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.
After a cerebral hemorrhage, lysis of the clot causes a buildup of iron in the brain. Brain iron accumulation can cause brain cell death and neurological deficits. Lipocalin-2 is a mediator of a transferrin-independent pathway for cellular iron delivery and may affect brain iron homeostasis following cerebral hemorrhage. The purpose of this project is to investigate the role of lipocalin-2 in brain iron overload and brain injury after cerebral hemorrhage. The long-term goal of our studies is to limit brain damage following cerebral hemorrhage.
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