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Annexin A2 as a cerebrovascular therapy in traumatic brain injury

膜联蛋白 A2 作为创伤性脑损伤的脑血管疗法

基本信息

批准号：
9231513
负责人：
XIAOYING WANG
金额：
$ 37.54万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-03-15 至 2020-02-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9231513
关键词：
Acute Amplifiers Angiogenic Factor Annexins Area Astrocytes Binding Biological Assay Blood - brain barrier anatomy Blood Vessels Brain Brain Edema Brain Injuries Cell Differentiation process Cell Membrane Permeability Cell Membrane Proteins Cell Proliferation Cell membrane Cell secretion Cellular biology Cerebral Edema Cerebrum Clinical Coculture Techniques Conditioned Culture Media Data Dextrans Endothelial Cells F-Actin Functional disorder Hippocampus (Brain)Hour Hypoxia Immunohistochemistry Impairment In Situ In Vitro Injury Interleukin-1 beta Learning Memory Messenger RNA Modeling Molecular Biology Molecular Profiling Mus Nerve Degeneration Nervous System Physiology Neurons Oligodendroglia Outcome Patients Peptides Permeability Pharmacology Phase Physiology Plasmin Play Principal Investigator Process Recombinants Recovery Recovery of Function Regulation Reverse Transcriptase Polymerase Chain Reaction Role Sensorimotor functions Signal Pathway Signal Transduction Stress Fibers Surface Testing Therapeutic Agents Tight Junctions Time Traumatic Brain Injury Tube Vascular Endothelium Vascular remodeling Western Blotting angiogenesis cerebrovascular enhancing factor experimental study improved in vivo in vivo Model inhibitor/antagonist injury and repair insight migration morris water maze neuroblast neurogenesis neurovascular novel pleiotropism programs protein expression public health relevance targeted treatment therapeutic candidate therapeutic target therapy development tool white matter injury

项目摘要

DESCRIPTION (provided by applicant): Cerebrovascular sequelae comprise a critical part of traumatic brain injury (TBI). In the acute phase, damage to the blood-brain barrier (BBB) leads to cerebral edema. In the delayed phase, persisting dysfunction in microvessels impair angiogenesis and neurogenesis. Hence, any attempt to treat TBI must take into account these evolving cerebrovascular mechanisms over time. Our overall hypothesis states that (i) in the acute phase, recombinant annexin A2 binds endothelial cell membrane F-actin that preserves endothelial integrity thus protecting against TBI-induced BBB disruption; and (ii) in the delayed phase, annexin A2 promotes remodeling with enhanced angiogenesis, and concurrently increases vascular-derived trophic factor secretion for promoting endogenous neurogenesis and neurorepair. Aim 1: Investigate mechanisms of annexin A2 in early cerebrovascular protection after TBI. We will test temporal profile of BBB permeability and correlate with junction protein expression, and brain edema in vivo TBI model and in vitro endothelial/astrocytes co-cultures. Denatured rA2 or pharmacological inhibitors will be applied to test specific roles of rA2 in binding to F-actin, F-actin stress fiber formation, and permeability modulated signaling pathways. Aim 2: Investigate mechanisms of annexin A2 in cerebrovascular remodeling after TBI. We will test temporal profile of angiogenesis by immunohistochemistry. In situ plasmin activity assay will examine vascular fibrinolytic activity; mRNA microarrays will examine expression profiles of vascular endothelium derived angiogenic/anti-angiogenic, and trophic factors in isolated cerebral microvascular fragments. Long-term neurological function will be examined for up to three months post-TBI. In endothelial cultures, we will test rA2 effects and mechanisms in angiogenesis with in vitro angiogenic assays. Aim 3: Investigate mechanisms of annexin A2 in promoting vascular-derived trophic factor expression for enhancing endogenous neurogenesis and neurorepair. mRNA microarray will examine expression of neuronal trophic factors in isolated microvascular fragments, immunohistochemistry, RT-PCR and western blots will investigate hippocampus neuron degeneration, neurogenesis in different brain areas, and white matter injury and repair over time after TBI.

描述（由申请人提供）：脑血管后遗症是创伤性脑损伤（TBI）的一个关键部分。在急性期，血脑屏障（BBB）受损会导致脑水肿。在延迟期，微血管的持续功能障碍会损害血管生成和神经发生。因此，任何治疗 TBI 的尝试都必须考虑到这些随时间演变的脑血管机制。我们的总体假设是：(i) 在急性期，重组膜联蛋白 A2 结合内皮细胞膜 F-肌动蛋白，从而保持内皮完整性，从而防止 TBI 诱导的 BBB 破坏； (ii) 在延迟期，膜联蛋白 A2 促进重塑并增强血管生成，同时增加血管源性营养因子的分泌，从而促进内源性神经发生和神经修复。目的1：探讨膜联蛋白A2在TBI后早期脑血管保护中的作用机制。我们将在体内 TBI 模型和体外内皮/星形胶质细胞共培养物中测试 BBB 通透性的时间分布，并与连接蛋白表达和脑水肿相关。变性的 rA2 或药物抑制剂将用于测试 rA2 在与 F-肌动蛋白结合、F-肌动蛋白应力纤维形成和通透性调节信号通路中的特定作用。目标 2：研究膜联蛋白 A2 在 TBI 后脑血管重塑中的机制。我们将通过免疫组织化学测试血管生成的时间曲线。原位纤溶酶活性测定将检查血管纤溶活性； mRNA 微阵列将检查血管内皮衍生的血管生成/抗血管生成以及分离的脑微血管片段中的营养因子的表达谱。 TBI 后三个月内将进行长期神经功能检查。在内皮培养中，我们将通过体外血管生成测定来测试 rA2 在血管生成中的作用和机制。目标 3：研究膜联蛋白 A2 促进血管源性营养因子表达以增强内源性神经发生和神经修复的机制。 mRNA 微阵列将检查分离的微血管碎片中神经元营养因子的表达，免疫组织化学、RT-PCR 和蛋白质印迹将研究海马神经元变性、不同大脑区域的神经发生以及 TBI 后随时间的白质损伤和修复。