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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

基本信息

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
项目类别：
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

项目摘要

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.

项目总结