Post-ischemic stress responses:
study the mechanisms of cell death following brain ischemia and
reperfusion, focusing on the causes and consequences of
reperfusion-induced inhibition of protein synthesis, or translation
arrest. This translation arrest is part of the
post-ischemic neuronal stress response. We have evaluated
classical ribosome biochemistry, intracellular stress responses and
most recently began investigating mRNA regulatory mechanisms, including
stress granules and HuR granules.The MICROSCOPY section below shows some of our microscopic work identifiying new structures in post-ischemic neurons related to post-ischemic stress responses.
Cell injury dynamics: We recently developed a nonlinear dynamical model of cell injury. The model clearly predicts that cell injury should display bifurcations to bistable phase planes under the proper parameter constraints. Bistability in turn provides completely new insights about the nature of any protective therapeutics which are intended to take an injured system that is on a pro-death trajectory and convert it to a prosurvival trajectory. See DeGracia, Huang & Huang (2012) for a complete discussion. The following animations show some output from the cell injury model. Click on the image to see the animations in a new window.
The lab is currently funded by the National Institute of Neurological Disorders and Stroke at the NIH.
Jan. 2014 - Bingren Hu and I were co-editors of a Special Issue of Translational Stroke Research on Protein Misfolding and Organelle Damage Following Brain Ischemia.
|CELL INJURY ANIMATIONS
|1. Example of a single phase plane. This image simply rotates on a single phase plane and shows a pro-survival trajectory from initial conditions (D0, S0) = (0, 0) to the survival attractors at (D*, S*) = (0, 1).
||2. This animation illustrates a monstable injury course, where there is only one fixed point (D*, S*) at each value of injury, I, across the injury course.
||3. This animation illustrates a bistable type A injury course, where there are two fixed points (D*, S*) through a subrange of I values across the injury course. Note the abrupt transition to cell death.
||4. A higher dimensional parameter space in I and cS. For cS < 1.5, the system is doubley bistable. For 1.5 <= cS <= 4, the system is type A bistable. At some value of cS > 4, the system reverts to monstable (not shown on graph). Note topology of the parameters space.
- Szymanski JJ, Wang H, Jamison JT, DeGracia DJ. HuR function and translational state analysis following global brain ischemia and reperfusion. Transl Stroke Res. 2013 Dec;4(6):589-603.(PubMed)
- Lewis MK, Jamison JT, Dunbar JC, DeGracia DJ. mRNA redistribution during permanent focal cerebral ischemia. Transl Stroke Res. 2013 Dec;4(6):604-17. (PubMed)
- DeGracia DJ. A program for solving brain ischemia. Brain Sci. 2013, 3(2), 460-503. Invited paper for Special Issue of Brain Sciences: "Neuroprotection against Ischemic Brain Injury." [Download].
- DeGracia DJ, Huang ZF, Huang S. A nonlinear dynamical theory of cell injury. J Cereb Blood Flow Metab. 2012 Jun;32(6):1000-13. [Download] [Download Supplemental Files]
- Szymanski JJ, Jamison JT, DeGracia DJ. Texture analysis of poly-adenylated mRNA staining following global brain ischemia and reperfusion. Comput Methods Programs Biomed. 2012 Jan;105(1):81-94. [Download]
- Jamison JT, Szymanski JJ, DeGracia DJ. Organelles do not colocalize with mRNA granules in post-ischemic neurons. Neuroscience. 2011 Dec 29;199:394-400. [Download]
- Jamison JT, Lewis MK, Kreipke CW, Rafols JA, DeGracia DJ. Polyadenylated mRNA staining reveals distinct neuronal phenotypes following endothelin 1, focal brain ischemia, and global brain ischemia/ reperfusion. Neurol Res. 2011 Mar;33(2):145-61. [Download]
- DeGracia DJ. Towards a dynamical network view of brain ischemia and reperfusion. 2010. A four part series published in the Journal of Experimental Stroke and Translational Medicine.
- Part I: Background and Preliminaries. [Download]
- Part II: A Post-ischemic State Space. [Download]
- Part III: Therapeutic Implications. [Download]
- Part IV: Additional Considerations. [Download]
- Commentary by Professor Konstantine Hossmann on the Bistable Model of Brain Ischemia. [Download]
- Reply by Dr. DeGracia in response to Dr. Hossmann's comments. [Download]
- DeGracia DJ. Ischemic damage and neuronal stress responses: Towards a systematic approach with implications for therapeutic treatments. In New Frontiers in Neurological Research. Wang DQ and Ying W (eds). Research Signpost,Kerala, India. 2008. pp 235-264. [Download]
- DeGracia DJ, Jamison JT, Szymanski JR, Marshall MK. Translation Arrest and Ribonomics In Post-ischemic Brain: Layers and Layers of Players. J Neurochem. 2008 Sep;106(6):2288-301. Epub 2008 Jul 8. [Download]
JT, Kayali F, Rudolph J, Marshall M, Kimball SR, DeGracia DJ.
Persistent redistribution of poly-adenylated mRNAs correlates with
translation arrest and cell death following global brain ischemia and
reperfusion. Neuroscience. 2008 Jun 23;154(2):504-20. [Download]
GG, Di Loreto MJ, Marshall M, Wang J, DeGracia DJ. Hippocampal cellular
stress responses after global brain ischemia and reperfusion. Antioxid
Redox Signal. 2007 Dec;9(12):2265-75. [Download]
DJ, Rudolph J, Roberts GG, Rafols JA, Wang J. Convergence of stress
granules and protein aggregates in hippocampal cornu ammonis 1 at later
reperfusion following global brain ischemia. Neuroscience. 2007 May
DJ & Hu BR. Irreversible translation arrest in the reperfused
brain. J Cereb Blood Flow Metab. 2007 May;27(5):875-93. [Download]
DJ, Rafols JA, Morley SJ, Kayali F. Immunohistochemical Mapping of
Total and Phosphorylated eIF4G In Rat Hippocampus Following Global
Brain Ischemia and Reperfusion. Neuroscience.
F, Montie HL, Rafols JA, DeGracia DJ. Prolonged Translation Arrest in
Reperfused Hippocampal CA1 Is Mediated By Stress Granules.
Neuroscience. 2005;134(4):1223-45. [Download]
HL, Haezebrouck AJ, Gutwald JC, DeGracia DJ. PERK Is Differentially
Activated In Peripheral Organs Following Cardiac Arrest and
Resuscitation. Resuscitation. 2005 Sep;66(3):379-89. [Download]
HL, Kayali F, Haezebrouck AJ, Rossi NF, DeGracia DJ. Renal Ischemia and
Reperfusion Activates the eIF2 alpha kinase PERK. Biochim Biophys Acta.
2005 Sep 25;1741(3):314-24. [Download]
- DeGracia DJ, Montie HL. Cerebral ischemia and the unfolded protein response. J Neurochem. 2004 Oct;91(1):1-8. [Download]
DJ. Acute and persistent protein synthesis inhibition following
cerebral reperfusion. J Neurosci Res. 2004 Sep 15;77(6):771-6. [Download]
R, Krause GS, Yoshida H, Mori K, DeGracia DJ. Dysfunction of the
Unfolded Protein Response During Global Brain Ischemia and Reperfusion.
J Cereb Blood Flow Metab. 2003;23:462-471. [Download]
DJ, Kumar R, Owen C, Krause GS, White BC. Molecular Pathways of Protein
Synthesis Inhibition During Brain Reperfusion: Implications For
Neuronal Survival or Death. J Cereb Blood Flow Metab. 2002
R, Azam S, Sullivan JM, Owen C, Cavener DR, Zhang P, Ron D, Harding HP,
Chen JJ, Han A, White BC, Krause GS, DeGracia DJ. Brain ischemia and
reperfusion activates the eukaryotic initiation factor 2a kinase,PERK.
J. Neurochem. 2001;77:1418-1421. [Download]
DJ, Adamczyk S, Folbe AJ, Konkoly LL, Pittman JE, Neumar RW, Sullivan
JM, Scheuner DL, Kaufman RJ, White BC, Krause GS. Eukaryotic
initiation factor 2a (eIF2a) kinase and phosphatase activity during
post-ischemic brain reperfusion. Experimental Neurology,
DJ, Sullivan JM, Neumar RW, Alousi SS, Hikade KR, Pittman JE, White BC,
Rafols JA, Krause GS. Effect of brain ischemia and
reperfusion on the localization of phosphorylated eukaryotic
initiation factor 2a. J Cerebral Blood Flow and Metabolism.
DJ, Neumar RW, White, BC, Krause GS. Global brain ischemia and
reperfusion: Modifications in eukaryotic initiation factors are
associated with inhibition of translation initiation. J
Neurochem. 1996;67:2005-2012. [Download]