Targeting Phosphatase Regulated Cleavage of HIF-1α in Ischemic Brain Injury (R01 / NINDS)
De novo gene expression regulated by the hypoxia inducible factor-1α (HIF-1α) plays a decisive role in determining whether neurons live or die after an ischemic insult. While the molecular mechanisms regulating the balance between HIF’s adaptive and pathological effects remain unsettled, evidence supports a role for changes in HIF-1α dependent post-translational modifications (PTMs). Utilizing a combination of in vitro and in vivo modeling, this project seeks to understand how physiologically responsive PTMs and site-specific cleavage of HIF-1α influences neuron survival in the post-ischemic brain.
Defining Neurotherapeutic Targets in Hypoxia-Induced CHOP-10 Signaling Networks (R00 / NINDS)
The endoplasmic reticulum plays a central role in the cellular response to ischemia. However, the mechanisms governing the balance between ER-dependent protective and damaging responses remain unsettled. We have shown that the bZIP factor CHOP-10, previously linked to ER stress, differentiation and apoptosis, is both BDNF-responsive and neuroprotective in certain contexts. These observations suggest that CHOP-10 plays a more complex role after injury than previously recognized. In addition to defining the network of ER-responsive sensor-effector loops involved in regulating neuron survival after ischemic insult, we are also investigating how BDNF-CHOP-10 coupling regulates the fate and development of cells in the central nervous system.
Showing 2 of 33 journal articles.
Matthews TA; Abel A; Demme C; Sherman T; Pan PW; Halterman MW; Parkkila S; Nehrke K. "Expression of the CHOP-inducible carbonic anhydrase CAVI-b is required for BDNF-mediated protection from hypoxia." Brain research.. 2014; 1543():28-37. Epub 2013 Nov 23.
Rininger A; Wayland A; Prifti V; Halterman MW. "Assessment of CA1 injury after global ischemia using supervised 2D analyses of nuclear pyknosis." Journal of neuroscience methods.. 2012; 207(2):181-8. Epub 2012 Apr 21.