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Department of Pharmacology

Department of Pharmacology
 

Contact Information:

University of Colorado Denver
Department of Pharmacology
Mail Stop 8303, RC1-North
12800 East 19th Ave
Aurora CO 80045

Phone: (303) 724-3602
Fax: (303) 724-3663
E-mail: kim.heidenreich@ucdenver.edu
curriculum vitae

Affiliated Programs

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Molecular mechanisms of neuronal cell death

Neurons die as a normal physiological process during development and aging, or as a pathological process in chronic neurodegenerative diseases and acute insults to the brain like TBI and stroke.  Apoptosis, a type of programmed cell death, underlies neuronal death during development and contributes to the degeneration of specific populations of neurons in a variety of neurodegenerative disorders.  Recent studies have indicated that other forms of programmed cell death, i.e. autophagy, may contribute to neuronal death in chronic disease and after acute insults to the brain.  Understanding the molecular mechanisms that control the death of neurons is the first step to designing new drugs to slow or prevent neuronal cell loss in chronic and acute neurological disease.
 
Dr. Heidenreich’s laboratory uses 2 model systems to study neuronal cell death.  The in vitro model utilizes cultured neurons from newborn rat cerebellum.  These cultures consist of 95 % granule neurons (the most abundant neuron type in mammals), 3% Purkinje neurons, and a very small percentage of glial cells.  Granule neurons thrive in the presence of serum and the presence of depolarizing extracellular potassium. When this trophic support is removed, the granule neurons die by a classic intrinsic apoptotic cascade.  Purkinje neurons also die when trophic support is removed, but they die by different mechanism that involves enhanced autophagy.  Thus, the cerebellar cultures allow for the investigation of factors that regulate both intrinsic apoptosis and autophagic cell death.  The second model system utilized by the lab is an in vivo lateral fluid percussion model of experimental traumatic brain injury (TBI) in rats.  This model mimics many of the pathological features of human TBI and allows for the search of factors that may be useful in preventing the secondary phase of brain injury that follows TBI.
 
Dr. Heidenreich’s laboratory has identified a number of protein kinases that trigger or prevent neuronal apoptosis in response to neuronal insults and neurotrophic factors, respectively.  Ongoing research examines how these key proapoptotic and antiapoptotic protein kinases are regulated and identifies the cytoplasmic effectors and transcription factors downstream of these protein kinases.  Other aspects of her research focus on the regulation of critical mitochondrial proteins activated during intrinsic apoptosis and the role of the endoplasmic reticulum (ER) in mediating neuronal death.  More recent studies focus on the regulation of autophagy in neurons and its role in neuronal cell death. Using the knowledge gained from studying death signaling pathways in vitro, the laboratory hopes to find ways of preventing brain injury following TBI.
 

Current Lab Colleagues

 

Former Trainees 

 


View Dr. Heidenreich's Publications on PubMed​

Selected Publications:  

  1. Linseman, DA, ML McClure, RJ Bouchard, TA Laessig, D Brenner, and KA Heidenreich.  Suppression of death receptor signaling in cerebellar Purkinje  neurons protects neighboring granule neurons from apoptosis. J. Biol. Chem. 277: 24546-24553, 2002.
  2. Linseman, DA, RA Phelps, RJ Bouchard, TA Laessig, SS Le, and KA Heidenreich.  Insulin-like growth factor-I blocks Bim induction and intrinsic death signaling in cerebellar granule neurons.  J. Neuroscience 22: 9287-9297, 2002. 
  3. Linseman, DA, BJ Cornejo, SS Le, MK Meintzer, TA Laessig , RJ Bouchard, and KA Heidenreich.  A novel mechanism for lithium neuroprotection involving suppression of myocyte enhancer factor 2D hyperphosphorylation and degradation.  J.Neurochem. 85: 1488-1499, 2003.
  4. Heidenreich KA. Molecular Mechanisms of Neuronal Cell Death.  In Parkinson’s Disease, Annals of the New York Academy of Sciences, vol.991, 237-250, 2003.
  5. Linseman, DA, CM Bartley, SS Le, TA Laessig, RJ Bouchard, MK Meintzer, M Li, and KA Heidenreich.  Inactivation of the MEF2 repressor HDAC5 by endogenous CAMKII promotes depolarization-mediated neuronal survival. J. Biol. Chem. 278: 41472-41481, 2003.
  6. Ahmadi F, DA Linseman , TN Grammatopoulos, RJ Bouchard, SM Jones, CR Freed, KA Heidenreich, and WM Zawada.  The pesticide rotenone induces caspase-3 mediated apoptosis in ventral mesencephalic dopaminergic neurons.  J. Neurochem. 86: 914-921, 2003.
  7. Butts BD, DA Linseman, SS Le, TA Laessig, and KA Heidenreich.  Insulin-like growth factor-I suppresses degradation of the pro-survival transcription factor myocyte enhancer factor 2D (MEF2D) during neuronal apoptosis.  Horm. Metab. Res.35: 763-770, 2003.
  8. Heidenreich KA and DA Linseman.  Myocyte enhancer factor-2 (MEF2) transcription factors in neuronal differentiation and survival.  Mol. Neurobiol. 29: 155-166, 2004.
  9.  McClure ML, DA Linseman, CT Chu, RJ Bouchard, TA Laessig, SS Le, and KA Heidenreich.  Neurotrophins and death receptors regulate autophagic death in cerebellar Purkinje neurons.  J. Neuroscience 24: 4498-4509, 2004.
  10. Linseman, DA*, BD Butts*, TA Precht, RA Phelps, SS Le, TA Laessig, RJ Bouchard, ML McClure, and KA Heidenreich. Glycogen synthase kinase-3b phosphorylates Bax and promotes its mitochondrial localization during neuronal apoptosis. *co-first authors J. Neuroscience 24: 9993-10002, 2004.
  11. Precht, TA, RA Phelps, DA Linseman, BD Butts, RJ Bouchard, SS Le, TA Laessig, and KA Heidenreich.  Bax translocation to mitochondria is triggered by permeability transition pore opening in cerebellar granule neurons undergoing apoptosis. Cell Death and Differentiation 12: 255-265, 2005.
  12. Zimmermann, AK, FA Loucks, SS Le, BD Butts, M McClure, RJ Bouchard, KA Heidenreich, DA Linseman. Bcl-2 interacting mediator of cell death (Bim) induces cerebellar granule neuron apoptosis via a mechanism that is independent of Bcl-2 antagonism. J. Neurochem. 94: 22-36, 2005.
  13. Butts BD, HR Hudson, DA Linseman, SS Le, and KA Heidenreich.  Proteasome inhibition elicits a biphasic effect on neuronal apoptosis via differential regulation of pro-survival and pro-apoptotic transcription factors. Mol. Cell. Neurosci. 30: 279-289, 2005.
  14. Le, SS, FA Loucks, H Udo, S Richardson-Burns, RA Phelps, RJ Bouchard, H Barth, K Aktories, KL Tyler, ER Kandel, KA Heidenreich, and DA Linseman.  Inhibition of Rac GTPase triggers a c-jun -and Bim-dependent mitochondrial apoptotic cascade in cerebellar granule neurons.  J. Neurochem. 94: 1025-1039, 2005.
  15. Brewster JL, Linseman DA, Bouchard RJ, Loucks FA, Esche E, Precht T, and KA Heidenreich. Endoplasmic reticulum stress and trophic factor withdrawal activate distinct signaling cascades that converge at GSK-3b to trigger mitochondrial apoptosis in neurons.  Mol. Cell. Neurosci. 32:242-253, 2006.
  16. Klionsky, DJ et al. Guidelines for monitoring autophagy in higher eukaryotes. Autophagy 4 (2): 151-175, 2008.
  17.  Bains, Mona and KA Heidenreich. Live-cell imaging of autophagosome-lysosome fusion in primary neurons. Methods of Enzymology: Autophagy 253, ed D.L. Klionsky Invited chapter, 141-154, 2009
  18. Bains, M, ML Florez-McClure, and KA Heidenreich. IGF-I blocks autophagic cell death of Purkinje neurons by increasing the turnover of autophagic vesicles.  (in press).
  19. Farias, SE, LC Frey, RC Murphy, and KA Heidenreich. Blockade of leukotriene production reduces brain injury following experimental TBI.  J. Neurotrauma. (in press).

 

Traumatic Brain Injury: Research offers hope for effects of secondary brain injury

For just a moment, allow the science of today to become the reality of tomorrow.
 
A professional football player suits up for a Sunday night football game—donning pads, shoes, jersey and
of course, to protect himself from concussion, his helmet. Then, as part of his regular routine, he takes one single pill—a pill that could do more to protect his brain from long-term damage from concussion than the best-designed helmet ever could.
 
Consider another scenario. A young soldier in an armored vehicle travels along a dusty desert road in a war zone. Suddenly, an improvised explosive device (IED) explodes, flipping the vehicle. The blast sends him spinning into the air and crashing to the ground. Within minutes, a fellow soldier injects him with a drug that will protect his brain from the devastating effects of a traumatic brain injury (TBI).
 
These two scenarios may seem futuristic, but the research behind them is going on right now in the CU School of Medicine Pharmacology Department in the laboratory of Kim Heidenreich, PhD.  Continued...

 

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