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 中风会造成巨大的健康和经济负担。目前改善中风预后的策略是 使用组织纤溶酶原激活剂和机械血栓切除术对血栓进行纤溶，这涉及到 缺血区再灌流。然而，越来越多的证据表明，大脑再灌注 常伴有氧化应激、血栓形成和血管炎症，这会加重神经元 缺血半暗带内死亡。目前还没有有效的干预措施来保护大脑 再灌注治疗后的损伤。临床研究表明，两组之间存在正相关 再灌注后中性粒细胞大量涌入和损伤严重程度。整合素α9beta1高度 在中性粒细胞(相对于单核细胞)上表达，在激活和迁移时上调，并且是 已知通过与α2beta1整合素的协同作用稳定中性粒细胞与激活的内皮细胞的黏附。这个 Alpha9beta1在卒中结局中的作用机制尚不清楚。利用新突变菌株，在试点中 研究发现，α9β1通过调节血栓形成和血管而加重中风预后。 发炎。继卒中治疗学术行业圆桌会议(STAIR)临床前更新 指南和令人信服的试验数据，我们建议检验整合素α9β1这一创新假设 共病和靶向治疗对卒中模型中缺血性卒中加重的影响 Alpha9beta1将通过限制血栓形成和炎症来改善中风预后。为了实现这一目标，我们 将利用互补的遗传和药理学方法，最先进的活体显微镜， 磁共振成像、激光散斑成像，并遵循当前的阶梯/严格指南。老龄化和 生物性别是影响中风预后的关键决定因素。我们将确定目标是否 在生物学性别和老龄化的背景下，Alpha9beta1将改善中风的结局，因此观察到的 效果可以推广到更广泛的背景下。该项目可能具有重要的临床意义，因为 了解中性粒细胞在卒中模型再灌注损伤中的作用机制 合并症可能为治疗缺血性卒中提供新的治疗手段。

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

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

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

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.