Signal transduction

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.

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. 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"

Matthew Cordes, Ph.D. is an Associate Professor of Chemistry and Biochemistry at the University of Arizona College of Science. Dr. Cordes’ research focuses on the origin and evolution of new protein structures and functions. He has published approximately 30 original research papers and presents his work frequently at national meetings such as the Protein Society and Gordon Research Conferences on Proteins and Biopolymers. Dr. Cordes’ primary research contributions are in four fields of protein evolution. First, his laboratory has identified cases in which a new type of protein structure has evolved from a preexisting structure. Second, he has identified evolutionary codes by which proteins that bind specific sites on double-stranded DNA evolve to recognize new target sites. Third, he studies the evolution of proteins in bloodsucking insects and spiders that affect blood homeostasis or cause dermonecrotic effects in mammalian tissue. Finally, he uses bioinformatics to identify hidden patterns in protein sequences that allow them to fold correctly and avoid aggregation such as that which occurs in Alzheimer’s disease. Dr. Cordes presently holds a BIO5 pilot project seed grant to study the evolution of enzyme toxins in brown spider venom.

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

My work investigates the molecular mechanisms of axon degeneration, a molecular program triggered by toxic, metabolic, or traumatic stress to the axonal compartment of neurons. I use both fruit fly and mouse tools to ask questions about genes involved in axon degeneration and to place these genes in the context of pathways required for axon and synapse maintenance in the face of insults. I have discovered a number of axon degeneration mediators, including MORN4 and TMEM184b as well as others, and am currently following up on their roles within neurons during normal neuronal functioning and in the context of neurodegenerative disorders such as ALS and Alzheimer’s Disease. Keywords: Neurodegeneration, Neurogenetics, Behavior

Parker Antin is Professor of Cellular and Molecular Medicine in the College of Medicine, Associate Vice President for Research for the Division of Agriculture, Life and Veterinary Medicine, and Cooperative Extension, and Associate Dean for Research in the College of Agriculture and Life Sciences. In his positions of Associate Vice President and Associate Dean, he is responsible for developing and implementing the research vision for the Colleges of Agriculture and Life Sciences and the College of Veterinary Medicine, with total research expenditures of approximately $65M per year. His responsibilities include oversight of research strategy and portfolio investment, grants and contracts pre award services, research intensive faculty hires and retentions, research communication and marketing, research facilities, and research compliance services. In collaboration with Division and College leadership teams, he has shared responsibilities for philanthropy, budgets and information technology. Dr. Antin is a vertebrate developmental biologist whose research is concerned with the molecular mechanisms of embryonic development. His research has been supported by NIH, NSF, NASA, USDA, and the DOE, as well as several private foundations including the American Heart Association and the Muscular Dystrophy Association, He is the Principal Investigator of CyVerse, a $115M NSF funded cyberinfrastructure project whose mission is to design, deploy and expand a national cyberinfrastructure for life sciences research, and train scientists in its use (http://cyverse.org). With 65,000 users worldwide, CyVerse enables scientists to manage and store data and experiments, access high-performance computing, and share data and results with colleagues and the public. Dr. Antin is also active nationally in the areas of science policy and funding for science. He is a past President of the Federation of Societies for Experimental Biology (FASEB), an umbrella science policy and advocacy organization representing 32 scientific societies and 135,000 scientists. His continued work with FASEB, along with his duties as Associate Vice President and Associate Dean for Research, and CyVerse PI, brings him frequently to Washington, DC, where he advocates for support of science and science policy positions that enhance the scientific enterprise.