Show simple item record

dc.contributor.advisorShi, Honglian
dc.contributor.authorAlmutairi, Mohammed
dc.date.accessioned2021-04-25T20:15:20Z
dc.date.available2021-04-25T20:15:20Z
dc.date.issued2020-08-20
dc.date.submitted2020
dc.identifier.otherhttp://dissertations.umi.com/ku:17397
dc.identifier.urihttp://hdl.handle.net/1808/31612
dc.description.abstractIschemic stroke is one of the leading causes of death and disability in the US and worldwide. There has been very limited progress in developing effective therapeutic approaches for ischemic stroke, although numerous agents have been tested in animal models and in clinical trials. Among many issues, an incomplete understanding of the mechanism responsible for ischemia-induced neuronal injuries is a major limitation. Although iron plays important roles in mammalian metabolism and is essential for life, labile iron is highly toxic in the body. It has been clearly demonstrated that ischemia elevates labile iron levels in the brain. This elevation is a major damaging event in ischemic neurons and plays an important role in the evolution of a penumbra to infarct and subsequent worsening of the outcome after stroke. Additionally, post-ischemic reperfusion could cause a biochemical deterioration of ischemic brain tissue. It has been found that many vulnerable neurons undergo apoptosis during reperfusion. Research in the last 10 years has established that hepcidin is the central regulator of systemic iron homeostasis. It regulates the iron export function of the ferrous iron permease, ferroportin (FPN1), which is the only known iron exporter expressed by mammalian cells. Recently, we and others have revealed that hepcidin is widely expressed in rodent brains and that ischemia increases hepcidin levels in brain cells. This induction of hepcidin expression was associated with accumulation of intracellular labile iron. Furthermore, our data demonstrate that interfering with hepcidin binding to FPN1 did not rescue cells from cellular death following ischemia, so we postulate that targeting hepcidin directly could be an effective approach to protect against ischemia-induced neuronal death. Hypoxia-inducible factor 1 (HIF-1) is a master regulator in hypoxia. HIF-1 mediates angiogenesis, cell proliferation, and energy metabolism. Furthermore, upregulating HIF-1α, the regulatable subunit of HIF-1, provides neuroprotection in ischemic stroke. Heat shock protein 90 (HSP90), a molecular chaperone that protects its client proteins from misfolding and degradation, binds with HIF-1α PAS domain and promotes the stabilization of HIF-1α. Recent reports show that reactive oxygen species (ROS) induce HSP90 cleavage and loss of its chaperoning function. Interestingly, our data demonstrate that down-regulation of hepcidin with shRNA approach reduced OGD/R-induced ROS and improved mitochondrial function. To understand the role of hepcidin in ischemia-induced neuronal death, we studied the effect of downregulation of hepcidin on HIF-1α and its major regulator, HSP90. We demonstrate that downregulation of hepcidin induced both HSP90 and HIF-1α expression, which subsequently protected neuronal cells from oxygen glucose deprivation/reperfusion (OGD/R) injury. Collectively, these findings suggest that hepcidin is a promising therapeutic target against ischemia/reperfusion injury.
dc.format.extent119 pages
dc.language.isoen
dc.publisherUniversity of Kansas
dc.rightsCopyright held by the author.
dc.subjectPharmacology
dc.titleNeuroprotective Effect of Targeting Hepcidin against Ischemia-Induced Neuronal Damage
dc.typeDissertation
dc.contributor.cmtememberMoskovitz, Jackob
dc.contributor.cmtememberSmith, Adam
dc.contributor.cmtememberSubramanian, Jai
dc.contributor.cmtememberSiahaan, Teruna
dc.thesis.degreeDisciplinePharmacology & Toxicology
dc.thesis.degreeLevelPh.D.
dc.rights.accessrightsembargoedAccess


Files in this item

Thumbnail

This item appears in the following Collection(s)

Show simple item record