Clinical medicine

Stern lab research aims to understand the role of glucagon signaling in the pathogenesis of obesity, type II diabetes mellitus, and aging. Glucagon Signaling in Obesity and Type II Diabetes: Insulin resistance and elevated insulin are key to the metabolic disturbances in type II diabetes mellitus (T2DM). Yet, elevated glucagon, common to diabetes, may be equally important in the metabolic abnormalities in T2DM. Dr. Stern has shown that nutritional state differentially affects glucagon secretion in obesity. In turn, the glucagon:insulin ratio is dysregulated in obesity. Current Stern lab research aims to understand the metabolic consequences of a dysregulated glucagon response to fasting and re-feeding. Glucagon Signaling and Aging: More than 25% of the U.S. population greater than 65 years old has Type II diabetes mellitus, representing the highest prevalence of diabetes of any age group. Most research aimed at understanding the consequences of obesity in aging have focused on insulin and downstream signaling cascades, overlooking a potential role for glucagon. Given that many prominent diabetes treatments target glucagon or glucagon signaling pathways, it is essential to understand the role of glucagon in aging. Stern lab research examines 1) the tissue specific effects of glucagon signaling, 2) the role of glucagon signaling in obesity-accelerated aging, and 3) the role of glucagon signaling in healthspan extension promoted by calorie restriction. This work will close a significant gap in our understanding of how glucagon alters aging, while allowing us to assess the potential risks associated with inhibition of glucagon signaling. Other Stern Lab Research Foci: Sleep disturbance and metabolic dysfunction Obesity related cancer development and progression

Jean M. Wilson, Ph.D. is a Professor of Cellular and Molecular Medicine at the University of Arizona and member of the Arizona Cancer Center. Dr. Wilson’s work focuses on the establishment and maintenance of the mucosal barrier of the intestine. The cells of the intestine provide a selective barrier to pathogens and toxins, and loss of this barrier function is fundamental to pathologies such as inflammatory bowel disease and bacterial infection. In addition, loss of cellular interactions important for barrier function may predispose these cells to cancer. Work in Dr. Wilson’s laboratory focuses on a protein that is highly expressed in developing intestine, implying a critical role in the formation of the intestinal epithelium. Disruption of this protein compromises junctional integrity and epithelial polarity. Furthermore, expression of this protein is decreased in a model of neonatal necrotizing enterocolitis, a disease of newborns with high morbidity and mortality. These findings implicate this protein in the maintenance of intestinal barrier function in the neonate. In addition, continued expression in the adult intestine positions it to regulate epithelial permeability and polarity throughout life. Our studies focus on protein partners that interact with this protein with the goal of identifying the molecular machinery that regulates this pathway.

Dr. Viswanathan’s research efforts over the past 12 years have focused on the mechanisms of pathogenesis of the diarrheal disease pathogens enteropathogenic and enterohemorrhagic Escherichia coli (EPEC and EHEC). His laboratory characterized EPEC and EHEC virulence factors (specifically those secreted into host cells) and evaluates their effect on host cell physiology including barrier function, cell death pathways, and effects on innate immune responses. His specialization is innate immune signaling by intestinal epithelial cells in vitro and in vivo, and includes the use of cutting-edge technologies such as in vivo phosphoproteomics, and single-cell manipulation during bacterial infection. He also offers a very popular upper-division course in pathogenic bacteriology, and actively mentors undergraduate and graduate students, and post-doctoral fellows at the UA. Keywords: Pathogenic E. coli, Clostridium difficile, infection, host-pathogen interactions

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

John A Szivek, PhD, is a Professor of Orthopaedic Surgery at the University of Arizona, College of Medicine and the Director of the Orthopaedic Research Laboratory in the Arizona Arthritis Center. He holds the William and Sylvia Rubin, Chair of Orthopaedic Research and serves as the Chair of the Biomedical Engineering Graduate Interdisciplinary Program. Dr. Szivek is a member of the Physiological Sciences Graduate interdisciplinary Program as well as an adjunct faculty member of Materials Science and Engineering and Aerospace and Mechanical Engineering. He is internationally recognized for his research on the development of implantable measurements systems to characterize the effect of implants on tissue and on activity induced musculoskeletal tissue regeneration (specifically bone and cartilage). Recently he has utilized adult stem cells on 3D printed scaffolds to regenerate joint cartilage in efforts to develop techniques to help athletes and osteoarthritis patients. He has published over 180 research articles, several in collaboration with investigators from around the world, and authored 2 book chapters. As part of the sensor and transmitter systems developed in his lab, computer software programs for hand held devices (including tablets, hand held computers and smart phones) have been written to allow portable monitoring of tissue while it heals. He is a frequent presenter at national and international meetings, and has been an invited speaker at the Arizona Rheumatology Society; the Musculoskeletal Transplant Society Board meetings and the research forums at the Samuel Lunenfeld Research Institute of Mount Sinai Hospital in the University of Toronto. He has won more than 165 grants, specifically to provide support to undergraduate minority students, allowing them to do hands on research on a range of activity induced tissue engineering topics. He has trained graduate students with federal grant support and has had support through a number of regional and national foundations to train top tier undergraduates and medical students. Dr. Szivek believes it is essential to effectively train the next generation of bioengineering researchers, clinicians and clinician scientists, in cutting edge topics so that the progress that his lab has made in developing tissue regeneration approaches and sensor/transmitter systems used to design patient specific therapies will become widely utilized.

I have spent the past 21 years of his research career studying the properties of insulin-secreting tissue and their relationship to viability and function. I have worked on the development and validation of assays (especially ones based on mitochondrial function such as oxygen consumption rate) for the real-time, objective assessment of islet quality prior to transplantation. In particular the assay based on oxygen consumption rate has been recently validated based on its ability to predict diabetes reversal in mice and clinical human islet auto transplants in patients with chronic pancreatitis. I have used these assays along with engineering principles to optimize the islet transplantation process from pancreas procurement to islet infusion to the recipient. My group has also developed tools for the real time non-invasive assessment of pancreases and other organs during preservation, and i am actively involved in research for improvements in organ preservation technology aiming at extending the allowable time window from procurement to transplantation and the utilization of organs from expanded criteria donors without compromising clinical outcomes. I have had continuous NIH funding for the past 7 years in the area of pancreas preservation and I have spearheaded the effort for the development of humidified oxygen gas perfusion (persufflation) of the pancreas using novel technology for portable in situ oxygen generation from water via electrochemistry. I am also actively collaborating with leaders in the liquid perfusion field on NIH sponsored projects aiming at improving oxygenation.

Katrina Miranda, PhD, claims nitric oxide (NO), which is synthesized in the body via enzymatic oxidation of L-arginine, is critical to numerous physiological functions, but also can contribute to the severity of diseases such as cancer or pathophysiological conditions such as stroke. This diversity in the responses to NO biosynthesis is a reflection of the diverse chemistry of NO. For instance, NO can alter the function of enzymes by binding to metal centers. This type of interaction could result in outcomes as disparate as control of blood pressure or death of an invading bacterium. NO can also be readily converted to higher nitrogen oxides such as N2O3 or ONOOH, which have very different chemical and biological properties. The ultimate result will depend upon numerous factors, particularly the location and concentration of NO produced. Therefore, site-specific modulation of NO concentration offers intriguing therapeutic possibilities for an ever expanding list of diseases, including cancer, heart failure and stroke. As a whole, Dr. Miranda is interested in elucidating the fundamental molecular redox chemistry of NO and in developing compounds to deliver or scavenge NO and other nitrogen oxides. These projects are designed to answer questions of potential medical importance through a multi-disciplinary approach, including analytical, synthetic, inorganic and biochemical techniques.The project categories include five major disciplines. First, she will work on the development and utilization of analytical techniques for detection and measurement of NO and other nitrogen oxides as well as the resultant chemistry of these species. Second, she will synthesize potential donors or scavengers of NO and other nitrogen oxides. Third, it’s necessary to describe chemical characterization of these compounds (spectroscopic features, kinetics, mechanisms and profiles of nitrogen oxide release, etc.). Fourth, Dr. Miranda will try to describe the biological characterization of these compounds (assay of effects on biological compounds, mechanisms and pathways, in vitro determination of potential for therapeutic utility, etc.). Fifth, she will identify of potential targets, such as enzymes, for treatment of disease through exposure to nitrogen oxide donors. Keywords: cancer treatment, pain treatment

Ron Lynch received a B.S. from the University of Miami (1978) with a dual major in Chemistry (Physical) and Biology, and a Ph.D. degree from the University of Cincinnati (1984) in Physiology and Biophysics. Dr. Lynch began training in optical imaging and MR spectroscopy of cardiac metabolism while at the NIH/NHLBI under the direction of Dr. Robert Balaban from 1984-1987. In 1987, Dr. Lynch moved to a staff position in the Biomedical Imaging Group with appointment in the Physiology Department at the University of Massachusetts Medical Center where he was involved in the development of approaches for 3-dimensional imaging including deconvolution and confocal microscopy. Dr. Lynch joined the faculty of the University of Arizona in 1990 with dual appointment in the Departments of Physiology and Pharmacology, and is currently a full professor, and director of the Arizona Research Institute for Biomedical Imaging. In 2000, Dr. Lynch was a visiting scientist at the Laboratory of Functional and Molecular Imaging and the Magnetic Resonance Imaging Center with Dr. Alan Koretsky at the NIH/NINDS. Dr. Lynch is a member of the Biophysical Society, the American Physiological Society and American Diabetes Association, and regularly serves on grant review panels for the JDRF, NIH/NIDDK, and NSF. Research in the Lynch lab focuses on second messenger signaling in vascular smooth muscle cells and nutrient sensing cells (e.g., Pancreatic Beta-cells) with emphasis on alterations in signaling that occur during development of Diabetes. We are developing methods to modify and analyze beta cell mass in order to evaluate the initiation of the pre-diabetic state, and efficacy of its treatment. Analyses of subcellular protein distributions, second messenger signaling, and ligand binding is performed in our lab using state of the art microscopy and analysis approaches which is our second area of expertise. Over the past 3 decades, our lab has been involved in the development of unique microscopic imaging and spectroscopy approaches to study cell and tissue function, as well as screening assays for cell signaling and ligand binding. Keywords: Diabetes, Cancer, Optical Imaging, Targeted Contrast Agents, Metabolism, Biomedical Imaging, Drug Development

Dr. Ledford’s current work in the area of pulmonary surfactant immunobiology combines her knowledge of mouse genetics, pulmonary disease models and immune function regulation and focuses on understanding the role of Surfactant Protein-A (SP-A) and how it regulates signaling pathways within various immune cell populations. Specifically, she is interested in how SP-A regulates degranulation, either directly or indirectly, of two important cell types in asthma: mast cells and eosinophils. More recently, Dr. Ledford’s research has focused on understanding how genetic variation within human SP-A2 alters functionality of the protein in relation to eosinophil activities and how this translates to characteristics observed in human asthma.

Dr. Emmanuel Katsanis, MD, and his laboratory conduct basic and translational research aimed at advancing new cancer immunotherapeutic strategies. His expertise is in stem cell transplant immunology, cellular therapy, and cancer vaccine approaches.Immunity against tumors depends on complex innate and adaptive immune responses that involve the sequential mobilization of 'messenger' and 'killer' immune cells. However, despite the arsenal harbored by the immune system to ensure tumor immunosurveillance, cancers can escape immune detection and elimination. Current research in the laboratory is evaluating immuno- and chemo-immunotherapeutic strategies to promote anti-tumor immune responses following bone marrow transplantation, while investigating approaches to mitigate graft versus host effects. Keywords: Cancer Immunology, Hematopoietic Cell Transplantation