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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：
10642764
负责人：
Michelle Lee Theus
金额：
$ 34.86万
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/10642764
关键词：
Acute American Area Behavioral Binding Blood Vessels Blood flow Bone Marrow Brain Bypass Cardiovascular system Cell Line Cells Cerebrovascular Circulation Cerebrovascular Disorders Cerebrum Clinical Research Collateral Circulation Communities Coronary heart disease Development Dyes Endothelial Cells Endothelium 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 Leptomeninges Ligands Mediating Medical Membrane Middle Cerebral Artery Occlusion Molecular Morbidity - disease rate Mus Neuronal Dysfunction Neurons Obstruction Osmosis Outcome Paint Pathway interactions Patients Peptides Pericytes Peripheral 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 brain research cerebrovascular drug discovery experimental study immunoregulation improved in vivo inhibitor insight ischemic injury loss of function mortality motor deficit nerve injury neural neuron loss neuroprotection neurorestoration neurovascular new therapeutic target novel novel strategies novel therapeutics patient response pharmacologic post stroke pre-clinical prevent protein expression 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.

摘要软脑膜侧支循环和重塑最近已成为一个强大的治疗目标，中风后的神经恢复治疗脑血管闭塞阻止了足够的血液流向神经组织区域导致神经元细胞损失和严重的感觉运动缺陷。发生逆行再灌注在再通之前或之后，具有足够侧支反应的患者，脑血流量（CBF）和辅助半影组织保护。然而，细胞和分子侧支小生境中这种不同患者反应的潜在机制仍不清楚。证据表明侧支血管壁的内皮细胞（EC）对血流变化有积极反应，并帮助协调侧支重塑过程。我们新的临床前发现 Eph受体酪氨酸激酶（EphR）是一种细胞间接触蛋白，结合的肝配蛋白配体存在于脑侧支EC上，并在限制其反应中发挥重要作用中风后小鼠大脑中的变化。在本申请中概述的研究目标集中在新的增长 EphR信号传导对侧支重塑和神经功能恢复的抑制机制。EC- EphR的特异性缺失导致显著的神经保护和CBF的恢复，这反映了侧支生长和促动脉生成因子产生的巨大变化。我们假设 EphR信号传导的激活通过抑制EC介导急性神经组织损伤和功能障碍中风后侧支重塑的反应。为了验证这一点，我们将采用细胞特异性诱导敲除和骨髓嵌合小鼠。我们还将研究损伤诱导的使用功能丧失和逆转的微渗透输注方法在神经恢复中的侧支重塑。这些研究将揭示一种抑制中风侧支反应的新机制，为靶向该途径治疗和管理缺血性卒中提供治疗支持。