Therapeutic targeting of angiophagy to achieve microvascular recanalization

血管吞噬治疗靶向以实现微血管再通

基本信息

批准号：
9918474
负责人：
Jaime Grutzendler
金额：
$ 47.41万
依托单位：
YALE UNIVERSITY
依托单位国家：
美国
项目类别：
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/9918474
关键词：
Actins Acute Affect Alteplase Apoptotic Asses 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 Structure 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/antagonist 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

项目摘要

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.

概括在许多急性缺血状态下实施了微脉管系统的血栓栓塞性闭塞包括中风和心肌梗死，可能是“无流量”现象的部分原因。纤维蛋白水解系统和血液动力学冲洗被认为是去除闭塞的主要机制在所有血管床中微血管水平。这可能部分是由于我们发现并称为“血管性”的机制，内皮层状脂蛋白广泛包膜闭塞栓塞，将它们捕获在血管中管腔明显降低了血液动力学冲洗，并限制了进入血浆纤维蛋白水解酶的机会。诸如中风之类的条件，可能是诱因的早期阶段，因为它可以防止在大型封闭船或组织纤溶酶原激活剂给药或机械血栓切除术后。我们假设这一点从药理上预防或延迟血管含量的早期吞噬阶段，可以改善血栓栓塞冲洗，微血管流量和生存能力，导致更好的缺血后结果。我们旨在发现调节此涉及的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标。我们将使用创新的多学科阐明这些机制在内的方法，包括突变小鼠，药物操纵和高分辨率的闭塞微血管的浸润成像。此外，我们将在A中测试我们的候选药物瞬态缺血性中风的翻译模型。这些研究可能会提高我们对微血管遮挡和重新定性的机制，可以鉴定出新的靶标，以防止无中风和其他缺血状况中的回流现象。