Lipocalin-2 and Intracerebral Hemorrhage-induced Brain Injury

 描述(由申请人提供)：自发性脑出血(ICH)是一种常见且往往致命的中风亚型。如果患者在癫痫发作中幸存下来，脑实质内产生的血肿会触发一系列事件，导致二次侮辱和严重的神经功能障碍。脑铁超载在脑出血后继发性脑损伤中起重要作用。确定脑出血后脑损伤的机制是我们实验室的长期目标。脑出血后，血肿中的红细胞溶解，导致脑铁超载。Lipocalin 2(Lcn2)又称中性粒细胞明胶酶相关Lipocalin或24p3，是一种铁载体结合蛋白。Lcn2介导铁摄取。Lcn2在脑出血中的作用尚不清楚，但脑出血后脑内Lcn2表达上调可能影响铁的稳态。我们的初步研究表明：1)脑出血后Lcn2水平显著升高；2)脑出血后Lcn2阳性细胞大多为星形胶质细胞；3)铁可上调脑出血后Lcn2的表达；4)去铁胺可降低脑出血后Lcn2的表达；5)蛛网膜下腔出血可减少Lcn2基因敲除小鼠的脑白质损伤；6)脑内注射铁可减少Lcn2基因敲除小鼠的脑肿胀。这些发现表明，铁在脑出血后脑内Lcn2表达上调中起重要作用，并可能在处理脑出血后血肿释放的铁方面发挥作用。在这项应用中，我们建议测试以下特定目标：1)确定脑出血是否导致与野生型小鼠相比，Lipocalin 2基因敲除小鼠的脑水肿、血脑屏障破坏、神经元死亡和神经功能障碍减少；以及2)确定Lipocalin 2是否调节脑出血引起的脑铁超载。我们认为，这里提出的试点研究应该为NIH R01的应用奠定坚实的基础。我们研究的长期目标是限制脑出血后的脑损伤。

 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.