FOXOs in ischemic stroke

FOXOs在缺血性中风中的应用

基本信息

批准号：
10521856
负责人：
Hongmin Wang
金额：
$ 37.35万
依托单位：
UNIVERSITY OF SOUTH DAKOTA
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-05-15 至 2027-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10521856
关键词：
Affect Alteplase Alzheimer like pathology Alzheimer&apos s Disease Animals Attenuated Bioinformatics Blood Vessels Brain Diseases Brain Injuries Caenorhabditis elegans Cell Death Cell Nucleus Cell Survival Cells Cerebral Ischemia Clinical Trials Cytoplasm DNA Binding Data Dementia Development Down-Regulation Endothelial Cells FDA approved FOXO1A gene FOXO3A gene Female Gene Expression Genes Genetic Genetic Transcription Growth Factor Health Infiltration Inflammation Ischemia Ischemic Stroke Knock-out Knockout Mice Leukocytes Link MLLT7 gene Mass Spectrum Analysis Mediating Microglia Molecular Mus Myocardial Ischemia Nerve Degeneration Neurologic Deficit Neuronal Injury Neurons Neuroprotective Agents Organic Chemistry Oxidative Stress Pathologic Pathway interactions Peripheral Pharmaceutical Preparations Pharmacology Phosphatidylinositols Phosphorylation Phosphotransferases Physiological Protein Family Proteins Proteomics Reagent Recovery of Function Reperfusion Therapy Role Series Stroke Temperature Testing The Sun Therapeutic Time Tissues Translations Treatment Efficacy Tumor Suppressor Proteins United States Validation Variant Work angiogenesis base cell growth clinically translatable conditional knockout disability drug candidate drug development drug testing fight against functional disability gene product genome-wide inhibitor innovation insight limb ischemia male member mitochondrial dysfunction mouse model neovascularization neovasculature nervous system disorder neuroinflammation neuron loss neuroprotection new therapeutic target overexpression post stroke dementia sensor structural biology success therapeutic evaluation therapeutic target transcription factor transcriptome

项目摘要

PROJECT SUMMARY Cerebral ischemia-reperfusion (I/R) is associated with neuroinflammation, mitochondrial dysfunction and oxidative stress, leading to brain injury, function disability and development of Alzheimer’s disease-like pathology and dementia. To fight against I/R induced pathological cascades, numerous neuroprotective strategies and reagents have been identified and studied. However, translation of these neuroprotective strategies and reagents to clinical trials has been unsuccessful, and to date, the tissue plasminogen activator remains to be the only FDA approved drug for treating ischemic stroke. Thus, it is obligatory to identify and validate additional therapeutic targets and reagents for I/R-caused brain disorder. The objective of this project is to validate a novel therapeutic target, FOXO4, as previous data have shown that FOXO4 promotes early tissue inflammation, and downregulation of FOXO4 is associated with reduced cell death and increased neovasculature in ischemic peripheral tissues. Importantly, our pilot data have shown that knockout (KO) of FOXO4 gene dramatically attenuates I/R-caused brain injury and alters numerous genes linked to AD in an ischemic stroke mouse model. Based on these observations, we hypothesize that selective inhibition of FOXO4 activity is protective against ischemic stroke-caused brain injury and AD-like pathology. To test the hypothesis, we will (1) determine the role of FOXO4 in ischemic stroke-induced brain injury using genetically modified mice, (2) study the role of identified FOXO4 inhibitors in treating ischemic stroke-caused brain injury, and (3) understand how loss of FOXO4 confers neuroprotection following ischemic stroke.

项目概要脑缺血再灌注（I/R）与神经炎症、线粒体功能障碍和氧化应激，导致脑损伤、功能障碍和类似阿尔茨海默病的发展为了对抗缺血再灌注引起的病理级联反应，需要采取多种神经保护措施。然而，这些神经保护的策略和试剂已经被确定和研究。临床试验的策略和试剂均未成功，迄今为止，组织纤溶酶原激活剂仍然是 FDA 批准的唯一治疗缺血性中风的药物，因此，有义务识别和治疗。验证 I/R 引起的脑部疾病的其他治疗靶点和试剂该项目的目标。是为了验证一个新的治疗靶点FOXO4，因为之前的数据表明FOXO4促进早期 FOXO4 的下调与细胞死亡减少和细胞死亡增加相关重要的是，我们的试验数据表明，缺血性外周组织中的新生血管系统被敲除（KO）。 FOXO4 基因可显着减轻缺血再灌注引起的脑损伤，并改变许多与 AD 相关的基因基于这些观察，我们捕获了缺血性中风小鼠模型的选择性抑制。 FOXO4 活性可预防缺血性中风引起的脑损伤和 AD 样病理。假设，我们将 (1) 利用基因确定 FOXO4 在缺血性中风诱发的脑损伤中的作用改良小鼠，(2) 研究已确定的 FOXO4 抑制剂在治疗缺血性中风引起的脑损伤中的作用， (3) 了解 FOXO4 的缺失如何赋予缺血性中风后的神经保护作用。