Michelle Aarts

Canada Research Chair in Signal Transduction in Ischemia
Assistant Professor, Biological Sciences
Office: (416) 287-7405
Lab: (416) 287-7407
Fax: (416) 287-7676
e-mail: maarts@utsc.utoronto.ca



Research Focus

Signal Transduction from Calcium Channels in Regulating Cell Survival

Dr. Aarts' research interests lie in the cellular communication pathways that influence cell death and survival in complex tissues following periods of ischemic stress. Ischemic injury occurs when a block in blood flow significantly impairs the delivery of oxygen and nutrients to a tissue. Of particular interest are signal transduction pathways downstream of plasma membrane calcium channels that are involved in cell death following stroke and cardiac arrest. At the molecular level our targets include glutamate receptors, transient receptor potential (TRP) channels and intracellular kinases. The laboratory research uses a multidisciplinary approach from molecular biology and proteomics to cellular and animal models of disease in order to gain information about key cell death pathways.

Transient Receptor Potential Channels

This is an exciting new class of cation channels containing 26 identified members in six subfamilies. All members share key features including intracellular N- and C-terminal tails, six membrane spanning domains and a cation selective ion channel pore. Individual channels are thought to be comprised of four subunits based on homology to voltage gated potassium channels. Current specific projects include investigating the biochemical properties and intracellular interactions of the Transient Receptor Potential M-class (TRPM) channels. There are eight identified TRPM subunit proteins that possess very long, homologous intracellular tails. Three TRPM members also contain enzymatic domains making them unique among all channels. Two members, TRPM2 and TRPM7 have been implicated in regulating cell death in ischemic studies, however little is known about the biochemistry, function or physiology of any of the TRPM proteins. Our current work is focused on:

  • Discerning how TRPM subunits interact and form functional channels
  • Expression patterns of TRPM subunits in cells and tissues
  • Levels transcriptional and post-translational modification of channels proteins
  • Identifying intracellular interactions and signal complexes of TRPM channels

This research will provide essential tools for cation channel research and physiologic studies of TRPM channels in normal cellular communication and disease.

Glutamate Receptors

Glutamate receptor cation channels, and in particular NMDA receptors (NMDAR), have long been implicated in the excitotoxic cell death involved in CNS ischemia, epilepsy, and a host of neurodegenerative diseases. However, glutamate is also the major excitatory neurotransmitter in the brain responsible for such complex functions as learning and memory and blockade of glutamate receptors causes severe side effects. NMDAR activation produces a variety of intracellular signals and recent evidence suggests that changing the balance of these signals can regulate cell death or survival. NMDAR signals can be grouped by their association with upstream effectors including PSD-95 (excitotoxic), CaM (neuroprotective and excitotoxic) and Ras (neuroprotective). Currently we are investigating the role that each group of signal events plays in NMDAR communication and how shifting these pathways can influence neuronal death or survival. By gaining a full understanding of how glutamate receptors and PSD95-family scaffold proteins signal in normal and pathologic conditions we can design more effective neuroprotective drugs and combination therapies that will further the treatment of ischemic injury and other diseases related to excitotoxicity.

Cyclin Dependent Kinase 5

Glutamate receptor cation channels, and in particular NMDA receptors (NMDAR), have long been implicated in the excitotoxic cell death involved in CNS ischemia, epilepsy, and a host of neurodegenerative diseases. However, glutamate is also the major excitatory neurotransmitter in the brain responsible for such complex functions as learning and memory and blockade of glutamate receptors causes severe side effects. NMDAR activation produces a variety of intracellular signals and recent evidence suggests that changing the balance of these signals can regulate cell death or survival. NMDAR signals can be grouped by their association with upstream effectors including PSD-95 (excitotoxic), CaM (neuroprotective and excitotoxic) and Ras (neuroprotective). Currently we are investigating the role that each group of signal events plays in NMDAR communication and how shifting these pathways can influence neuronal death or survival. By gaining a full understanding of how glutamate receptors and PSD95-family scaffold proteins signal in normal and pathologic conditions we can design more effective neuroprotective drugs and combination therapies that will further the treatment of ischemic injury and other diseases related to excitotoxicity.

This work is currently funded by the Canadian Stroke Network.



Research Opportunities

Postdoctoral Fellow or Research Associate

January 2009 - Full funding (up to 3 years) is available for a Postdoctoral Fellow or Junior Research Associate to investigate molecular interactions of TRP channel subunits in excitable cells. Candidates should be Canadian Citizens or permanent residents and have a strong background in Molecular biology, Cell culture, Biochemical and/or animal surgical techniques. Advanced microscopy or electrophysiology training is a strong asset. Candidates should have a proven ability for independent research and strong teamwork skills. Forward C.V. and referee contact information to Dr. Michelle Aarts, maarts@utsc.utoronto.ca.

 


Research Group

 
  • Danny Chan (M.Sc. Candidate)
  • Luka Srejic (Ph.D. Candidate)
  • Melanie Ratnam (Ph.D. Candidate)
  • Kevin Sam (M.Sc. Candidate)
  • Colin Seepersad (Undergraduate assistant) (M.Sc. Candidate)
  • Waed Mallah (Undergraduate assistant)
  • Marc-Mir Patel (Technician)




Recent Publications

  • Soriano F., Martel M-A., Papadia S., Vaslin A., Baxter P., Rickman C., Forder J.P., Tymianski M., Duncan R., Aarts M.M., Clarke P., Wyllie D.J. and Hardingham G.E. (2008) Specific targeting of pro-death NMDA receptor signals with differing reliance on the NR2B PDZ ligand. J. Neuroscience 28(42):10696-710.

  • Cornell R., Bautista D., Garcia-Anoveros J., Kiselyov K., Aarts M., and Liman E. (2008) ¡°A double TRPtych: six views of transient receptor potential channels in disease and health.¡± J. Neuroscience 28(46):11778-84.

  • Sun H-S., Doucette T.A., Liu Y., Fang Y., Ryan C.L., Bernard P.B., Forder J.P., Teves L., Aarts M.M., Salter M.W., Wang Y-T., Tasker R.A., Tymianski M.. (2008) Effectiveness of PSD95 inhibitors in permanent and transient focal ischemia in the rat. Stroke 39(9):2544-53.

  • Liu Y., Wong T.P., Aarts M.M., Liu L., Wu D.C., Lu J., Tymianski M., Wang Y-T. (2007) NMDA receptor subunits have differential roles in mediating excitotoxic neuronal death both in vitro and in vivo. J.Neuroscience. 27(11):2846-2857

  • Aarts M.M., Tymianski M. (2005) TRPMs and neuronal cell death. Pflugers Arch. 451(1):243-9.

  • Aarts M.M., Tymianski M. (2005) TRPM7 and ischemic CNS injury. Neuroscientist 11(2):116-23.

  • Arundine M., Aarts M.M., Lau A., Tymianski, M. (2004) Vulnerability of Central Neurons to Secondary Insults Following In-Vitro Mechanical Stretch. J. Neuroscience. 24(37):8106-23.

  • Aarts M.M., Iihara K, Wei WL, Xiong ZG, Arundine M, Cerwinski W, MacDonald JF, Tymianski M. (2003). A key role for TRPM7 channels in anoxic neuronal death. Cell. 115(7): 863-77.

  • Aarts M.M., Tymianski M. (2004) Molecular Mechanisms Underlying Specificity of Excitotoxic Signaling in Neurons. Current Molecular Medicine. 4: 133-143.

  • Arundine, M., Chopra, G.K., Wrong, A.W., Lei, S., Aarts, M.M., MacDonald, J.F., Tymianski, M. (2003) Enhanced Vulnerability to NMDA Toxicity in Sublethal Traumatic Neuronal Injury In-Vitro. J. Neurotrauma. 20(12): 1377-89.

  • Aarts M.M., Arundine M., Tymianski M. (2003) Novel concepts in excitotoxic neurodegeneration after stroke. Expert Reviews in Molecular Medicine. 5: 1-22.

  • Aarts M.M., Tymianski M. (2003) Peptide action in stroke therapy. Expert Opin Biol Ther. 3(7):1093-104. (Peer Reviewed)

  • Aarts M.M., Tymianski M. (2003) Novel treatment of excitotoxicity: targeted disruption of intracellular signalling from glutamate receptors. Biochem Pharmacol. 66(6): 877-86.

  • Aarts M.M., Liu Y., Liu L., Besshoh S., Arundine M., Gurd J.W., Wang Y-T, Salter M.W., Tymianski M. (2002) Treatment of Ischemic Brain Damage by Perturbing NMDA Receptor- PSD-95 Protein Interactions. Science 298 (5594): 846-850.

  • Lin R., Amizuka N., Sasaki T., Aarts M.M., Ozawa H., Goltzman D., Henderson J.E., White J.H.. (2002) 1Alpha, 25-dihydroxyvitamin D3 promotes vascularization of the chondro-osseous junction by stimulating expression of vascular endothelial growth factor and matrix metalloproteinase 9. J. Bone Min. Res. 17(9): 1604-1612.

  • Aarts M.M., Davidson D., Corluka A., Petroulakis E., Guo J., Bringhurst F.R., Galipeau J., Henderson J.E.. (2001) PTHrP Promotes Quiescence and Survival of Serum Deprived Chondrocytes by Inhibiting rRNA Synthesis. J. Biol. Chem. 276(41): 37934 - 37943.

  • Henderson J.E., Naski M.C., Aarts M.M., Wang DS., Cheng L., Goltzman D., Ornitz D.M.. (2000) Expression of FGFR3 with the G380R achondroplasia mutation inhibits proliferation and maturation of CFK2 chondrocytes. J. Bone Min. Res. 15 (1): 155-165.

  • Aarts M.M., Rix A., Guo J., Bringhurst R., Henderson J.E.. (1999) The Nucleolar Targeting Signal of Parathyroid Hormone-relate Protein Mediates Endocytosis and Nucleolar Translocation. J. Bone Min. Res. 14(9): 1493-1503.

  • Aarts M.M., Levy D., He B., Stregger S., Chen T., Richard S., Henderson J.E.. (1999) Parathyroid Hormone-related Protein Interacts with RNA. J. Biol. Chem. 274 (8): 4832-4838.

  • Publications -- Book Chapters

  • Michelle M. Aarts and Michael Tymianski. Therapeutic Tools in Brain Damage. In: Proteomics and Protein-Protein Interactions: Biology, Chemistry, Bioinformatics and Drug Design. Ed. Gabriel Waksman. Series: Protein Reviews, Vol 3. Ed. M. Zouhair Atassi. Springer Press, New York. 2005


Teaching
  • BGYC13 Biochemistry II Introduction to Metabolism
  • BGYD27 Molecular Endocrinology



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