Pharmacology

Our laboratory studies cellular and tissue injury due to oxidative stress. We pioneered the discovery that cells surviving oxidative stress develop hypertrophy. This discovery has been validated in many cell types as a consequence of cellular stress and survival response. Enlarged cells contribute to loss of functionality during the development of diseases. In the myocardium, cardiomyocyte hypertrophy can be detected as a result of ischemic injury and contributes to heart failure. Continuing on the investigation of mechanisms of cell survival has led us to focus on cellular defense system. From our many years of comprehensive and systematic studies on cellular and molecular events initiated by oxidative stress, Nrf2 stands out as the key controller for cell defenses. We have made several discoveries in recent years, including 1) oxidative stress induced de novo Nrf2 protein translation; 2) Nrf2 physically interacts with mitochondria and protects mitochondria against oxidative stress induced decay; and 3) deficiency in Nrf2 sensitizes the myocardium to ischemic injury.

Mechanisms and pharmacology of acute and chronic models of pain; endogenous opioid systems; sensory neural systems; opioid tolerance; antinociceptive synergy between cannabinoids and opioids.

Every investigation that they have pursued, even investigating novel disease models, has produced profound discoveries in basic biology and biochemistry. They are currently working in collaborations with labs to exploit three system to explore the basic function of the RNA-binding protein FUS. First, they are collaborating with the lab of Rob Batey (UC Boulder) to investigate the role of RGG-rich domains in mediating RNA recognition. Next they are collaborating with lab of Kate Fitzgerald (U Mass Med) to investigate the role of FUS in transcriptional pause release and initiation as macrophage cells respond to stimulation of Toll-like receptor 4. Lastly, they are collaborating with the lab of Ran Taube (Ben-Gurion U) to investigate the role of FUS as a scaffold protein to promote the formation of the Super Elongation Complex (SEC) both genome-wide and for the Tat gene in HIV. They are also pursuing the role of FUS and noncoding RNAs in DNA damage repair. They believe that the function of FUS in affecting transcription is also crucial to the repair of DNA damage in cells.

Dr. Tally Largent-Milnes Ph.D., is a Research Assistant Professor of Pharmacology at the University of Arizona. Dr. Largent-Milnes is a member of the International Association for the Study of Pain, the Society for Neuroscience, and the American Pain Society. Her major research focus is on trigeminal (Vc) synaptic physiology, neuropathic pain and rational design of multifunctional compounds to treat chronic pain. Dr. Largent-Milnes uses whole-cell patch clamp electrophysiology, immunohistochemistry, behavior, and pharmacology, to explore excitatory synaptic transmission between trigeminal afferents and nucleus caudalis (Vc) neurons as well as the adaptations that accompany certain pathologies/pharmacological interventions. Her work is critical to improve our understanding of the construction of the trigeminal system at the synaptic level, and will allow for the development of better therapeutics to treat select craniofacial pain disorders through her research.

Thomas Davis, PhD, and his lab continue its long-term CNS biodistribution research program, funded by NIH since 1981, by studying the mechanisms involved in delivering drugs across the blood-brain barrier to the C.N.S. during pathological disease states. Recently, Dr. Davis and his lab discovered specifica drug transporters which can be targeted to enhance delivery. They are also interested in studying the effect of hypoxia/aglycemia/inflammatory pain on endothelial cell permeability and structure at the blood-brain barrier. Dr. Davis has recently shown that short-term hypoxia/aglycemia leads to significant alterations in permeability which can be reversed by specific calcium channel antagonists. This work has significant consequences to the study of stroke. Additionally, he has discovered that peripheral pain has significant effects on BBB tight junction protein cytoarchitecture leading to variations in the delivery of analgesics to the CNS.