All ETDs from UAB

Advisory Committee Chair

Gail V W Johnson

Advisory Committee Members

Shannon M Bailey

Thomas L Clemens

Richard S Jope

Kevin A Roth

Document Type

Dissertation

Date of Award

2009

Degree Name by School

Doctor of Philosophy (PhD) Heersink School of Medicine

Abstract

Stroke is a leading cause of long term disabilities in the US. Currently, administration of thrombolytics is the only approved therapy. Due to the variability, small management time window, and lack of options for effective treatment, there is a clear need for new compounds to alleviate cell death post-stroke. Transglutaminase 2 (TG2) can decrease apoptotic signaling during stroke and lead to increased neuronal survival making it a potential target for therapeutic intervention. TG2, a multifunction enzyme that has both transamidase (TG) and GTPase activities, amongst others, has recently been shown to be upregulated in numerous neurodegenerative conditions, including stroke. In the central nervous system, TG2 is predominately found in neurons where it functions in neurite development and neuronal remodeling. Further, there is increasing evidence that TG2 plays a pivotal role influencing life and death decisions of the cell. In hypoxic environments, neurons adapt to decreases in oxygen by up-regulating genes controlled by the hypoxia inducible factor 1 (HIF1). This transcription factor is comprised of two subunits: HIF1α and HIF1β. Recent studies have provided evidence that increased HIF1α can result in increased neuronal cell death in response to hypoxia, in part due to upregulation of apoptotic genes. In this dissertation we analyzed the role of TG2 in neuronal ischemia in two main studies. iii In the first study, we show that TG2 protects primary cortical neurons from oxygen and glucose deprivation (OGD). We identified HIF1β as a novel TG2 binding partner and this binding leads to the attenuation of HIF controlled proapoptotic Bnip3 in response to OGD yet cell survival factor VEGF remained elevated to an equal level as controls. In the second study, we show that TG2 translocates to the nucleus in both human stroke samples and a mouse model of stroke. Using rat cortical cultures, we observed this translocation to take place immediately after OGD and TG2 remained in the nucleus up to 24 hours after oxygen and glucose were replenished. Furthermore, overexpression of human TG2 (hTG2) in mouse neurons of the CNS decreased infarct volumes after permanent middle cerebral artery (MCA) ligation.

Share

COinS