Cell signaling

I am an Associate Professor in the department of Nutritional Sciences (College of Agriculture and Life Sciences) at the University of Arizona and hold joint appointments in Pediatrics (College of Medicine) and Immunobiology (College of Medicine). I am also part of the mentoring team for the Physiological Sciences and Cancer Biology Graduate Interdisciplinary Programs, which recruit students who are continuing in education. My research interests are concerned with the effects of aging, stress and exercise on the immune system, and the role of adrenergic receptor signaling on immune cell redistribution and activation. Major focus areas include understanding (1) how exercise and other behavioral interventions can offset age-related decrements in the normal functioning of the immune system (immunosenescence), (2) how adrenergic receptor signaling can be used to improve cellular products for hematopoietic stem cell transplantation and immunotherapy, (3) the interplay between the immune and neuroendocrine system during high level human performance and extreme isolation (i.e. space travel), and (3) how persistent virus infections such as cytomegalovirus (CMV) can alter the phenotype and function of T-cells and NK-cells to protect the host from certain hematological malignancies. My current research is supported by NASA, the NIH (National Cancer Institute) and industry. I am a fellow of the American College of Sports Medicine (ACSM) and an honorary board member of the International Society of Exercise Immunology (ISEI). I am an active member of the Pychoneuroimmunology Research Society (PNIRS) and the Society for Immunotherapy of Cancer (SITC) and sit on the editorial board of the following scientific journals: Brain, Behavior and Immunity; Exercise Immunology Reviews (Associate Editor); Immunity and Ageing; American Journal of Lifestyle Medicine.

Diana Wheeler, PhD, and her research interests are dominated by the physiological basis of caste differences in social insects, especially ants. Why ants? She is especially interested in the relevance of physiology to both social organization and evolution of insect sociality. Research has included included regulation of oogenesis, storage of proteins by adult workers and queens, mechanisms of sperm storage by queens, and, of course, caste determination.Dr. Wheeler is working on the molecular basis of caste determination in honey bees. Since caste is determined by the diet larvae receive, caste determination involves signaling pathways that are fundamental to pathways regulated by nutrition in all organisms, even single-celled ones. Insulin and TOR signaling pathways are turning out to be especially important. Her team also works to understand how pathways are shaped by natural selection acting at the level of the colony, in addition to the level of the individual.

Richard Vaillancourt, PhD, studies the regulation of serine/threonine protein kinase pathways that function in stress-related signal transduction pathways. These intracellular serine/threonine protein kinase pathways, which are referred to as mitogen-activated protein (MAP) kinase pathways, are activated by a number of hormones, growth factors, cytokines, and environmental agents. Currently, at least five MAP kinase pathways have been identified, and there are many protein kinases that function within a defined MAP pathway. One role for these sequential kinase pathways is to transmit an extracellular signal from the plasma membrane to the nucleus. Simply stated, these sequential protein kinase pathways provide the cell with an intracellular signal, which elicits a biological response that is appropriate for the type of stimulus. The cytoplasmic kinases that transmit the signal from the plasma membrane to various MAP kinase proteins include the MAP/Extracellular signal-regulated kinase (ERK) Kinase Kinase (MEKK) proteins. To date, at least four MEKK proteins have been identified based on a homology to similar protein kinases found in the budding yeast, Saccharomyces cerevisiae. However, the extracellular molecules that regulate the MEKK proteins remain largely undefined in mammalian cells. A major focus in Dr. Vaillancourt's lab is to characterize the role of MEKK3 and MEKK4 in cellular signal transduction pathways. Current research focuses on the regulation of MEKK3 by the serine/threonine kinase, Akt, which functions in cell survival pathways and the inhibition of apoptosis. In another project, Dr. Vaillancourt and his team are characterizing the regulation of MEKK4 in response to arsenic in human keratinocytes. Finally, they are also studying the role of the PITSLRE protein kinase in the regulation of tyrosine hydroxylase, as it relates to nicotine signal transduction.

We study control of cell fate and self-organization in intestinal renewal and drug response in cancer. Utilizing the fascinating characteristics of intestinal stem cells combined with chemical biology and computational image analysis approaches, we are addressing fundamental questions of multicellular systems: How do cells identify, measure, and respond to each other and to their environment? What are the signals that control the renewal and regeneration of tissues? How do these signals become defective in colorectal cancer? Our long-term goal is to uncover an underlying circuit theory behind these behaviors – a set of predictive principles that tell us how complex functionality arises from simpler biological components. We have a particular interest in kinase networks that regulate healthy tissue homeostasis and become damaged in cancer. Through our quantitative high-throughput imaging and drug discovery efforts, we are finding new ways to understand and repair these networks. Keywords: Stem cells, Cancer, Regeneration, Drug discovery

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

The broad goal of research in our laboratory is to understand how inhibitory inputs influence neuronal signaling and sensory signal processing in the healthy and diabetic retina. Neurons in the brain receive inputs that are both excitatory, increasing neural activity, and inhibitory, decreasing neural activity. Inhibitory and excitatory inputs to neurons must be properly balanced and timed for correct neural signaling to occur. To study sensory inhibition we use the retina, a unique preparation which can be removed intact and can be activated physiologically, with light, in vitro. Thus using the retina as a model system, we can study how inhibitory synaptic physiology influences inhibition in visual processing. This intact system also allows us to determine the mechanisms of retinal damage in early diabetes. Keywords: neuroscience, diabetes, vision, electrophysiology, light

Dr. Thomas Doetschman, PhD, Biochemistry & Biophysics, University of Connecticut, has been involved in cardiovascular research for over a decade through investigations into the cardiovascular roles of the three TGFβ ligands and FGF2 ligand isoforms in genetically engineered mice. These mice have determined that TGFβ2 plays major roles in heart and vascular development and for maintenance of valvular and large vessel integrity in the adult and that both the TGFβ1 and FGF2 are involved in adult heart disease.His work has also demonstrated roles of TGFβ in cancer and immunology. He found that a major function of TGFβ1 is to inhibit autoimmunity and to establish homeostatic balance between immune regulatory and inflammatory cells. He has shown that an imbalance in the latter is critical in the tumor suppressor function of TGFβ in the colon.Dr. Doetschman has also played an important role in the development of the mouse genetic engineering field. He has been responsible for the establishment of 3 mouse genetic engineering facilities, in Cincinnati OH, Singapore and the University of Arizona’s BIO5 Institute. Keywords: "Cancer", "Microbiome", "Mouse Genetic Engineering", "Connective Tissue Disorder"

Our research focuses on the signal transduction pathways and molecular mechanisms controlling directed cell migration, or chemotaxis, in eukaryotic cells. Chemotaxis is central to many biological processes, including the embryonic development, wound healing, the migration of white blood cells (leukocytes) to sites of inflammation or bacterial infection, as well as the metastasis of cancer cells. Cells can sense chemical gradients that are as shallow as a 2% difference in concentration across the cell, and migrate towards the source of the signal, the chemoattractant. This is achieved through an intricate network of intracellular signaling pathways that are triggered by the chemoattractant signal. These pathways ultimately translate the detected chemoattractant gradient into changes in the cytoskeleton that lead to cell polarization and forward movement. In addition, many cells such as leukocytes and Dictyostelium, transmit the chemoattractant signal to other cells by themselves secreting chemoattractants, which increases the number of cells reaching the chemoattractant source.To investigate key mechanisms of signal transduction underlying chemotaxis, we are using the social amoeba Dictyostelium discoideum as well as human cancer cell models. Cell motility and chemotaxis of Dictyostelium cells is very similar to that of leukocytes and cancer cells, using the same underlying cellular processes as these higher eukaryotic cells. Dictyostelium is amenable to cell biological, biochemical, and genetic approaches that are unavailable in more complex systems. The discoveries we make using Dictyostelium are then confirmed in human cells and, in particular, in the context of directed cancer cell migration and metastasis. Our aim is to understand the molecular foundation of directed cell migration, which is expected to guide the design of efficient anti-metastatic treatments.Our approach is interdisciplinary, in which we combine molecular genetics and proteomics to identify new signaling proteins and pathways involved in the control of chemotaxis, with live cell imaging using fluorescent reporters to understand the spatiotemporal dynamics of the signaling events, as well as biochemical analyses and proximity assays [including Bioluminescence Resonance Energy Transfer (BRET) and FRET] to understand how proteins interact and function within the signaling network. In addition, in collaboration with Dr. Wouter-Jan Rappel at UC San Diego, we generate quantitative models of the chemotactic signaling networks to help identify key regulatory mechanisms and link them to whole cell behavior

Andrew Capaldi, PhD, researches the signaling pathways and transcription factors in a cell that are organized into circuits. They allow cells to process information and make decisions. For Dr. Capaldi, the work arises in understanding both how these circuits are built from their components, and how they function and malfunction. To address these questions, he is working to reverse engineer the circuitry that controls cell growth in budding yeast using a combination of genomic, proteomic and computational methods. http://capaldilab.mcb.arizona.edu

Dr. Scott Boitano Ph.D., is a Professor of Physiology, Cellular and Molecular Medicine, the BIO5 Institute and Associate Research Scientist of the Arizona Respiratory Center. Dr. Boitano received a B.S. in Plant Biology from University of California; Berkeley and a Ph.D. in Genetics & Cell Biology from Washington State University. Dr. Boitano’s primary research interest is in cell respiration. This encompasses the analysis and observation of cell physiology, cell-cell communications and cell-pathogen interactions. Dr. Boitano’s research pertains to the upper airway epithelium is an active cellular layer with ciliary movement to clear materials, the ability to secrete inflammatory effectors, and a biological barrier function that helps protect against pathogenic microorganisms, foreign insults and injury. Although much is known concerning the microbial genetics and microbial signaling of infection by Bordetella, relatively little is known about host cell pathology after exposure to Bordetella. Individuals have a primary tissue culture system that serves as an in vitro model of airway cell signaling and communication, and a battery of B. bronchiseptica strains, some of which are mutant in key factors shown to inhibit their ability to establish infection in animal models. His research goal is to define specific pathogen factors that alter host cell physiology to initiate or overcome host cell defense. The Boitano lab also analyzes the layers of the alveoli of the distal mammalian lung. Minimal information is known about this subject and Dr. Boitano believes that this model system for alveolar intercellular communication could expedite the formulating and testing of new medical treatments for dysfunctional alveolar cell physiology that underlies specific airway conditions following disease, insult and injury in the lung.