Novel Cellular and Molecular Regulation of Collateral Remodeling in Ischemic Stroke

缺血性中风侧枝重塑的新型细胞和分子调节

基本信息

批准号：
10452552
负责人：
Michelle Lee Theus
金额：
$ 34.87万
依托单位：
VIRGINIA POLYTECHNIC INST AND ST UNIV
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：
2019-07-01 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10452552
关键词：
Acute American Area Behavioral Blood Vessels Blood flow Bone Marrow Brain Cardiovascular system Cells Cerebrovascular Circulation Cerebrovascular Disorders Cerebrum Clinical Research Collateral Circulation Communities Coronary heart disease Development Dyes Endothelial Cells Eph Family Receptors EphA4 Receptor Ephrins Functional disorder Gene Targeting Goals Growth Histologic Immune In Vitro Infarction Infusion procedures Injury Intervention Ischemia Ischemic Stroke Knock-out Knockout Mice Label Ligands Mediating Medical Membrane Middle Cerebral Artery Occlusion Molecular Morbidity - disease rate Mus Neuronal Dysfunction Neurons Obstruction Outcome Pathway interactions Patients Peptides Pericytes Peripheral Pharmacology Play Prevention strategy Process Production Proteins Receptor Signaling Recovery Recovery of Function Regulation Reperfusion Therapy Research Role Signal Transduction Solid Stroke TIE-2 Receptor Testing Therapeutic Therapeutic Intervention Tissues angiogenesis arteriole base brain research cerebrovascular drug discovery experimental study immunoregulation improved in vivo inhibitor insight ischemic injury loss of function mortality motor deficit nerve injury neuron loss neuroprotection neurorestoration neurovascular new therapeutic target novel novel strategies novel therapeutics patient response post stroke pre-clinical prevent protein expression relating to nervous system repaired response restoration stroke recovery stroke therapy therapeutic target tool treatment strategy

项目摘要

ABSTRACT Leptomeningeal collateral circulation and remodeling has recently emerged as a powerful therapeutic target for neurorestorative therapy following stroke. Cerebral vascular occlusion prevents adequate blood flow to neural tissue regions resulting in neuronal cell loss and severe sensorimotor deficits. Retrograde reperfusion occurring in patients with a sufficient collateral response, either prior to or following recanalization, can help stabilize cerebral blood flow (CBF) and aide in penumbral tissue protection. However, the cellular and molecular mechanism(s) underlying this differential patient response in the collateral niche remains unclear. Evidence suggests that endothelial cells (ECs) lining the collateral vessel wall actively respond to changes in blood flow following obstruction and help orchestrate the collateral remodeling process. Our novel pre-clinical findings demonstrate, cell-to-cell contact proteins called Eph receptor tyrosine kinases (EphR), and their membrane bound ephrin ligand(s), are present on cerebral collateral ECs and play a central role in limiting their response in the murine brain following stroke. The research objectives outlined in this application focus on the novel growth suppressive mechanism(s) of EphR signaling on collateral remodeling and neural functional recovery. EC- specific deletion of EphR results in significant neuroprotection and restoration of CBF which reflects a monumental change in collateral growth and production of pro-arteriogenic factors. We hypothesize that activation of EphR signaling mediates acute neural tissue damage and dysfunction by suppressing the EC response during collateral remodeling after stroke. To test this, we will employ cell-specific inducible knockout and bone marrow chimeric mice. We will also investigate the relevance and mechanism(s) of injury-induced collateral remodeling in neural recovery using loss- and reverse-of-function mini-osmotic infusion approaches. These studies will reveal a novel mechanism suppressing the collateral response to stroke and provide therapeutic support for targeting this pathway for the treatment and management of ischemic stroke.

抽象的瘦脑附带循环和重塑最近已成为强大的治疗靶点中风后神经训练疗法。脑血管闭塞可预防足够的血液流向神经组织区域导致神经元细胞丧失和严重的感觉运动缺陷。发生逆行再灌注在具有足够抵押反应的患者中，无论是在重新开放之前还是在重新加续后，都可以帮助稳定脑血流（CBF）和半身组织保护中的助手。但是，细胞和分子在附带利基市场中这种差异患者反应的基础机制尚不清楚。证据表明内皮细胞（ECS）内衬侧支容器壁会积极应对血流的变化障碍物并帮助策划侧支重塑过程。我们的新颖临床前发现证明，称为EPH受体酪氨酸激酶（EPHR）的细胞间接触蛋白及其膜绑定的埃弗林配体（S）存在于脑侧支EC上，并在限制其反应中起着核心作用中风后的鼠大脑。该应用程序中概述的研究目标集中于新颖的增长 EPHR信号的抑制机制在侧支重塑和神经功能恢复中。 ec- EPHR的特定缺失会导致CBF的显着神经保护和恢复，这反映了A 附带生长的巨大变化和促动脉粥样因素的产生。我们假设这一点 EPHR信号的激活通过抑制EC介导急性神经组织损伤和功能障碍中风后抵押重塑期间的响应。为了测试这一点，我们将采用特定细胞的诱导型敲除和骨髓嵌合小鼠。我们还将研究伤害诱导的相关性和机制使用功能损失和功能反向的微型渗透输注方法进行神经恢复中的侧支重塑。这些研究将揭示一种新的机制，以抑制对中风的附带反应并提供用于针对这种途径的治疗和管理缺血性中风的治疗支持。