Cell biology

Gregory C. Rogers, PhD, is an Assistant Professor at the University of Arizona College of Medicine in the Department of Cellular and Molecular Medicine. His laboratory is located in the University of Arizona Cancer Center.The Rogers laboratory is interested in the molecular mechanisms cells use to maintain stability of their genomes. This is medically relevant because genomic instability can promote tumorigenesis. During mitosis, cells face particular risk, as errors in chromosome segregation can lead to chromosome instability (CIN) which is characterized, in part, by an abnormal chromosome complement (known as aneuploidy). Indeed, aneuploidy promotes malignant transformation and is an underlying cause of birth defects. Mitotic spindles are used to faithfully segregate chromosomes into daughter cells and, for this to occur properly, it is critical that cells assemble spindles with a bipolar fusiform-shape. Cells control spindle shape using centrosomes, tiny organelles that nucleate the microtubule cytoskeleton and organize the two spindle poles. Normally, cells contain a single centrosome which duplicates once per cell cycle, thus ensuring that cells enter mitosis with only two centrosomes to build a bipolar spindle. Cancer cells, however, overduplicate their centrosomes, which leads to multipolar spindle formation and chromosome instability. In fact, most human tumors contain cells with elevated centrosome numbers and aneuploid genomes. Importantly, the fundamental mechanisms that cells use to control their centrosome number are unclear, nor is it understood how this regulation goes awry in cancer. His work centers on characterizing a particular pathway (the Plk4 pathway) to control the biogenesis of centrosomes. This pathway utilizes both phosphorylation and ubiquitin-mediated proteolysis as regulatory mechanisms in a complex signaling pathway to control the biogenesis of centrosomes.

Dr. Polt began his research career by developing methods for amino acid synthesis in Prof. Marty O’Donnell’s lab at IUPUI. After that he was trained in the art of Organic Synthesis in the laboratories of Profs. Gilbert J. Stork at Columbia University and Dieter Seebach at the ETH in Zürich. He has continued to develop novel synthetic methods for amino acids, amino alcohols, glycosides and glycopeptides. Application of these methods resulted in the production of a number of pharmacologically active glycopeptides (GPCR agonists), alkaloid-like inhibitors of glycolipid processing enzymes and glycosyltransferases, as well as glycolipids with biological activity such as glycosphingolipids and rhamnolipids. The biological focus of his work has been in attempting to understand the chemistry of carbohydrates (e.g. glycolipids, glycoproteins) at cell membranes, membrane trafficking, and using these insights to design glycopeptide drugs from endogenous peptide neurotransmitters (neuromodulators, hormones) with enhanced stability in vivo that are capable of penetrating the Blood-Brain Barrier and interacting with GPCRs as agonists or antagonists. Presently, Polt studies the design, synthesis and testing of agonists related to the hormones Oxytocin and PACAP (Pituitary Adenyl Cyclase Activating Peptide), as well as other glycopeptide drug candidates.

Clinical applications of the glycopeptide drugs include pain, opioid use disorder, migraine, Parkinsons, Alzheimers and other neurogenerative diseases. In addition to lecturing and laboratory teaching during 35 years at the University of Arizona, and the publication of more than 137 scientific papers, he has mentored a large number of undergraduate, graduate (21 Ph.D.s granted, 2 in progress) and post-doctoral students who have taken positions in academia, industry and the US government. His Ph.D.s have hailed from the US (10), Czech Republic*, China, Germany*, India, Iran*, Ireland, Jordan*, Kenya*, Korea, Mexico* and Sri Lanka. Six of these Ph.D. graduates (*) have gone on to become naturalized citizens or obtain permanent resident status. Recent undergraduates associated with his research group have gone to graduate schools at Harvard, MIT, Boston University, University of Wisconsin, and Columbia University.

Membrane proteins play a number of critical biochemical roles and make up the majority of drug targets. Despite their importance, membrane proteins remain challenging systems for analysis due to their amphipathic nature and low expression levels. Moreover, the lipid bilayer can play an important but largely unexplored role in regulating membrane protein structure and function. New analytical and biochemical methods are necessary to better understand and design drugs to target membrane proteins.

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

Xianchun Li, PhD, is interested in understanding the physiological, biochemical, molecular and evolutionary bases of fundamental processes in the life history of insects such as embryonic polarity, metamorphosis, developmental commitment, host usage and environmental adaptation. One focus of his research is to elucidate the reciprocal signaling interactions between plants and insects, and the resulted on-going defense (in the case of plants) / counterdefense (in the case of herbivorous insects) phenotypic arm race over ecological time scale, with emphasis on the genetic machinery that percepts and transduces the reciprocal cues into genome and regulate defense / counterdefense phenotypes. Working systems include Helicoverpa zea, the corn earworm, a polyphagous noctuide of economic importance, and Drosophila melanogaster, the fruit fly, a model organism. State of arts and traditional techniques are combining to identify the cues and to uncover the signaling transduction cascade that links environmental cues, gene expression and the resulted defense/counterdefense phenotypes. This research may lead to characterization of genes for designing new insecticides and/or genetically modifying crops. The second focus of Dr. Li’s research is to define, globally, the regulatory triangle between nuclear receptors (NRs), their ligands, and cytochrome P450s (P450s) in Drosophila melanogaster. Nuclear receptors (NRs) constitute a transcription factor superfamily that has evolved to sense and bind endogenous (e.g., hormones) and/or exogenous (e.g., naturally-occurring or synthetic xenobiotics) signal compounds, resulting in differential expression of particular target genes, which underlies a range of fundamental biological processes, including growth, development, reproduction, behavior, host usage, and environmental adaptation. Many of those cue chemicals, namely NR ligands, are synthesized and/or metabolized by members of the P450s gene superfamily, whose expression may be regulated by certain NRs. Bioinformatics analyses as well as systematic functional genomic techniques such as microarray, X-ChIP, mutation and ectopic expression will be combined to define the genome-wide regulatory interaction loops between NRs and P450s as well as to assign, at least partially, functions of individual NRs and P450s in the life history of fruit fly. Given the evolutionary conservations of homologous NRs and P450s between vertebrates and invertebrates, the results obtained in this project are expected to provide insights into the reciprocal regulatory interactions between NRs and P450s in other animals including humans as well as to provide great insights into new avenue for human NR ligand identification and NR-related drug design. The third focus of his research is to investigate the molecular mechanisms of Bt and conventional insecticide resistance, which is a major threat in current IPM system. In collaboration with Dr. Bruce Tabashnik, Timothy Dennehy, and Yves Carriere in our Department, Dr. Li is going to compare Bt toxin binding affinity and other defects of natural (s, r1, r2, r3) and artificial mutant PBW (Pink Bollworm) cadherin proteins and thus define the key functional domains of PBW cadherin.

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.

David Harris, PhD, occupies research efforts directed at the application of (cord blood and adipose) stem cells to transplantation, regenerative medicine and tissue engineering. The difficulty in locating bone marrow donors for patients needing transplants, particularly for minority patients, led to the investigation of other potential sources of stem cells. One such source that has become a viable alternative to bone marrow is umbilical cord blood. Not only has the use of cord blood allowed more patients to go to transplant due to less restrictive matching requirements between donor and recipient, but cord blood transplants are associated with fewer post-transplant complications, such as a lower incidence and severity of graft-versus-host disease (GVHD). In 1989, he began work on the use of cord blood for transplantation, which led to the establishment of the first cord blood bank in the United States in 1992, which is currently the largest such establishment in existence. Work continues today using animal models for cord blood transplantation to explore such research areas as graft-versus-leukemia, GVHD, regenerative medicine and tissue engineering applications. However, studies performed in his lab examining the use of cord blood stem cells in regenerative medicine is now our major emphasis. Work in regenerative medicine has focused on several specific areas of interest. The first area is the use of stem cells in an ischemia/reperfusion injury model of myocardial infarction in a rat model, with positive results. Efforts are underway to understand the molecular mechanisms involved and to derive small molecule drugs in collaboration with Dr. M. Gaballa at Sun Health Research Institute. Secondly, Dr. Harris has been successful in deriving epithelial tissues in vitro that mimic corneal tissues, both morphologically and histologically. When transplanted in vivo in rabbits, the tissues are equivalent to cadaver corneas in terms of sight restoration and function. Dr. Harris and his team are currently developing a human-to-human eye model that will avoid some of the xenogeneic complications associated with the rabbit model, in conjunction with the Dept. of Ophthalmology.Third, they have successfully derived glial, astrocyte and oligodendrocyte cell types from cord blood stem cells in vitro. Currently, these cells are used to study pediatric HIV infection at the molecular level, but are also amenable to work in Parkinson’s and spinal cord injury models. Dr. Harris is now collaborating with Dr. Madhavan of Neurology to study Parkinson’s disease and with Dr. Rogers of Stanford Research Institute to study Alzheimer’s disease. Fourth, recent work has begun comparing various stem cells sources (cord blood, bone marrow and adipose tissue) for the capacity to be used in regenerative medicine. Finally, over the past year they have investigated the use of cord blood stem cells for epithelial wound healing, with the goal being the treatment of non-healing wounds and ulcers in diabetic and bed-ridden patients. It has been found that injections of bone marrow stem cells, both intravenously as well as in the wound margins, significantly reduce healing time as well as minimizing scar formation. Of interest, the age of the recipient plays a significant role in wound healing. Keywords: stem cells, regenerative medicine, biobanking

Carol Gregorio, PhD, performs research in her lab that is focused on identifying the components and molecular mechanisms regulating actin architecture in cardiac and skeletal muscle during normal development and disease. Control of actin filament lengths and dynamics is important for cell motility and architecture and is regulated in part by capping proteins that block elongation and depolymerization at both the fast-growing (barbed) and slow-growing (pointed) ends of the filaments. Striated muscle is an ideal model system to test for the functional properties of various actin regulatory proteins due to the precise organization and polarity of cytoskeletal components within repeating sarcomeric units (for example, the ~1 mm long actin filaments are easily resolved by light microscopy). Using this system, she can combine advanced cell biological and biochemical approaches with direct tests of physiological function in live beating muscle cells.The research objectives of the laboratory can be broadly summarized as follows: 1) understanding the cellular mechanisms involved in the assembly, regulation and maintenance of contractile proteins in cardiac muscle in health and disease; 2) deciphering the mechanisms critical for precisely specifying and maintaining the lengths of actin filaments; 3) discovery of novel models of de novo cardiac muscle assembly, with special emphasis on differentiating murine embryonic stem (ES) cells to study all stages of heart muscle development. Actin is an indispensable structural element of cells and is the major component of heart muscle. Changes in actin, caused by genetic mutations, which have been identified in humans, are a frequent cause of several forms of cardiomyopathy. Her lab is determining how genetic defects in this protein affect muscle force generation and muscle contraction, leading to sudden cardiac death.

David Galbraith obtained undergraduate and graduate degrees in Biochemistry from the University of Cambridge, and postdoctoral training as a NATO Fellow at Stanford University. His first academic appointment was at the University of Nebraska Lincoln, and he became Professor of Plant Sciences at the University of Arizona in 1989. His research has focused on the development of instrumentation and methods for the analysis of biological cells, organs, and systems. He is internationally recognized as a pioneer in the development and use of flow cytometry and sorting in plants, developing widely-used methods for the analysis of genome size and cell cycle status, and for the production of somatic hybrids. He also was among the first to develop methods for the analysis of gene expression within specific cell types, using markers based on Fluorescent Protein expression for flow sorting these cells, and microarray platforms for analysis of their transcriptional activities and protein complements. Current interests include applications of highly parallel platforms for transcript and protein profiling of minimal sample sizes, and for analysis of genetic and epigenetic mechanisms that regulate gene expression during normal development and in diseased states, specifically pancreatic cancer. He is also funded to study factors involved in the regulation of bud dormancy in Vitis vinifera, and has interests in biodiversity and improvement of third-world agriculture. He has published more than 180 scholarly research articles, holds several patents, was elected a Fellow of the American Association for Advancement of Science in 2002, and serves on the editorial board of Cytometry Part A. He is widely sought as a speaker, having presented over 360 seminars in academic, industrial and conference settings. He was elected Secretary of the International Society for Advancement of Cytometry in 2016. Keywords: Plant and Animal Cellular Engineering; Biological Instrumentation; Flow Cytometry and Sorting

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"