Novel therpeautic interventions to treat ischemic stroke

治疗缺血性中风的新型治疗干预措施

• 批准号: 10517515
• 负责人: Anil Kumar Chauhan
• 金额: $ 46.89万
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-12-01 至 2024-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10517515
• 关键词: Adhesions; Aging; Alteplase; Animal Model; Binding; Biological Aging; Blood Platelets; Blood capillaries; Brain Injuries; Cell Adhesion; Cerebrovascular Circulation; Cerebrum; Clinical; Clinical Research; Coagulation Process; Complex; Data; Deposition; Economic Burden; Economics; Endothelium; Environmental sludge; Evaluation; Evolution; Exhibits; Extracellular Matrix; Extracellular Matrix Proteins; Fab Immunoglobulins; Fibrin; Fibrinolysis; Fibronectins; Free Radicals; Functional disorder; Genetic; Guidelines; Health; Hour; Human; Hyperlipidemia; Industry; Infarction; Inflammation; Inflammation Mediators; Inflammatory; Injury; Integrin alpha2beta1; Integrins; Ischemia; Ischemic Penumbra; Ischemic Stroke; Laser Speckle Imaging; Ligands; Magnetic Resonance Imaging; Measures; Mechanics; Mediating; Modeling; Mus; Myelogenous; Neurologic; Neurologic Deficit; Neuronal Injury; Outcome; Oxidative Stress; Patients; Peptides; Pilot Projects; Platelet aggregation; Predisposition; Randomized; Recommendation; Reperfusion Injury; Reperfusion Therapy; Research; Role; Severities; Stroke; Testing; Therapeutic; Thrombectomy; Thrombosis; Treatment Efficacy; United States; Update; Wild Type Mouse; biological sex; comorbidity; diet-induced obesity; effective intervention; efficacy testing; extracellular; genetic approach; high risk; human subject; improved; inhibitor; innovation; integrin alpha9 beta1; intravital microscopy; migration; monocyte; multiphoton microscopy; mutant; nanoparticle; neuron loss; neutrophil; novel; novel therapeutic intervention; pharmacologic; pre-clinical; response; sex; stroke model; stroke outcome; stroke risk; stroke therapy; synergism; systemic inflammatory response; therapeutic target; thromboinflammation; thrombolysis; vascular inflammation

Project Summary Stroke results in immense health and economic burden. Current strategies to improve stroke outcome is fibrinolysis of the clot with tissue plasminogen activator and mechanical thrombectomy, which involves reperfusion of the ischemic region. However, accumulating evidence suggests that cerebral reperfusion is often accompanied by oxidative stress, thrombosis, and vascular inflammation, which exacerbates neuronal death in the ischemic penumbra. There is currently no effective intervention available to protect the brain damage following reperfusion therapy. Clinical studies have shown a positive correlation between the massive influx of neutrophils and severity of injury following reperfusion. Integrin alpha9beta1 is highly expressed on neutrophils (relative to monocytes), upregulated upon activation and transmigration, and is known to stabilize neutrophil adhesion to activated endothelium in synergy with alpha2beta1 integrin. The mechanistic role of alpha9beta1 in stroke outcome is not explored yet. Utilizing novel mutant strains, in pilot studies, we found that alpha9beta1 exacerbates stroke outcome by modulating thrombosis and vascular inflammation. Following updated Stroke Therapy Academic Industry Roundtable (STAIR) pre-clinical guidelines and compelling pilot data, we propose to test the innovative hypothesis that integrin alpha9beta1 contributes to ischemic stroke exacerbation in stroke models with comorbidities and therapeutic targeting alpha9beta1 will improve stroke outcome by limiting thrombosis and inflammation. To accomplish this, we will utilize complementary genetic and pharmacological approaches, state-of-the-art intravital microscopy, magnetic resonance imaging, laser speckle imaging and follow current STAIR/RIGOR guidelines. Aging and biological sex are key determinants that influence stroke outcome. We will determine whether targeting alpha9beta1 will improve stroke outcome in the context of biological sex and aging so that the observed effect is generalizable to the broader context. This project may have significant clinical implications since understanding the mechanisms by which neutrophils contribute to reperfusion injury in stroke models with comorbidities may provide new therapeutic interventions to treat ischemic stroke.

项目摘要 中风会导致巨大的健康和经济负担。当前改善中风结果的策略是 用组织纤溶酶原激活剂和机械血栓切除术对凝块的纤维蛋白溶解，这涉及 缺血区域的再灌注。但是，积累的证据表明脑再灌注是 通常伴有氧化应激，血栓形成和血管炎症，这会加剧神经元 缺血性半衰期死亡。目前尚无有效的干预措施来保护大脑 再灌注疗法后的损害。临床研究表明 大量中性粒细胞的流入和再灌注后的损伤严重程度。整合素alpha9beta1高度 以中性粒细胞（相对于单核细胞）表示，在激活和移民时上调，IS 已知可以稳定与α2Beta1整联蛋白协同活化的内皮粘附。这 尚未探索α9BETA1在中风结果中的机械作用。利用新型突变菌株，在飞行员中 研究，我们发现α9Beta1通过调节血栓形成和血管加剧了中风结果 炎。随着更新的中风疗法学术行业圆桌会议（楼梯）前临床前 指南和引人注目的飞行员数据，我们建议测试整合素alpha9beta1的创新假设 在具有合并症和治疗靶向的中风模型中导致缺血性中风加剧 alpha9beta1将通过限制血栓形成和炎症来改善中风结果。为此，我们 将利用互补的遗传和药理学方法，最先进的插入显微镜， 磁共振成像，激光斑点成像并遵循当前的楼梯/严格指南。老化和 生物性别是影响中风结果的关键决定因素。我们将确定是否针对 alpha9beta1将在生物性别和衰老的背景下改善中风结果，以便观察到 效果可以推广到更广泛的环境。该项目可能具有重大的临床意义 了解中性粒细胞在中风模型中导致再灌注损伤的机制 合并症可能会提供新的治疗干预措施来治疗缺血性中风。

项目成果

Characterization of bleeding symptoms in Ehlers-Danlos syndrome.

埃勒斯-当洛斯综合征出血症状的特征。

• DOI: 10.1016/j.jtha.2023.04.004
• 发表时间: 2023
• 期刊: Journal of thrombosis and haemostasis : JTH
• 作者: Kumskova,Mariia;Flora,GaganD;Staber,Janice;Lentz,StevenR;Chauhan,AnilK
• 通讯作者: Chauhan,AnilK

Metabolic targeting of platelets to combat thrombosis: dawn of a new paradigm?

血小板代谢靶向对抗血栓形成：新范式的曙光？

• DOI: 10.1093/cvr/cvad149
• 发表时间: 2023
• 期刊: Cardiovascular research
• 影响因子: 10.8
• 作者: Flora,GaganD;Nayak,ManasaK;Ghatge,Madankumar;Chauhan,AnilK
• 通讯作者: Chauhan,AnilK

Myeloid Cell PKM2 Deletion Enhances Efferocytosis and Reduces Atherosclerosis.

• DOI: 10.1161/circresaha.121.320704
• 发表时间: 2022-04-29
• 期刊: CIRCULATION RESEARCH
• 影响因子: 20.1
• 作者: Doddapattar, Prakash;Dev, Rishabh;Ghatge, Madankumar;Patel, Rakesh B.;Jain, Manish;Dhanesha, Nirav;Lentz, Steven R.;Chauhan, Anil K.
• 通讯作者: Chauhan, Anil K.

Constitutively active ADAMTS13: An emerging thrombolytic agent for acute ischemic stroke.

• DOI: 10.1111/jth.15649
• 发表时间: 2022-04
• 期刊: Journal of thrombosis and haemostasis : JTH

Mitochondrial pyruvate dehydrogenase kinases contribute to platelet function and thrombosis in mice by regulating aerobic glycolysis.

• DOI: 10.1182/bloodadvances.2023010100
• 发表时间: 2023-06-13
• 期刊: Blood advances
• 影响因子: 7.5