The sudden loss of oxygen and nutrients results in ischemic tissue damage underlying a large number of emergent conditions including cardiac arrest, myocardial infarction, sepsis, and trauma. My lab studies processes of cellular and tissue ischemic injury using a model of sudden cardiac arrest. In particular, we are interested in changes in mitochondrial function and cellular metabolism following ischemia and how these processes are affected by hypothermia. Our lab has made 3 important discoveries in these areas.

  • Increased mitochondrial fission (division) occurs following ischemia/reperfusion injury in a process regulated by dynamin related protein 1 (Drp1), a mitochondrial fission protein. Inhibiting Drp1 pharmacologically improves cardiac arrest outcomes. Work demonstrating the genetic modification of Drp1 improves outcomes are ongoing.
  • Ischemia reperfusion injury results in the inhibition of pyruvate dehydrogenase (PDH), a key enzyme that regulates glucose entry into the Krebs cycle. Enhancing PDH function following cardiac arrest is a promising target for improving post cardiac arrest resuscitation outcomes.
  • Post-cardiac arrest hypothermia improves outcomes following cardiac arrest in both animal models of cardiac arrest and in clinical trials. Physical cooling methods are difficult and time consuming to implement. Alternatively, cooling may be achievable by metabolic inhibition. Current studies to investigate the pharmacological induction of torpor (metabolic inhibition) in the setting of cardiac arrest are on-going.

Our hope is to develop new insights into the basic cellular mechanisms of ischemic injury that will lead to the development of new therapeutic agents to treat emergent ischemic injury and improve patient outcomes from a variety of acute injury processes.

  • Sharp, W.W#., Fang,YH, Han, M., Zhang, HJ, Hong, Z., Banathy, A., Morrow, E., Ryan, J.J., Archer, S.L., Dyanamin Related Protein 1 (Drp1)-Mediated Diastolic Dysfunction in Myocardial Ischemia-Reperfusion Injury: Therapeutic Benefits of Drp1 Inhibition to Reduce Mitochondrial Fission. FASEB J. 2014 Jan;28(1):316-26. PubMed PMID: 24076965; PubMed Central PMCID: PMC3868827. # Denotes corresponding author
  • Sharp, W.W#., Beiser, D.G., Fang, Y.H., Varughese,J., Piao,L., Archer, S.L.  Inhibition of the mitochondrial fission protein Drp1 improves survival in a murine cardiac arrest model. Crit Care Med. 2015 Feb 1;43(2):e38-347. Doi; 10.1097/CCM.0000000000000817. PMID: 25599491. # Denotes corresponding author.
  • Sharp, W.W., Dynamin Related Protein 1 (Drp1) as a therapeutic target in cardiac arrest. Journal of Molecular Medicine 2015. Feb 8. [Epub ahead of print] PubMed PMID: 25659608
  • Sharp, W.W., Archer,S.L. Mitochondrial Dynamics in Cardiovascular Disease: Fission and Fusion Foretell Form and Function. Journal of Molecular Medicine. 2015 Feb 12. [Epub ahead of print] PubMed PMID: 25669447
  • Sharp, W.W., The Crisis in the Emergency Medicine Physician Scientist Workforce. Acad Emerg Med. 2015 Mar 13. doi: 10.1111/acem.12635. [Epub ahead of print] PubMed PMID: 25773995.

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    Institute for Integrative Physiology

    The University Of Chicago
    Aurora Parra
    Administrative Specialist
    5841 South Maryland Avenue
    Chicago, Illinois 60637