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Lipocalin-2 and Intracerebral Hemorrhage-induced Brain Injury

Lipocalin-2 与脑出血引起的脑损伤

基本信息

批准号：
8997135
负责人：
YA HUA
金额：
$ 23.25万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
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：
2015-02-01 至 2019-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8997135
关键词：
Acute Affect Apoptosis Astrocytes Binding Binding Proteins Blood Blood - brain barrier anatomy Brain Brain Edema Brain Injuries Carrier Proteins Cell Death Cells Cerebral hemisphere hemorrhage Chelating Agents Clinical Data Coagulation Process Contralateral Cytolysis Data Deferoxamine Edema Erythrocytes Event Family Family suidae Ferritin Figs - dietary Goals Health Heart Hematoma Homeostasis Human Infusion procedures Injection of therapeutic agent Ipsilateral Iron Iron Overload Knock-out Knockout Mice LCN2 gene Laboratories Mediating Mediator of activation protein Names Neurologic Outcome Pathway interactions Patients Phase Pilot Projects Play Production Protein Export Pathway Proteins Rattus Role Secondary to Series Serum Siderophores Stroke Subarachnoid Hemorrhage Supportive care Testing Thrombin Time Tissues Toxic effect Transferrin United States National Institutes of Health Up-Regulation Wild Type Mouse X-Ray Computed Tomography aged base brain cell brain parenchyma brain tissue cerebral atrophy member neuron loss new therapeutic target uptake white matter injury

项目摘要

DESCRIPTION (provided by applicant): Spontaneous intracerebral hemorrhage (ICH) is a common and often fatal stroke subtype. If the patient survives the ictus, the resulting hematoma within the brain parenchyma triggers a series of events leading to secondary insults and severe neurological deficits. Brain iron overload plays an important role in the secondary brain injury following ICH. It is the long-term goal of our laboratory to identify the mechanisms involved in brain damage following ICH. After an ICH, lysis of erythrocytes in the hematoma results in brain iron overload. Lipocalin 2 (LCN2), also known as neutrophil gelatinase associated lipocalin or 24p3, is a siderophore-binding protein. LCN2 mediates iron uptake. The role of LCN2 in ICH is unclear, but LCN2 upregulation in the brain after ICH may affect iron homeostasis. Our preliminary studies showed: 1) brain LCN2 levels are markedly increased after ICH; 2) most LCN2 positive cells after ICH are astrocytes; 3) iron can upregulate brain LCN2; and 4) deferoxamine reduces ICH-induced LCN2 upregulation; 5) subarachnoid hemorrhage results in less white matter injury in LCN2 knockout mice; and 6) intracerebral injection of iron causes less brain swelling in LCN2 knockout mice. These findings suggest an important role of iron in brain LCN2 upregulation after ICH and potentially a role of LCN2 in handling iron that is released from the hematoma after ICH. In this application, we propose to test the following specific aims: 1) To determine whether or not ICH results in less brain edema, blood-brain barrier disruption, neuronal death and neurological deficits in lipocalin 2 knockout mice compared to wild type mice; and 2) To determine whether or not lipocalin 2 modulates intracerebral hemorrhage-induced brain iron overload. We believe that the pilot studies proposed here should form a strong basis for a NIH R01 application. The long-term goal of our studies is to limit brain damage following ICH.

描述（由申请人提供）：自发性脑内出血（ICH）是一种常见且往往致命的卒中亚型。如果患者在发作后存活，脑实质内产生的血肿会引发一系列事件，导致二次损伤和严重的神经功能缺损。脑铁超载在脑出血继发性脑损伤中起重要作用。我们实验室的长期目标是确定ICH后脑损伤的机制。在ICH后，血肿中的红细胞溶解导致脑铁超负荷。脂质运载蛋白2（LCN 2），也称为中性粒细胞明胶酶相关脂质运载蛋白或24 p3，是一种铁载体结合蛋白。LCN 2介导铁摄取。LCN 2在ICH中的作用尚不清楚，但ICH后脑中LCN 2的上调可能影响铁稳态。我们的初步研究表明：1）ICH后脑LCN 2水平显著增加; 2）ICH后大多数LCN 2阳性细胞是星形胶质细胞; 3）铁可以上调脑LCN 2;和4）去铁胺减少ICH诱导的LCN 2上调; 5）蛛网膜下腔出血导致LCN 2敲除小鼠中较少的白色损伤;和6）脑内注射铁导致LCN 2敲除小鼠中较少的脑肿胀。这些发现表明铁在脑出血后脑LCN 2上调中的重要作用，以及LCN 2在处理脑出血后血肿释放的铁中的潜在作用。在本申请中，我们提出测试以下具体目的：1）确定与野生型小鼠相比，在脂质运载蛋白2敲除小鼠中ICH是否导致较少的脑水肿、血脑屏障破坏、神经元死亡和神经功能缺损;以及2）确定脂质运载蛋白2是否调节脑内脑水肿诱导的脑铁过载。我们认为，这里提出的试点研究应该为NIH R 01的应用奠定坚实的基础。我们研究的长期目标是限制ICH后的脑损伤。