Medical College of Wisconsin

Zeljko Bosnjak PhD

Zeljko Bosnjak PhD and colleagues have developed and validated clinically relevant models of cardiac protection and developmental neuroapoptosis using human cardiomyocytes and neurons derived from the stem cells, respectfully. For the first time they demonstrated that isoflurane mediates protection of cardiomyocytes against oxidative stress via miR-21/programmed cell death protein 4 pathway. These results reveal a novel mechanism by which the damage done by ischemia/reperfusion injury may be decreased. In addition, they reported that propofol induces cell death in human embryonic stem cell-derived neurons via a signal transducer and activator of transcription 3/miR-21/Sprouty 2-dependent mechanism.

Amadou Camara PhD and David Stowe MD, PhD

In their most recent study, Drs. Amadou Camara and David Stowe have published a seminal article on the dynamic interactions between Ca2+ and ROS under mitochondrial simulated ischemic conditions. In addition, they recently reported novel findings on mitochondrial Ca2+ dynamics and bioenergetics, and their physiological and pathophysiological implications. The experiments revealed characteristics of the mitochondrial Na+-Ca2+ exchanger and for the first time, a quantitative assessment of the mitochondrial buffering power. These studies led to additional computational modeling and experimental observations from their group that clearly show two modes of mitochondrial Ca2+ uptake during exposure to Ca2+, which for the first time strongly implicates a mitochondrial ryanodine type receptor that modulates the primary conduit for Ca2+ uptake, the mitochondrial Ca2+ uniporter. These findings are significant in the understanding of mitochondrial Ca2+ overload during ischemia and reperfusion injury and during the transient increases in mitochondrial Ca2+ within the microdomain during cardiac excitation-contraction coupling.

Anthony Hudetz PhD

The goal of Anthony Hudetz’ PhD research has been to better understand the mechanisms by which general anesthetics modulate the state of consciousness. In a recent investigation Dr. Hudetz and colleagues tested a leading theory for anesthetic unconsciousness. They examined the dose-dependent effect of a general anesthetic, propofol, on the diversity of global brain states using functional magnetic resonance imaging (fMRI) in rats. They were able to demonstrate that the repertoire of large-scale brain states derived from the spatiotemporal dynamics of intrinsic brain networks was substantially reduced at an anesthetic dose associated with loss of consciousness. This result lends direct support for the first time to the explanation of anesthetic mechanism in the context of the Information Integration Theory of Consciousness.

Martin Bienengraeber PhD

Using an innovative non-pharmacological strategy Martin Bienengraeber PhD and coinvestigators were able to harness the power of near-infrared light-emitting diodes (LEDs) to liberate nitric oxide from heme proteins in a manner that exerted a potent protective effect against ischemia and reperfusion injury. The findings not only expanded the understanding of the mechanism by which NIR elicits cardioprotection, they convincingly documented its utility in the setting of diabetes mellitus where many other cardioprotective strategies, including pharmacologic conditioning, fail.

Quinn Hogan MD

Recent findings from the pain neuroscience laboratory of Quinn Hogan MD include the following. 1) Peripheral nerve injury leads to overexpression of thrombospondin-4 in the dorsal root ganglia and elevates the excitability of these neurons, making it likely that this extracellular protein contributes to the generation of neuropathic pain. 2) Mitochondria show signs of diminished function in axotomized sensory neurons but elevated function in adjacent uninjured neurons, suggesting a key role of mitochondria in producing neuropathic pain. 3) Depressed function of the kinase CaMKII after nerve injury depresses voltage-gated Ca2+ currents and leads to increased neuronal excitability. This explains the pain-generating consequences of avoiding natural sensory stimulation. 4) Using a safe adeno-associated viral vector, Dr. Hogan and colleagues have reversed neuropathic pain by causing the affected sensory neurons to express a peptide that blocks presynaptic Ca2+ current. This molecular approach to therapy could be employed to disrupt any of the numerous signaling pathways known to contribute to chronic pain. 5) The sigma receptor has been shown to modulate opioid activity but the mechanism has been unknown. They have now demonstrated that sigma activation reduces sensory modulates Ca2+ current in peripheral sensory neurons.