Therapeutic targeting of angiophagy to achieve microvascular recanalization

血管吞噬治疗靶向以实现微血管再通

• 批准号: 10394881
• 负责人: Jaime Grutzendler
• 金额: $ 45.34万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-05-01 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10394881
• 关键词: Actins; Acute; Affect; Alteplase; Apoptotic; Basic Science; Blood Platelets; Blood Vessels; Blood flow; Brain; Brain Ischemia; Capillary Endothelial Cell; Cell Adhesion; Cell Adhesion Molecules; Cells; Cellular biology; Cerebral Emboli; Cerebrum; Clinical Data; Coagulation Process; Complex; Data; Distal; Embolism; Endothelial Cells; Endothelium; Enzymes; Extravasation; FDA approved; Failure; Family; Functional disorder; Goals; Growth; Hemorrhage; Histology; Hour; Hypoxia; Image; Individual; Integrins; Ischemic Stroke; Lysophospholipids; MERTK gene; Magnetic Resonance Imaging; Mechanics; Mediating; Modeling; Molecular; Monomeric GTP-Binding Proteins; Mus; Mutant Strains Mice; Myocardial Infarction; Outcome; P-Selectin; Pathway interactions; Pharmaceutical Preparations; Pharmacological Treatment; Pharmacology; Phosphatidylserines; Plasma; Play; Process; Receptor Activation; Receptor Protein-Tyrosine Kinases; Resolution; Role; Signal Pathway; Signal Transduction; Stroke; System; Testing; Thrombectomy; Thrombus; Vascular Endothelial Growth Factors; aged; base; behavioral phenotyping; drug candidate; edg-1 Protein; hemodynamics; improved; improved outcome; in vivo imaging; inhibitor; innovation; interdisciplinary approach; intravital imaging; mouse model; neurovascular unit; novel; optical imaging; post stroke; pre-clinical; prevent; retention rate; rho; sphingosine 1-phosphate; stroke outcome; stroke-like outcome; therapeutic target; translational model; two photon microscopy; vascular bed

SUMMARY Thromboembolic occlusions of the microvasculature are implicated in many acute ischemic conditions including stroke and myocardial infarction and may be partly responsible for the “no-reflow“ phenomenon. The fibrinolytic system and hemodynamic washout are considered the principal mechanisms for removing occlusive thromboemboli in all vascular beds, however we have shown that they have a high failure rate at the microvascular level. This may be partly due to a mechanism that we discovered and termed “angiophagy”, whereby endothelial lamellipodia extensively envelop occluding emboli, trapping them within the vascular lumen, markedly reducing hemodynamic washout and limiting access to plasma fibrinolytic enzymes. In conditions such as stroke, it is likely that the early stage of thromboembolus engulfment is highly detrimental as it prevents distal microvascular recanalization following spontaneous reopening of large occluded vessels or after tissue plasminogen activator administration or mechanical thrombectomy. We hypothesize that pharmacologically preventing or delaying the early engulfment stages of angiophagy, can improve thromboembolic washout, and microvascular flow and viability, leading to better post-ischemic outcomes. We aim to discover signaling pathways that regulate the various stages of endothelial plasticity involved in this process, with the goal of identifying potential therapeutic targets. We will use an innovative multidisciplinary approach to elucidate these mechanisms including mutant mice, pharmacological manipulations and high resolution intravital imaging of occluded microvessels. Additionally, we will test our candidate drugs in a translational model of transient ischemic stroke. These studies are likely to advance our understanding of mechanisms of microvascular occlusion and recanalization and could identify novel targets to prevent the no- reflow phenomenon in stroke and other ischemic conditions.

总结 微血管的血栓栓塞性闭塞与许多急性缺血性疾病有关 包括中风和心肌梗塞，并且可能是“无复流”现象的部分原因。的 纤维蛋白溶解系统和血流动力学洗脱被认为是清除闭塞性动脉瘤的主要机制。 血栓栓塞在所有血管床，然而，我们已经表明，他们有一个高失败率在 微血管水平这可能部分是由于我们发现并命名为“血管吞噬”的机制， 由此内皮板状伪足广泛地包裹闭塞的栓子，将它们捕获在血管内， 管腔，显著减少血流动力学洗脱和限制血浆纤溶酶的进入。在 在中风等疾病中，血栓栓塞物吞噬的早期阶段可能是非常有害的， 它可防止大闭塞血管自发再开放后远端微血管再通， 组织纤溶酶原激活剂给药或机械血栓切除术后。我们假设 预防或延迟血管吞噬的早期吞噬阶段，可以改善 血栓栓塞洗脱和微血管流动和活力，导致更好的缺血后结果。我们 目的是发现调节内皮可塑性各个阶段的信号通路， 过程，目的是确定潜在的治疗靶点。我们将采用创新的多学科 方法来阐明这些机制，包括突变小鼠，药理学操作和高 闭塞微血管的高分辨率活体成像。此外，我们将在一个 短暂性缺血性卒中的转化模型。这些研究可能会促进我们对 微血管闭塞和再通的机制，并可以确定新的目标，以防止没有， 中风和其他缺血性疾病中的再流现象。