Mechanisms of persistent translation arrest following global brain ischemia and reperfusion

<p>ABSTRACT</p> <p>MECHANISMS OF PERSISTENT TRANSLATION ARREST FOLLOWING GLOBAL BRAIN ISCHEMIA and REPERFUSION</p> <p>by</p> <p>JILL T. JAMISON</p> <p>December 2011</p> <p>Advisor: Donald J. DeGracia, Ph.D.</p> <p>Major: Physiology</p> <p>Degree: Doctor of Philosophy</p> <p>The information presented here studies the mechanisms that underlie persistent translation arrest (TA) following global brain ischemia and reperfusion (I/R). To summarize the main findings I have discovered a new mechanism for prolonged post-ischemic TA that correlated exactly with <i>in vivo</i> translation rates and correlated precisely with cell outcome. Through the extensive colocalization studies, my results indicate that the mRNA granules are ribonomic structures involved with mRNA regulation. This finding is significant because it shifts the focus onto mRNA metabolism and away from ribosomal molecular biology. I have identified new pathways to investigate for understanding why there is selective delayed death in post-ischemic neurons, however my work also gives insight into why resistant neurons survive. The results were tested in a whole animal (male Long Evans rats) model of global brain I/R using <i>in situ</i> antibodies and mRNA staining methods, <i>in viv0</i> protein synthesis and Western blots. Results are collectively summarized below:</p> <p>1. Cytoplasmic poly(A) containing mRNAs redistributed to form mRNA granules in reperfused neurons.</p> <p>2. mRNA granules sequester mRNA away from both the small and large ribosomal subunits, providing a novel mechanism of prolonged TA in post-ischemic neurons.</p> <p>3. mRNA granules are ribonomic structures.</p> <p>4. mRNA granules, are neither stress granules, processing bodies, or polysomes.</p> <p>5. mRNA granules were found to only colocalize with eIF4G, PABP and HuR, suggesting that mRNA granules may itself be related to or a subset of the ELAV/Hu granule.</p> <p>6. HuR co-localized to mRNA granules and translation of HSP-70. This correlation suggests mRNA granules are involved in post-transcriptional stress gene regulation in reperfused neurons.</p> <p>7. mRNA granules are causally linked to TA.</p>

Name thesis:degree_name

Ph.D.

Level thesis:degree_level

Open Access Dissertation

Discipline thesis:degree_discipline

Physiology

Year dc:date.available

2011

Author dc:creator

• Jamison, Jill Theresa

Contributors dc:contributor

• Donald J. DeGracia

• Delayed Neuronal Death, Ischemia and Reperfusion, mRNA granules, Ribonomics, Stress Response, Translation Arrest
• Neurosciences
• Physiology

Repository record dc:identifier

https://digitalcommons.wayne.edu/oa_dissertations/414

OAI identifier oai:identifier

oai:digitalcommons.wayne.edu:oa_dissertations-1413