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（适用提供）：脑血管后遗症完成了创伤性脑损伤（TBI）的关键部分。在急性阶段，对血脑屏障（BBB）的损害导致脑水肿。在延迟阶段，微血管中持续的功能障碍会损害血管生成和神经发生。因此，随着时间的流逝，任何治疗TBI的尝试都必须考虑到这些不断发展的脑血管机制。我们的总体假设指出，（i）在急性期重组膜联蛋白A2结合了内皮细胞膜F-肌动蛋白，从而保留内皮完整性，从而防止TBI诱导的BBB破坏；（ii）在延迟阶段，膜联蛋白A2通过增强的血管生成促进重塑，并同时增加血管衍生的营养因子分泌，以促进内源性神经发生和神经膜。目标1：研究TBI后早期脑血管保护中膜联蛋白A2的机制。我们将测试BBB渗透性的临时轮廓，并与结型TBI模型和体外内皮/星形胶质细胞共培养物中的结蛋白表达以及脑水肿相关。变性的RA2或药理学抑制剂将用于测试RA2与F-肌动蛋白，F-肌动蛋白应力纤维形成和渗透率调制信号通路的特定作用。目标2：研究TBI后脑血管重塑中膜联蛋白A2的机制。我们将通过免疫组织化学测试血管生成的临时谱。原位纤溶酶活性评估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/抗血管生成和营养因子的表达谱图。 TBI后最多三个月检查长期神经功能。内皮培养物，我们将使用体外血管生成测定法测试RA2效应和机制。 AIM 3：研究膜联蛋白A2在促进血管衍生的营养因子表达方面的机制，以增强内源性神经发生和神经膜。 mRNA微阵列将检查神经元营养因子在分离的微血管碎片，免疫组织化学，RT-PCR和Western印迹中的表达，将研究Hippocampus神经元退化，不同大脑区域的神经发生，白质损伤以及TBI后时间随时间的修复。

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.