Lipocalin-2 and Intracerebral Hemorrhage-induced Brain Injury

 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。

 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.