Mechanisms Regulating Cerebral Arteriogenesis and Neurorestoration

调节脑动脉生成和神经恢复的机制

基本信息

批准号：
9316077
负责人：
Michelle Lee Theus
金额：
$ 5.05万
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：
2016
资助国家：
美国
起止时间：
2016-03-01 至 2021-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9316077
关键词：
ANGPT1 gene Acute Adoptive Transfer Area Behavior Behavioral Biological Preservation Blood Vessels Blood flow Brain Brain Injuries Cardiovascular system Cell Line Cell Proliferation Cell Survival Cells Cerebrovascular Circulation Cerebrum Chronic Clinical Research Cognitive deficits Communities Contusions Craniocerebral Trauma Development Dyes Endothelial Cells Eph Family Receptors EphA4 Receptor Ephrins Functional disorder Gene Targeting Goals Growth Health Hippocampus (Brain)Histologic Immune In Vitro Infusion procedures Injury Intervention Ischemia Knockout Mice Label Left Lesion Ligands Mechanics Mediating Medical Research Modeling Molecular Mus Neuronal Dysfunction Neurons Outcome Pathway interactions Perfusion Peripheral Play Prevention Process Production Proteins Quality of life Recombinants Recovery Recovery of Function Regulation Reporter Research Role Signal Transduction Solid Survivors Testing Therapeutic Tissues Transgenic Organisms Trauma Traumatic Brain Injury Vascular remodeling angiogenesis arteriole base brain research central nervous system injury cerebrovascular drug discovery effective therapy gain of function improved in vivo injured insight migration motor deficit nerve injury neuron loss neuroprotection neurorestoration neurovascular novel novel therapeutic intervention novel therapeutics protein expression relating to nervous system repaired research study response restoration tissue trauma tool treatment strategy

项目摘要

DESCRIPTION (provided by applicant): Promoting vascular remodeling has emerged as a potential therapeutic approach for neurorestorative therapy. Cerebral vascular trauma leads to inadequate cerebral blood flow which potentiates neuronal cell loss resulting in motor and cognitive deficits in models of brain injury. Endothelial cells (ECs) lining the blood vessels actively respond to tissue trauma. Our novel findings demonstrate, cell-to-cell contact proteins called Eph receptor tyrosine kinases (EphR), and their ephrin ligand(s), are present on cerebral arteriole ECs and play a central role in limiting arteriogenesis in the murine brain following injury. The research objectives in this application focus on the novel growth suppressive mechanism(s) of EphR signaling on arteriole remodeling and neural recovery. Endothelial-specific deletion of EphR resulted in significant neuroprotection and restoration of blood flow which reflects a monumental change in arteriogenic growth and production of pro-arteriogenic factors. We hypothesize that activation of EphR signaling mediates neural tissue damage and dysfunction by suppressing the EC response during arteriole vascular remodeling. To test this, we will employ novel cell-specific and inducible knockout mice, double reporter labeling and adoptive transfer. We will also investigate the relevance and mechanisms of injury-induced arteriogenesis in neural recovery using gain- and reverse-of-function infusion approaches. These studies will reveal a novel therapeutic strategy to enhance this important adaptive process which will greatly impact treatment and management of acute and chronic head injuries.

描述（由适用提供）：促进血管重塑已成为神经理化疗法的潜在治疗方法。脑血管创伤导致脑血流不足，这可能会导致神经元细胞损失，从而导致脑损伤模型的运动和认知缺陷。血管内衬的内皮细胞（EC）对组织创伤有积极反应。我们的新发现表明，称为EPH受体酪氨酸激酶（EPHR）的细胞对细胞接触蛋白和它们的ephrin配体在脑大动脉ECS上存在，并在受伤后的鼠大脑中限制动脉生成方面起着核心作用。该应用程序中的研究目标集中于动脉重塑和神经记录的EPHR信号的新型生长抑制机制。 EPHR的内皮特异性缺失导致了显着的神经保护和血流的恢复，这反映了动脉生长生长的巨大变化和促动脉粥样硬化因素的产生。我们假设EPHR信号传导的激活通过抑制动脉血管重塑过程中的EC反应来介导神经元组织损伤和功能障碍。为了测试这一点，我们将采用新颖的细胞特异性和诱导的敲除小鼠，双报告标签和自适应转移。我们还将使用增益和反向功能输注方法研究神经元恢复中损伤诱导的动脉生成的相关性和机制。这些研究将揭示一种新的治疗策略，以增强这种重要的适应性过程，从而极大地影响急性和慢性头部损伤的治疗和管理。