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：
9986277
负责人：
XIAOYING WANG
金额：
$ 12.92万
依托单位：
TULANE UNIVERSITY OF LOUISIANA
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：
2019-08-02 至 2021-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9986277
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 Assay Cellular biology Cerebral Edema Cerebrum Clinical Coculture Techniques Conditioned Culture Media Data Dextrans Endothelial Cells Endothelium Expression Profiling 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 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 preservation 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（申请人提供）：脑血管后遗症是创伤性脑损伤（TBI）的一个重要组成部分。在急性期，血脑屏障（BBB）受损会导致脑水肿，在迟发期会导致持续性功能障碍。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。重组膜联蛋白 A2 结合内皮细胞膜 F-肌动蛋白，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，增强血管生成，同时增加血管源性营养因子的分泌目的 1：研究膜联蛋白 A2 在 TBI 后早期脑血管保护中的机制。将测试 BBB 通透性的时间分布并与连接蛋白表达相关，并且将应用体内 TBI 模型和体外内皮/星形胶质细胞共培养物中的脑水肿来测试 rA2 在与 F- 结合中的特定作用。肌动蛋白、F-肌动蛋白应力纤维形成和通透性调节信号通路目标 2：研究膜联蛋白 A2 在 TBI 后脑血管重塑中的机制。将通过免疫组织化学测试血管生成的时间特征；将检查血管纤溶活性；mRNA微阵列将检查分离的脑微血管片段中血管内皮衍生的血管生成/抗血管生成和营养因子的表达特征。将在 TBI 后长达三个月的时间内进行检查。在内皮培养中，我们将通过体外血管生成测试 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的机制，mRNA 微阵列将检查分离的微血管片段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。 TBI 后随着时间的推移，神经元变性、不同大脑区域的神经发生以及白质损伤和修复。

项目成果

期刊论文数量（4）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Recombinant Annexin A2 Administration Improves Neurological Outcomes After Traumatic Brain Injury in Mice.

DOI：
10.3389/fphar.2021.708469
发表时间：
2021
期刊：
Frontiers in pharmacology
影响因子：
5.6
作者：
Cheng C;Wang X;Jiang Y;Li Y;Liao Z;Li W;Yu Z;Whalen MJ;Lok J;Dumont AS;Liu N;Wang X
通讯作者：
Wang X

Recombinant annexin A2 inhibits peripheral leukocyte activation and brain infiltration after traumatic brain injury.