We are an interdisciplinary research group at the interface of carbohydrate research and immunology. Our objective is to explore treatment of and protection from infectious diseases and cancer by understanding key molecular and cellular interactions between the components of the immune system and carbohydrate antigens associated with microbes or cancers.
Our research program is directed at: delineating immune mechanisms involved in carbohydrate-mediated adaptive immune response, and designing, synthesizing and testing vaccine targets against model pathogens and cancers. Our research approach involves: (1) identification of the molecular interactions involved in uptake, processing and presentation of carbohydrate antigens by the antigen presenting cells (APCs), (2) isolation and characterization of T cells and their epitopes generated from model carbohydrate antigens, (3) understanding the basis for cellular and humoral immune responses induced by carbohydrate presentation and recognition that enable eradication of disease causing agents, (4) design and synthesis of new-generation therapeutic and/ or prophylactic agents based on the knowledge gained from mechanisms discovered.
Bacillus thuringiensis (Bt) is a bacterium the produces protein crystals that are toxic to insects. The greatest usage of Bt has come from the engineering of Bt genes into crop plants. In the Adang laboratory, we combine mutational analyses of Bt toxins with molecular characterization of glycoprotein receptors in the insect midgut to elucidate the steps in Bt toxin action. We also are using a proteomic approach to identify proteins in the brush border epithelium of pest insects of agricultural and medical importance. The goal is to understand, at the molecular level, how insects adapt to Bt toxins and pathogens.
Our work focuses on the generation of therapeutically useful cell types that can be used to treat cardiovascular disease, diabetes, stroke, autoimmune disease, spinal cord injury and neurological diseases. We are also interested in early development and how pluripotent cells contribute to the developing embryo. For further information, visit our lab website: www.daltonlab.uga.edu
Darvill's research focuses on structurally characterizing the five major noncellulosic carbohydrates of plant primary cell walls homogalacturonan, rhamnogalacturonan I and II, xyloglucan, and glucuronoarabinoxylan. Plant primary cell walls control the rate and direction of cell growth that determine ultimately the shapes of cells, tissues, and organs; they form a barrier to pathogens, are the source of oligosaccharins that elicit plant defense responses to pathogens, and participate in controlling plant growth and development. New analytical techniques are continually developed to isolate and determine the complicated structures and functions of these molecules. Interactions between wall-matrix polysaccharides is being characterized by examining the cell-, tissue-, and species-dependent expression of cell wall epitopes using well-characterized monoclonal antibodies.
We study how protein glycosylation affects cellular communication as well as protein folding using biochemical, cell biological and animal studies. The forms of glycosylation we study affect development, birth defects, and cancer.
Pectin is a family of complex polysaccharides present in all plant primary cell walls. Pectin plays multiple roles in plant growth, development, and defense responses; in part through contributing to cell wall strength, wall ion exchange and sieving properties, cell-cell adhesion, and cell-cell communication. Pectin is a food fiber and a commercial gelling agent that has beneficial effects on human health. Our long term goal is to decipher how the 53 distinct enzyme activities required for pectin synthesis interact to synthesize pectin and to modify pectin synthesis in order to study pectin function. Towards this goal we are purifying, cloning, and characterizing the biosynthetic enzymes; many of which are Golgi localized and membrane bound enzymes. Current emphasis is on the galacturonosyltransferase and the methyltransferase that synthesize the pectic polysaccharide homogalacturonan.
Research in the Moremen lab focuses on the structure, enzymology, regulation, and localization of enzymes involved in the biosynthesis, recognition, and catabolism of mammalian glycoproteins. Carbohydrate structures on glycoproteins contribute to many biological recognition events between molecules and between cells in an organism. Alterations in the synthesis and degradation of these structures can also occur in human genetic disease. Work in the Moremen lab is focused on (1) the characterization of enzymes involved in mammalian glycoprotein biosynthesis and catabolism and the functionally defective forms of these enzymes involved in human genetic disease and (2) the identification and characterization of carbohydrate-binding proteins and their roles in vertebrate development and physiology.
My research focuses on the use of mass spectrometry to answer biological / biomedical questions. The majority of our projects involve characterizing the post-translational modifications (e.g., glycosylation, phosphorylation) present in the protein of interest. For example, we are currently investigating the in vivo changes that occur in human eye lenses upon normal aging and cataract formation. We hope that this research ultimately will provide a mechanism to prevent cataracts. We also conduct research into developing new methodologies to increase the amount of information obtained from these MS experiments and to reduce the quantity of material needed for analysis.
Our research focuses on the function of glycoconjugates in the regulation of cell adhesion. 1) investigation of the mechanism how glycosyltransferases and oligosaccharide expression regulate cell adhesion, migration, and invasiveness; 2) structure and function of the glycosyltransferase GlcNAc-T V to develop an inhibitor as a cancer therapeutic; 3) identification of glycoprotein glycoforms diagnostic for carcinomas; 4) function of a novel endothelial cell lectin, most likely in pathogen surveillance; 5) structural determination of a new family of animal and fungal lectins, the X-type lectins; 6) functions of lectins in animal development and as ligands for BT toxins.
The Prestegard group applies Nuclear Magnetic Resonance (NMR) spectroscopy to the investigation of structural and functional properties of biologically important systems. Systems of interest include carbohydrate binding proteins, metallo-proteins and membrane associated proteins. These systems play important roles in cell signalling, cell differentiation, and cell-cell interaction. As such, they become targets for rational drug design. NMR provides a useful tool for these investigations. However, NMR is also an evolving tool, limited both by current experimental approaches and data analysis procedures. To push back limits of applicability the group also devotes considerable effort to method development.
We are trying understand how the protozoan parasite, Trypanosoma brucei, regulates telomeric gene expression and evades the host immune response. Our current focus is on the role of the novel DNA base, base J, and in regulating telomeric homologous recombination events.
Our laboratory utilizes multiple model systems including zebrafish to study the developmental consequences of impaired lysosomal catabolism of glycoproteins. We are focused on understanding how the mislocalization and inappropriate activity of specific enzymes impacts the normal development and function of several tissues including cartilage.
Specific cell surface oligosaccharides function as identity tags, allowing cells to appropriately interact with each other and with their environment. We utilize genetic, molecular, and chemical techniques in vertebrate (mouse) and insect (Drosophila) model systems to study two aspects of carbohydrate expression: 1) the influence of cell surface carbohydrates on development of the nervous system, 2) mechanisms that control tissue- and stage-specific oligosaccharide expression. Our results have implications for facilitating regeneration of axon pathways in the nervous system, for understanding innate immunity and tissue surveillance, and for controlling the cellular changes that precede tumor metastasis.
Research in the Wang laboratory focuses on the structure and function of heparan sulfate proteoglycans in vasculature and cancer biology. Heparan sulfate proteoglycans are glycoconjugates which are abundant on the cell surface and in the extracellular matrix. In vitro studies have suggested that heparan sulfate proteoglycans interact with growth factors, growth factor binding proteins, extracellular proteases, protease inhibitors, chemokines, morphogens, and cell adhesive proteins to modulate cell differentiation, proliferation, migration, blood coagulation, lipid metabolism, and leukocyte trafficking. However, the biological and pathological functions of heparan sulfate proteoglycans in vivo are still largely unknown. Using techniques, including conditional mouse gene targeting, embryonic stem (ES) cell differentiation, primary cell culture, and mouse models, the Wang lab is aiming to understand the roles and the underlying mechanisms of heparan sulfate proteoglycan in vascular development, cancer biology and blood coagulation in vivo, and to develop novel approaches to cure the related pathological conditions.
Our laboratory is interested in how post-translational modifications of proteins increase functional diversity. Primarily, we are interested in glycosylation, with a focus regarding: 1. O-GlcNAc in Type II diabetes and stem cell biology 2. O-Mannosylation in Congenital Muscular Dystrophy and viral entry into host cells 3. Glycoproteins as biomarkers in human disease, specifically pancreatic cancer and metabolic syndrome 4. Development of technology-based approaches, primarily mass-spectrometry, for quantitive proteomics/ glycomics/ glycoproteomics.
Glycosylation regulates the activities of proteins via multiple intrinsic and extrinsic mechanisms. A remarkable example, in our laboratory’s view, is the glycosylation of a subunit of the E3(SCF)ubiquitin ligases, Skp1. Skp1 glycosylation, which depends on its prior oxygen-dependent prolyl hydroxylation, promotes assembly and presumably the activities of this enzyme family toward the degradation of a whole host of cell regulatory factors. This mechanism underlies oxygen-sensing by a variety of unicellular organisms, including the social amoeba Dictyostelium and the human pathogen Toxoplasma gondii. Our multidisciplinary approaches to understand this mechanism, and exploit our understanding to control parasite virulence, embrace structural biology, metabolomics, bioinformatics, molecular genetics, enzymology, cell and developmental biology, and parasitology.
The focus of my group's research is to examine the relationships between carbohydrate conformation and biological recognition and activity. We are particularly interested in the mechanisms of carbohydrate recognition in the immune system. Current research projects include examinations of bacterial antigen-antibody interactions, as well as other carbohydrate-protein interactions. The carbohydrate antigens associated with bacteria, such as Salmonella paratyphi B and group B Streptococcus are being studied in order to quantify the contributions made by hydrophobic and hydrophilic interactions. In conjunction with experimental methods (NMR and X-ray), we apply molecular dynamics simulations with the GLYCAM parameters and the AMBER force field.
The "primary" cell wall, which surrounds growing plant cells, plays a key role in plant development. One of its most important functions is to control the rate and orientation of cell expansion. Polysaccharide networks in the wall expand by gradually yielding under osmotic stress, allowing the cell to grow in a controlled, oriented fashion. This process determines the morphology of each cell, which ultimately determines the shape of the entire plant. Research in my laboratory is aimed at characterizing the molecular dynamics and topology that lead to the assembly and controlled expansion of the cell wall.