteins; Public Health; Rattus; Reactive Oxygen Species; Reperfusion Injury; Reperfusion Therapy; Research; Risk; Rodent; Role; Severities; Specificity; Stroke; Sulfur; Testing; Therapeutic; Therapeutic Effect; Therapeutic Intervention; Tissues; United States National Institutes of Health; Work; aged; blood-brain barrier disruption; blood-brain barrier function; blood-brain barrier permeabilization; brain endothelial cell; brain tissue; cell injury; cerebral microvasculature; deprivation; design; disability; drug discovery; functional disability; functional improvement; improved; improved outcome; in vitro Model; injured; innovation; insight; interest; male; mitochondrial dysfunction; nervous system disorder; neuroinflammation; neuron loss; neuronal survival; neuropathology; neuroprotection; new therapeutic target; novel; novel therapeutics; post stroke; pre-clinical; preclinical study; repaired; response; sensor; stressor; stroke outcome; stroke recovery; targeted treatment; temporal measurement; therapeutic target; tool

PROJECT SUMMARY Accumulating evidence suggests that following ischemic stroke hypoperfused brain tissue is functionally disabled as electrical communication among penumbral neurons is disrupted due to marked reductions in oxidative metabolism. Thus, it is apparent that mitochondrial dysfunction plays a central role in the degree of neuronal cell death encountered following ischemic brain injury; however, mitochondria have been slow to be fully investigated. Through a serendipitous discovery of an off-target therapeutic effect of pioglitazone, a small mitochondrial iron-sulfur cluster protein, mitoNEET (mNT) was identified that has renewed interest in therapeutic targeting of mitochondria. MitoNEET is embedded in the outer mitochondrial membrane and acts as a redox and pH sensor to regulate mitochondrial bioenergetics, especially in response to cellular stress. Using pioglitazone as our parent compound, we designed NL-1, a first-in-class ligand with high specificity for mN. Using NL-1, we have demonstrated marked improvements in stroke neuropathology and functional impairment following transient middle cerebral artery occlusion (MCAO) in mice and rats. The objective of this proposal is to address fundamental gaps in knowledge regarding how mNT works within the brain to mitigate acute ischemic brain injury. Our central hypothesis is that modulation of mNT acts to improve vulnerable neurons within the penumbra by reducing the vicious cycle of excessive iron-induced lipid peroxidation and increased neuronal death. Based on a strong body of prior literature and pilot data, we postulate the initial target of activity for NL-1 is the cerebral microvasculature; thus, we propose two specific aims to test our hypothesis. In specific aim 1, we will test if mNT selective ligand, NL-1, mitigates ferroptosis using a 4 cell Transwell in vitro model of the blood- brain barrier following oxygen-glucose deprivation with reperfusion. Whereas, in specific aim 2, we will test if mNT ligand, NL-1, reduces brain iron accumulation and blood-brain barrier dysfunction post-MCAO. Successful completion of the proposed research is expected to provide a: (1) greater understanding of how & where mNT mitigates brain injury following ischemic stroke; (2) new insight into the impact of mitochondrial dysfunction & diminished bioenergetics on ischemic stroke outcomes; & (3) strong scientific foundation for an interventional therapeutic approach for treating ischemic stroke. The mechanistic & preclinical data obtained through these studies will serve as critical milestones for advancing the development of mitochondria-targeted therapies for treating neurological injuries & disease.

项目摘要 积累的证据表明，以下缺血性中风脑组织在功能上是残疾 由于氧化的明显减少，由于半神经元之间的电通通信破坏了 代谢。因此，很明显，线粒体功能障碍在神经元细胞的程度中起着核心作用 脑缺血性脑损伤遇到死亡；但是，线粒体的完全缓慢 调查。通过偶然发现Pioglitazone的脱靶治疗作用 线粒体铁硫簇蛋白，Mitoneet（MNT）被鉴定出对治疗的兴趣的重新兴趣 线粒体的靶向。线粒体嵌入线粒体膜中，充当氧化还原和 pH传感器调节线粒体生物能学，尤其是在响应细胞应激的情况下。使用吡格列酮 作为我们的母体化合物，我们设计了NL-1，这是一种具有高特异性MN的第一类配体。使用NL-1，我们 在以下情况下，已经证明了中风神经病理学和功能障碍的明显改善 小鼠和大鼠的瞬时脑动脉闭塞（MCAO）。该提议的目的是解决 关于MNT如何在大脑内部工作以减轻急性缺血大脑的知识的基本差距 受伤。我们的核心假设是，MNT的调节是为了改善弱势神经元 通过减少过度铁诱导的脂质过氧化的恶性循环并增加神经元的阴影 死亡。根据先前的文献和试点数据的强大，我们假设NL-1活动的初始目标 是脑微脉管系统；因此，我们提出了两个特定的目的来检验我们的假设。在特定的目标1中， 我们将测试MNT选择性配体NL-1是否使用4个细胞在血液的体外模型中减轻屈服 再灌注后，氧气 - 葡萄糖剥夺后的脑屏障。鉴于，在特定的目标2中，我们将测试是否 MNT配体NL-1可减少MCAO后脑铁的积累和血脑屏障功能障碍。成功的 预计拟议研究的完成将提供a：（1）对MNT的方式和何处的更多了解 缺血性中风后减轻脑损伤； （2）对线粒体功能障碍的影响的新见解和 关于缺血性中风结果的生物能量减少； ＆（3）介入的强大科学基础 治疗缺血性中风的治疗方法。通过这些获得的机械和临床前数据 研究将是推进线粒体靶向疗法的关键里程碑 治疗神经损伤和疾病。