All ETDs from UAB

Advisory Committee Chair

Peter H King

Advisory Committee Members

Scott R Barnum

Candace L Floyd

John J Shacka

Sunnie R Thompson

Document Type


Date of Award


Degree Name by School

Doctor of Philosophy (PhD) Heersink School of Medicine


Neuroinflammation is a defining event during the acute phase of spinal cord injury (SCI). The inflammatory cascade is initiated by activated glial cells such as astrocytes and microglia in the milieu of the injured tissue through release of pro-inflammatory cytokines, matrix metalloproteinases, and reactive oxygen species. These soluble factors produce cytotoxicity to neurons and other cells either directly or indirectly by promoting permeabilization of the blood-spinal cord barrier, edema and subsequent ischemia. These factors also serve to recruit and activate additional glia and peripheral immune cells. The mRNAs of many of these soluble factors such as TNFα, IL-1β, CXCL1, and MMP-12 share common regulatory sequences in the 3’-untranslated region called adenylate- and uridylate rich elements (ARE). AREs are targets for RNA-binding proteins (RBP) that modulate mRNA turnover and translational efficiency. HuR is a RBP that positively regulates ARE-containing mRNAs through binding to the ARE. The hypothesis of this thesis was that HuR enhances the inflammatory response by astrocytes in the setting of trauma through positive modulation of key inflammatory mediators. We used in vitro and in vivo models of CNS trauma to test this hypothesis. We found that HuR translocated from nucleus to cytoplasm in astrocytes in the setting of injury consistent with its activation. Targeting HuR with siRNA or chemically inhibiting it led to the suppression of key inflammatory mediators and attenuated astrocyte chemoattraction of neutrophils and microglia. Well established in the literature for its role in stabilizing mRNA, we were surprised to find that silencing HuR did not affect mRNA stability of the targets; rather there was inhibition of promoters driving cytokine transcription. In a mouse model, transgenic overexpression of HuR in astrocytes resulted in increased astrocyte activation across the epicenter of injury in the acute phase of a mid-thoracic contusion injury. Increased edema and neuronal death were also observed in the same time interval. However, no change in white matter damage was observed and is a likely explanation for why functional recovery was also not affected. In conclusion, the hypothesis proved true as HuR was found to be a positive regulator of key inflammatory mediators in astrocytes, and its overexpression accentuated toxicity in the acute setting of SCI. These findings highlight HuR as a potential therapeutic target for limiting secondary tissue damage in SCI.



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