Laura L Kiessling
University Of Wisconsin Madison
Project start date: 2005-03-15
Project end date: 2014-12-31
Sponsored Links Excellgen http://Excellgen.com
The Chemistry And Biology Of Galactofuranose Residues
Laura L Kiessling, Professor
University Of Wisconsin Madison Suite 6401 Madison, Wi 537151218
Grant 5R01AI063596-03 from National Institute Of Allergy And Infectious Diseases IRG: BNP
Abstract: The overall objective of the proposed research is to explore the biosynthetic incorporation of galactofuranose (Galf) residues. Galf residues are found in many pathogens, but they are not present in mammals. In this application, we focus on understanding and inhibiting two enzymes involved in the biosynthesis of glycoconjugates containing Galf residues the flavoenzyme UDP-galactopyranose mutase (UGM) and the putative galactofuranosyltransferase GlfT. Both of these enzymes are involved in mycobacterial cell wall biosynthesis, and both are essential for the viability of Mycobacterium tuberculosis, the causative agent of tuberculosis. Despite their potential importance as therapeutic targets, many questions regarding how these enzymes participate in biosynthesis of the mycobacterial cell wall remain. For example, the mechanism by which UGM catalyzes the isomerization of UDP-galactopyranose (UDP-Galp) and UDP-galactofuranose (UDP-Galf) is unknown. Even less is known about GlfT, which appears to transfer galactofuranose residues to lipid precursors. The proposed research has three aims. The first aim is focused on testing our hypothesis that the isomerization of UDP- Galp and UDP-Galf proceeds via an N(5) flavin-derived iminium ion. This mode of flavin catalysis has not been observed previously/and the experiments are proposed in aim 1 are designed to evaluate the feasibility of this mechanistic proposal. Aim 2 is directed at identifying inhibitors of UGM using a fluorescence polarization assay. One goal of this aim is to identify molecular scaffolds from which combinatorial libraries can be generated to optimize potency. In aim 3, we propose to investigate GlfT. The goals are to develop an effective method to produce this putative glycosyltransferase and to characterize its substrate specificity. We anticipate that the studies proposed here will open new avenues for investigating the roles of this interesting carbohydrate unit. Moreover, we hope that by pursuing the proposed investigations, new leads for the treatment of tuberculosis may emerge.
Keywords: Mycobacterium tuberculosis, enzyme activity, enzyme biosynthesis, enzyme inhibitor, flavin, glycolipid, glycoprotein, glycosyltransferase, monosaccharide, biological signal transduction, galactose, pathologic process, phosphomutase, protein structure function, uridine diphosphate, Escherichia coli, X ray crystallography, fluorescence polarization, high performance liquid chromatography, high throughput technology, mass spectrometry, site directed mutagenesis
Project start date: 2005-03-15
Project end date: 2009-02-28
5R01AI063596-03 (2007): $305377
5R01AI063596-02 (2006): $301319
Grants awarded to Laura L Kiessling
TRAINING IN USE OF DMX ELECTRONICS
Laura L Kiessling, Professor
Institution:
Grant 5P41RR002301-120058 from National Center For Research Resources
Abstract: Training in the use of DMX electronics.
MULITVALENT LIGANDS AS EFFECTORS
Laura L Kiessling
Department/ Educational Institution Type:
Grant 5R01GM055984-12 from National Institute Of General Medical Sciences
Abstract: This proposal is a competitive renewal of program with a long-term objective to elucidate the molecular details of chemotactic signaling in bacteria using chemical biology strategies. A second objective of the proposed research is to ascertain whether our findings in bacteria are relevant for leukocyte chemotaxis. The signaling pathway that results in bacterial chemotaxis serves as a model for understanding two- component signaling in particular and transmembrane signaling in general. Bacteria respond sensitively to changes in chemoeffector concentration over a large concentration range. We hypothesize that bacteria amplify subtle differences in signal concentration through a signaling lattice, and there is mounting evidence for such a model. This model raises several questions How are proteins organized within the lattice? How does attractant binding alter interactions within the lattice? What is the effect of repellents on the lattice structure? How does covalent modification (phosphorylation and methylation) affect interactions within the lattice? Are there parallels in the signal amplification mechanisms of bacteria and neutrophils? We propose to address these questions using a variety of approaches. These include the synthesis and testing of monovalent and multivalent chemoeffectors, protein footprinting experiments, and x-ray crystallography. Aim 1 is focused on understanding how periplasmic binding proteins (PBPs) function. We have identified a ligand for the periplasmic glucose/galactose binding protein (GGBP), and this ligand inhibits GGBP- mediated chemotaxis. We propose to carry out structural studies to understand how this PBP antagonist functions. We envision that such studies will be useful in devising inhibitors of other bacterial processes mediated by PBPs including biofilm formation and virulence. In aim 2, we plan to continue studies initiated in the past grant period explore the role of inter-chemoreceptor interactions in chemotactic signal amplification in bacteria. In aim 3, we propose to use protein footprinting experiments to investigate protein - protein interactions important in chemotaxis signal transduction. We anticipate that the studies proposed in aims 2 and 3 will provide an increased understanding of how bacteria transduce and amplify signals. In aim 4, we propose to evaluate multivalent ligands as leukocyte chemoattractants. The goal of this aim is to determine whether there are similarities in the mechanisms by which bacteria and leukocytes amplify signals. We anticipate that our studies will facilitate the development of agents that interfere with key two- component signaling pathways; therefore, they may result in the development of new anti-microbial agents. Moreover, neutrophil chemotaxis occurs in the inflammatory/immune response. Thus, conclusions from our studies will be broadly applicable to understanding other signaling pathways involved in human disease
Keywords: 1-Phosphatidylinositol 3-Kinase; Address; Affect; Agonist; anti-microbial agent; anti-microbial drug; Antigenic Determinants; antimicrobial agent; antimicrobial drug; ATP[{..}]1-phosphatidyl-1D-myo-inositol 3-phosphotransferase; Bacteria; base; beta-D-galactoside transport protein; Binding; Binding (Molecular Function); Binding Determinants; biofilm; biological signal transduction; Biology; Blood leukocyte; Blood Neutrophil; Blood Polymorphonuclear Neutrophil; Blood Segmented Neutrophil; Cell Communication and Signaling; Cell Signaling; Chemicals; Chemoattractant Receptor; Chemoattractants; Chemoreceptors; Chemotactic Factors; Chemotactic Peptide Receptor; Chemotaxins; Chemotaxis; Chemotaxis, Leukocyte; Communication; complement chemotactic factor; Complex; Crystallographies; Crystallography; D-Galactose; D-galactose chemosensory receptor; D-galactose-binding protein; D-galactose-hydrogen symport protein; D-Glucose; Data; design; designing; Development; Dextrose; E coli; Epitopes; Escherichia coli; experiment; experimental research; experimental study; F-Chemotactic Peptide Receptor; fMet-Leu-Phe receptor; FMLP Receptor; Formyl Peptide Receptor 1; FPR1; G Protein-Complex Receptor; G-Protein-Coupled Receptors; Galactopyranose; Galactopyranoside; Galactose; galactose chemoreceptor protein; galactose transport protein; galactose-binding protein; galactose-H+ symport protein; GalP transport protein; gene product; Glucose; Goals; Grant; H+ element; Heterophil Granulocyte; host response; human disease; Hydrogen Ions; Immune response; immunoresponse; Inflammatory; inhibitor; inhibitor/antagonist; Intracellular Communication and Signaling; Investigators; Leukocyte Chemotaxis; Leukocytes; Leukotaxis; Ligand Binding; Ligands; Marrow leukocyte; Marrow Neutrophil; Mass Spectrum; Mass Spectrum Analysis; Mediating; Methylation; Microbial Biofilms; Modeling; Modification; Molecular; Molecular Interaction; Mutagenesis, Site-Directed; N-formyl Hexapeptide Receptor; N-Formylmethionyl Peptide Receptor; neutrophil; Neutrophilic Granulocyte; Neutrophilic Leukocyte; novel; Output; periplasm; periplasmic; Periplasmic Binding Proteins; Periplasmic Space; Phosphatidylinositol 3-Kinase; Phosphatidylinositol-3-OH Kinase; Phosphoinositide 3-Hydroxykinase; Phosphorylation; Photometry/Spectrum Analysis, Mass; PI-3 Kinase; PI-3K; PI3-Kinase; Polymorph; Polymorphonuclear Cell; Polymorphonuclear Leukocytes; Polymorphonuclear Neutrophils; Process; programs; Programs (PT); Programs [Publication Type]; Property; Property, LOINC Axis 2; protein complex; Protein Footprinting; protein function; Protein Methylation; Protein Phosphorylation; protein protein interaction; Proteins; Protons; PtdIns 3-Kinase; Reagent; receptor; Receptor Protein; Receptors, Formyl Peptide; reconstitute; reconstitution; Research; Research Personnel; research study; Researchers; response; Reticuloendothelial System, Leukocytes; Role; Side; Signal Pathway; Signal Transduction; Signal Transduction Systems; Signaling; Signaling Protein; Site-Directed Mutagenesis; Site-Specific Mutagenesis; small molecule; social role; Spectrometry, Mass; Spectroscopy, Mass; Spectrum Analyses, Mass; Spectrum Analysis, Mass; Stimulus; Structure; sugar; Targeted DNA Modification; Targeted Modification; Testing; Type I Phosphatidylinositol Kinase; Type III Phosphoinositide 3-Kinase; VESCL; Vesicle; Virulence; white blood cell; White Blood Cells; white blood corpuscle; White Cell
Project start date: 1997-06-01
Project end date: 2011-06-30
Budget start date: 1-JUL-2009
Budget end date: 30-JUN-2011
5R01GM055984-12 (2009): $287148
5R01GM055984-11 (2008): $287349
2R01GM055984-09 (2006): $296326
5R01GM055984-10 (2007): $287544
Probes Of Carbohydrate Function
Laura L Kiessling, Professor
University Of Wisconsin Madison Suite 6401 Madison, Wi 537151218
Grant 5R01GM049975-13 from National Institute Of General Medical Sciences IRG: BNP
Abstract: This is a competitive renewal of a program focused on exploring protein - carbohydrate-binding interactions using synthetic ligands. The research proposed has three objectives. First, we shall investigate the recognition properties of the receptors DC-SIGN and DC-SIGNR by synthesizing and identifying inhibitors of these lectins. DC-SIGN has been shown to mediate the interaction of dendritic cells with T cells. Both DCSIGN and DC-SIGNR can facilitate HIV infection of CD4-positive cells in trans. The physiological and pathological functions of DC-SIGN and DC-SIGNR are mediated through their interactions with N-linked carbohydrates. We propose to use methods developed in the past grant period to synthesize libraries of ligands and to identify active DC-SIGN and DC-SIGNR inhibitors. Both monovalent and multivalent inhibitors will be synthesized and tested for their ability to block key pathological and physiological functions of these lectins. Second, we shall use the inhibitors identified to probe the biological functions of DC-SIGN and DCSIGNR. Third, we shall continue our efforts to develop methods for the synthesis of N-linked glycopeptides. The proposed research is divided into 5 aims. The proposed studies in aim 1 are focused on developing a high throughput assay for identifying DC-SIGN and DC-SIGNR ligands. In Aim 2, we propose to synthesize and evaluate compounds libraries designed to inhibit DC-SIGN, DC-SIGNR and other C-type lectins. The goal of aim 3 is to generate multivalent compounds that inhibit and/or cluster DC-SIGN and DC-SIGNR. We postulate that multivalent ligands will more potently block the target lectins. Aim 4 is focused on testing the activities of synthetic inhibitors in relevant assays. The ligands for their abilities to bind to cells producing DC-SIGN or DC-SIGNR, to inhibit the binding of ICAM-3 to dendritic cells, to block the binding of HIV-1 gp120 to DC-SIGN(DC-SIGNR)-positive cells, to inhibit HIV transmission, and to promote DC-SIGN and DCSIGNR internalization. Aim 5 is focused on the development of a new approach to the convergent synthesis of glycopeptides. We anticipate that the results from our studies will provide new tools for the investigation of DC-SIGN and DC-SIGNR function in particular and for probing C-type lectin function in general.
Keywords: carbohydrate structure, cell adhesion, chemical binding, lectin, protein structure, technology /technique development, T lymphocyte, dendritic cell, glycopeptide, inhibitor /antagonist, ligand, protein binding, receptor binding, receptor expression, flow cytometry, surface plasmon resonance
Project start date: 1993-07-01
Project end date: 2007-12-31
5R01GM049975-13 (2006): $280161
5R01GM049975-12 (2005): $287022
5R01GM049975-11 (2004): $287138
SOLUTION STRUCTURES OF LEWISA And LEWISX BASED SELECTION LIGANDANALOGS
Laura L Kiessling, Professor
Institution:
Grant 5P41RR002301-120057 from National Center For Research Resources
Abstract: The solution structures of trisaccharide inhibitors of selectin-mediated cell adhesion are being studied by NOESY and ROESY NMR spectroscopy. E- and P-selectin are multi-domain proteins expressed on vascular endothelial cell surfaces in response to tissue damage; their function is to induce leukocyte transient attachment and rolling by binding carbohydrates on the mobile cells surfaces. These events are critical parts of the inflammatory immune response. L-selectin, on the leukocyte surface, binds to carbohydrates on endothelial cells as part of regular trafficking to the lymph. Afflictions such as rheumatoid arthritis and reperfusion injury are caused in large part by disruptions in the normal functioning of these systems. Minimal carbohydrate motifs that promote binding are related to the trisaccharides Lewisa (Fuc(1-4[Gal(1-3]Glc) and Lewisx (Fuc(1-3[Gal(1-4]Glc); charge has also been identified as an important factor in binding specificity and strength. To investigate the relationships between charge location on the trisaccharide units and binding strength, specificity, and mode, several sulfated derivatives of Lewisa and Lewisx have been synthesized. It is important to know what effects sulfation has on the carbohydrate structure in order to infer useful information about possible binding modes from binding data. To accomplish this end and the lay the groundwork for NMR studies on the selectin-carbohydrate complexes, the determination of the solution structures of Lewis a derivatives sulfated at the 3(-Gal, 6(-Gal, 3(-6(-Gal positions and phosphorylated at the 3(-Gal positions have been initiated. Similar studies are being undertaken with the Lewisx derivatives as they are made available.
MULTIVALENT PROTEIN CARBOHYDRATE INTERACTIONS
Laura L Kiessling, Professor
Chemistryuniversity Of Wisconsin Madison
21 N. Park Street, Suite 6401
madison, Wi 537151218
Grant 5R01GM055984-04 from National Institute Of General Medical Sciences IRG: BNP
Abstract: The overall objectives of this research project are to elucidate the role of multivalent binding in biological processes mediated by protein-saccharide interactions, to develop new methods to synthesize multivalent saccharide derivatives, and to generate multivalent saccharide derivatives with significant biological activity and medicinal functions. The carbohydrate-binding proteins to be studied range from structurally well-characterized systems to those in which the carbohydrate-binding site has not yet been definitively identified. The former group is composed of a series of mannose-binding proteins, which form defined oligomers and bind multivalent saccharide ligands (including Con A, serum mannose-binding protein and the liver mannose-binding protein). The wealth of structural information on these proteins makes them excellent systems in which to study structure/function relationships for multivalent saccharide ligands. The selectins, a family of proteins that mediates the tethering and rolling of leucocytes and lymphocytes along the vascular endothelium, comprise the second set. Several high affinity physiological ligands that bind the selectins present multiple carbohydrate determinants to the proteins; however the molecular bases of these high affinity interactions are unknown. The tools and information gained from investigating multidentate interactions with the mannose-binding proteins will be applied to the study of the selectins
Keywords: binding protein, chemical binding, mannose, protein structure /function, selectin
Project start date: 1997-06-01
Project end date: 2001-05-31
5R01GM055984-04 (2000): $162257
Sponsored Links Excellgen http://Excellgen.com
5R01GM055984-03 (1999): $158295
1R01GM055984-01 (1997): $172881
PROBES OF CARBOHYDRATE FUNCTION
Laura L Kiessling, Professor
Chemistryuniversity Of Wisconsin Madison
21 N. Park Street, Suite 6401
madison, Wi 537151218
Grant 5R01GM049975-08 from National Institute Of General Medical Sciences IRG: ZRG1
Abstract: The overall objectives of this research project are to ascertain the principles that determine binding affinity and specificity in the recognition of the tetrasaccharide sialyl-Lewis x by the E-selectin receptor and to generate molecules that inhibit this interaction. Sialyl-Lewis x is found on the surface of leukocytes, and the E-selectin receptor is expressed on endothelial cells. Mounting evidence suggests that the formation of a protein-complex between these molecules, mediates call adhesion between leukocytes and the vascular endothelium. This intercellular interaction is an early event in an inflammatory or immune response. Inhibitors of this adhesive interaction could be used to develop new strategies for treatment of inflammatory conditions such as rheumatoid arthritis, multiple sclerosis, and reperfusion injury. These cell adhesion processes represent fundamentally new therapeutic targets. The generation of molecules to interfere with carbohydrate function offers a new frontier in inhibitor design. The proposed approach involves combining concepts and synthetic methods from organic chemistry with techniques from biochemistry and molecular and structural biology to generate the component molecules and to study the structure-function relationships in this system. The specific aims of this research are as follows (1) To use organic synthesis to generate the naturally-occurring carbohydrate sialyl-Lewis x and to investigate the folding properties of this carbohydrate by multi- dimensional NMR spectroscopy, (2) To produce the region of the E-selectin receptor that is responsible for carbohydrate-binding using a fusion expression system, which will allow for the generation of the free protein for NMR studies and immobilized protein for carbohydrate-binding studies, (3) To study the conformation of the oligosaccharide bound to the carbohydrate recognition domain of the E-selectin protein by multi- dimensional NMR spectroscopy, (4) To synthesize polymers containing carbohydrate residues in defined locations as potential multivalent inhibitors of cell adhesion. The information that is gained from the studies of the complex will be incorporated into the design of anti-adhesive compounds. The proposed research will generate insight into the molecular recognition and biological role for oligosaccharides in cell adhesion. It is anticipated that these studies will lead to the development of new methodologies for the modulation of cell-cell and carbohydrate-receptor interactions
Keywords: carbohydrate structure, cell adhesion, chemical binding, oligosaccharide chemical synthesis, conformation, inhibitor /antagonist, leukocyte adhesion molecule, protein structure, receptor binding, receptor expression, selectin, sialate, vascular endothelium fusion gene, nuclear magnetic resonance spectroscopy, recombinant protein
Project start date: 1993-07-01
Project end date: 2003-03-31
5R01GM049975-08 (2001): $282227
5R01GM049975-07 (2000): $276942
2R01GM049975-06 (1999): $275265
BIOORGANIC STUDIES OF CARBOHYDRATE FUNCTION
Laura L Kiessling, Professor
University Of Wisconsin Madison Suite 6401 Madison, Wi 537151218
Grant 5R29GM049975-05 from National Institute Of General Medical Sciences IRG: BNP
Abstract: The overall objectives of this research project are to ascertain the principles that determine binding affinity and specificity in the recognition of the tetrasaccharide sialyl-Lewis x by the E-selectin receptor and to generate molecules that inhibit this interaction. Sialyl-Lewis x is found on the surface of leukocytes, and the E-selectin receptor is expressed on endothelial cells. Mounting evidence suggests that the formation of a protein-complex between these molecules, mediates call adhesion between leukocytes and the vascular endothelium. This intercellular interaction is an early event in an inflammatory or immune response. Inhibitors of this adhesive interaction could be used to develop new strategies for treatment of inflammatory conditions such as rheumatoid arthritis, multiple sclerosis, and reperfusion injury. These cell adhesion processes represent fundamentally new therapeutic targets. The generation of molecules to interfere with carbohydrate function offers a new frontier in inhibitor design. The proposed approach involves combining concepts and synthetic methods from organic chemistry with techniques from biochemistry and molecular and structural biology to generate the component molecules and to study the structure-function relationships in this system. The specific aims of this research are as follows (1) To use organic synthesis to generate the naturally-occurring carbohydrate sialyl-Lewis x and to investigate the folding properties of this carbohydrate by multi- dimensional NMR spectroscopy, (2) To produce the region of the E-selectin receptor that is responsible for carbohydrate-binding using a fusion expression system, which will allow for the generation of the free protein for NMR studies and immobilized protein for carbohydrate-binding studies, (3) To study the conformation of the oligosaccharide bound to the carbohydrate recognition domain of the E-selectin protein by multi- dimensional NMR spectroscopy, (4) To synthesize polymers containing carbohydrate residues in defined locations as potential multivalent inhibitors of cell adhesion. The information that is gained from the studies of the complex will be incorporated into the design of anti-adhesive compounds. The proposed research will generate insight into the molecular recognition and biological role for oligosaccharides in cell adhesion. It is anticipated that these studies will lead to the development of new methodologies for the modulation of cell-cell and carbohydrate-receptor interactions.
Keywords: carbohydrate structure, cell adhesion, chemical binding, oligosaccharide, chemical synthesis, conformation, inhibitor /antagonist, leukocyte adhesion molecule, protein structure, receptor binding, receptor expression, selectin, sialate, vascular endothelium, fusion gene, nuclear magnetic resonance spectroscopy, recombinant protein
Project start date: 1993-07-01
Project end date: 1999-03-31
5R29GM049975-05 (1997): $84639
5R29GM049975-03 (1995): $87496
5R29GM049975-02 (1994): $101593
1R29GM049975-01 (1993): $104557
Multivalent Ligands As Effectors
Laura L Kiessling, Professor
University Of Wisconsin Madison Suite 6401 Madison, Wi 537151218
Grant 5R01GM055984-08 from National Institute Of General Medical Sciences IRG: ZRG1
Abstract: The overall objectives of the proposed research are to understand how cells control their responses to stimuli in the environment and to develop ligands that can regulate these responses. The binding of a ligand to a cell surface receptor can give rise to a signal; its magnitude and duration can be influenced by changes in receptor occupation. We hypothesize that signal amplification and integration is also achieved through receptor clustering. Synthetic multivalent ligands are ideally suited to investigating the contributions of receptor clustering to signal output. Because multivalent ligands can influence cell surface receptor occupation and clustering, we propose to examine their utility as effectors (compounds that elicit a cellular response). In the systems we shall investigate, bacterial and leukocyte chemotaxis, we hypothesize that signal amplification and integration occurs via extended receptor arrays. Through the formation of non-covalent interactions with receptors in these arrays, multivalent ligands can stabilize supramolecular complexes through which information can be transferred. To test this hypothesis, we will explore the relationship between the structure of a multivalent ligand and its ability to promote chemotaxis of bacteria or leukocytes. The specific aims of this proposal are 1) to develop methods to synthesize libraries of multivalent ligands that vary in recognition element identity, length, and shape; 2) to explore bacterial chemotactic responses to synthetic multivalent ligands and to probe the mechanisms by which these responses are elicited; 3) to examine the ability of synthetic multivalent ligands to influence swarmer cell differentiation; and 4) to investigate the chemotactic responses of neutrophils to synthetic multivalent ligands mediated through the N-formyl peptide receptor, a member of the chemoattractant/chemokine G protein- coupled receptor (GPCR) family. An understanding of the mechanisms that control bacterial chemotaxis is important for devising approaches to manipulate prokaryotic signaling events. As an application of our ligands that alter bacterial chemotaxis, we will investigate their ability to interfere with differentiation of pathogenic swarmer cells. Our studies of leukocyte chemotaxis may lead to new strategies for the control of inflammation and a deeper understanding of the role of receptor clustering in GPCR-mediated signal amplification and integration.
Keywords: biological signal transduction, chemoreceptor, chemotaxis, ligand, protein structure function, receptor binding, G protein, cell differentiation, chemoattractant, chemokine, method development, peptide library, Bacillus subtilis, Escherichia coli, Proteus
Project start date: 1997-06-01
Project end date: 2006-06-30
5R01GM055984-08 (2004): $291000
Sponsored Links Excellgen http://Excellgen.com
2R01GM055984-05A1 (2001): $291000
The Chemistry And Biology Of Galactofuranose Residues
Laura L Kiessling, Professor
University Of Wisconsin Madison Suite 6401 Madison, Wi 537151218
Grant 1R01AI063596-01 from National Institute Of Allergy And Infectious Diseases IRG: BNP
Abstract: The overall objective of the proposed research is to explore the biosynthetic incorporation of galactofuranose (Galf) residues. Galf residues are found in many pathogens, but they are not present in mammals. In this application, we focus on understanding and inhibiting two enzymes involved in the biosynthesis of glycoconjugates containing Galf residues the flavoenzyme UDP-galactopyranose mutase (UGM) and the putative galactofuranosyltransferase GlfT. Both of these enzymes are involved in mycobacterial cell wall biosynthesis, and both are essential for the viability of Mycobacterium tuberculosis, the causative agent of tuberculosis. Despite their potential importance as therapeutic targets, many questions regarding how these enzymes participate in biosynthesis of the mycobacterial cell wall remain. For example, the mechanism by which UGM catalyzes the isomerization of UDP-galactopyranose (UDP-Galp) and UDP-galactofuranose (UDP-Galf) is unknown. Even less is known about GlfT, which appears to transfer galactofuranose residues to lipid precursors. The proposed research has three aims. The first aim is focused on testing our hypothesis that the isomerization of UDP- Galp and UDP-Galf proceeds via an N(5) flavin-derived iminium ion. This mode of flavin catalysis has not been observed previously/and the experiments are proposed in aim 1 are designed to evaluate the feasibility of this mechanistic proposal. Aim 2 is directed at identifying inhibitors of UGM using a fluorescence polarization assay. One goal of this aim is to identify molecular scaffolds from which combinatorial libraries can be generated to optimize potency. In aim 3, we propose to investigate GlfT. The goals are to develop an effective method to produce this putative glycosyltransferase and to characterize its substrate specificity. We anticipate that the studies proposed here will open new avenues for investigating the roles of this interesting carbohydrate unit. Moreover, we hope that by pursuing the proposed investigations, new leads for the treatment of tuberculosis may emerge.
Keywords: Mycobacterium tuberculosis, enzyme activity, enzyme biosynthesis, enzyme inhibitor, flavin, glycolipid, glycoprotein, glycosyltransferase, monosaccharide, biological signal transduction, galactose, pathologic process, phosphomutase, protein structure function, uridine diphosphate, Escherichia coli, X ray crystallography, fluorescence polarization, high performance liquid chromatography, high throughput technology, mass spectrometry, site directed mutagenesis
Project start date: 2005-03-15
Project end date: 2009-02-28
1R01AI063596-01 (2005): $330535
CHEMICAL BIOLOGY INTERFACE TRAINING GRANT
Laura L Kiessling
University Of Wisconsin Madison, 21 N. Park Street, Suite 6401, Madison, Wi 53715-1218
Grant 5T32GM008505-17 from National Institute Of General Medical Sciences
Abstract: The overall objective of the Chemistry-Biology Interface Predoctoral Training Program (CBIT) at the University of Wisconsin-Madison is to facilitate interdisciplinary research in which chemical and biological approaches are applied to illuminate and manipulate biological processes. To achieve these ends, the program provides multidisciplinary research opportunities and interactions, forums to develop trainee communication skills, and mechanisms for exploring scientific creativity and critical thinking. The CBIT offers interdisciplinary research opportunities in 45 research groups. There are 5 major participating graduate programs from which most CBI trainees earn their degrees the Integrated Program in Biochemistry, the Department of Chemical and Biological Engineering, the Division of Pharmaceutical Sciences, the Microbiology Doctoral Training Program, and the Department of Chemistry. In the past grant period,14-18 outstanding predoctoral trainees have participated in the CBI-TP (approximately 2/3 is supported by the program and 1/3 by other fellowships). These trainees are recruited from a national pool of students and trainers engage in a variety of approaches to attract trainees from groups that are underrepresented in the biomedical sciences. The research being pursued in these venues is directly relevant to addressing the major challenges facing human health. Trainees take courses that use innovative teaching methods to show them how to merge chemical and biological concepts to explore biological systems (Chemical Biology), discuss recent key publications in chemical biology (Chemical Biology Advanced Seminar), get a grounding in scientific research ethics (Ethics), participate in discussions focused on developing academic and professional skills, complete a 10-12 week industrial internship, and present their research to peers (Highlights at the Chemistry-Biology Interface). Since the CBI-TP was initiated in 1993, UW-Madison has built an extensive infrastructure for conducting chemical biology research. This infrastructure, when combined with the interactive and collaborative atmosphere on campus and an emphasis on graduate training, affords an environment uniquely conducive to interdisciplinary training in chemical biology. RELEVANCE The relevance of the Chemical-Biology Interface Predoctoral Training Program to public health is significant. The course selection and associated programmatic features ensure that the prospective trainees have an appropriate means to obtain quantitative backgrounds and exposure to topics directly related to human health, physiology, and disease mechanisms
Keywords: Biology; Chemicals; Grant; Training
Project start date: 1993-09-01
Project end date: 2014-06-30
Budget start date: 1-JUL-2010
Budget end date: 30-JUN-2011
PFA/PA: PA-06-468
5T32GM008505-17 (2010): $397634
2T32GM008505-16A1 (2009): $395429
Synthetic Ligands For Modulating B-Cell Responses
Laura L Kiessling, Professor
University Of Wisconsin Madison Suite 6401 Madison, Wi 537151218
Grant 5R01AI055258-04 from National Institute Of Allergy And Infectious Diseases IRG: BNP
Abstract: The antigen receptors on lymphocytes play pivotal roles in controlling the balance between tolerance and immunity. In B cells, the B cell antigen receptor (BCR) transmits signals that positively or negatively regulate lymphocyte survival, growth, and differentiation. B cell activation can be modulated by co-receptors, proteins on the cell surface that positively or negatively influence the threshold for BCR activation. The long-term goals of the proposed research are 2-fold to use synthetic ligands to investigate how the organization of proteins on the B cell surface influences signaling and to develop a general strategy to modulate specifically the output responses of B cell clones. The proposed research is divided into 4 aims. Aim 1 is to synthesize multivalent ligands that vary in valency and can activate signaling through the BCR. The goal of this aim is to address the questions Does the extent of BCR clustering influence B cell activation? Does the extent of clustering influence the localization of the BCR into lipid rafts? Aim 2 is focused on investigating the effects of co-clustering the positive regulatory receptor CD19/CD21 complex with the BCR. We propose to evaluate how a ligand s structure influences its ability to potently activate positive B cell responses. Aim 3 is to compare the effects of co-clustering negative regulatory co-receptors and the BCR. These studies will examine the relative ability of the inhibitory receptors CD22 and FcgammaRIIb, which negatively regulate B cell activation through the recruitment of different phosphatases, to influence cellular responses. Aim 4 is directed at testing the effects of the multivalent ligands on primary B-cells in vitro and in vivo. The goal of this aim is to examine how different populations of primary B cells respond to potent BCR modulators identified in aims 1-3 and to investigate whether these synthetic ligands can be used to manipulate primary B cell populations. We anticipate that our studies will provide insight into the signaling processes and may lead to new strategies for the generation of vaccines and/or compounds that inhibit autoimmune responses.
Keywords: B cell receptor, B lymphocyte, leukocyte activation /transformation, ligand, protein structure function, receptor binding, CD19 molecule, CD22 molecule, calcium flux, cell population study, cell surface receptor, endocytosis, immunologic receptor, membrane structure, protein localization, receptor expression, fluorescence microscopy, laboratory mouse
Project start date: 2003-04-15
Project end date: 2007-09-30
5R01AI055258-04 (2006): $350347
5R01AI055258-03 (2005): $358923
5R01AI055258-02 (2004): $359064
1R01AI055258-01 (2003): $359200
Chemical Biology Interface Training Grant
Laura L Kiessling, Professor
Chemistryuniversity Of Wisconsin Madison
21 N. Park Street, Suite 6401
madison, Wi 537151218
Grant 3T32GM008505-15S1 from National Institute Of General Medical Sciences IRG: BRT
Abstract: Start with Principal Investigator. List Name Kiessling, Laura L. Thorson, Jon Belshaw, Peter Burstyn, Judith Burke, Steve McEIroy, Erin Raines, Ronald Ruoho, Arnold Shen, Ben Use continuation pages as needed to provide the required information all other key personnel in alphabetical order, last name first. Organization UW-Madison UW-Madison UW-Madison UW-Madison UW-Madison UW-Madison UW-Madison UW-Madison UW-Madison 7 . o . . . PHS 398 (Rev. 05/01) Page 2 in the format shown below. Role on
Project start date: 1993-09-01
Project end date: 2009-06-30
3T32GM008505-15S1 (2008): $176255
Sponsored Links Excellgen http://Excellgen.com
5T32GM008505-15 (2007): $423700
5T32GM008505-14 (2006): $330350
5T32GM008505-13 (2005): $440638
5T32GM008505-12 (2004): $484701
2T32GM008505-11 (2003): $475150
GLYCOPEPTIDES AND OTHER NON-NATURAL VARIANTS: PROBES OF CARBOHYDRATE FUNCTION
Laura L Kiessling
University Of Wisconsin Madison, 21 N. Park Street, Suite 6401, Madison, Wi 53715-1218
Grant 3R01GM049975-15S1 from National Institute Of General Medical Sciences
Abstract: Lectins play critical roles in the immune system. The lectins on dendritic cells participate in antigen recognition and internalization and thereby serve as critical mediators of immunity. One such lectin, DC-SIGN, which mediates the beneficial process of antigen uptake for processing, can be co-opted by pathogens to suppress immune responses and promote their dissemination. For example, DC-SIGN can bind to HIV and facilitate its dissemination. It also has been shown to suppress immune responses to Mycobacterium tuberculosis. Because HIV and Mycobacterium tuberculosis are the two most significant threats to human health worldwide, it is critical to elucidate the molecular mechanisms underlying the function of DC-SIGN. The long-term goals of the proposed research are to use chemical biology to illuminate how DC-SIGN functions in signaling, antigen recognition, and antigen internalization. Insight into these processes can facilitate the design of agents to enhance the effectiveness of vaccines or prevent pathogen infection. The specific aims of the project follow (1) to identify non-carbohydrate, small-molecule ligands for DC- SIGN, (2) to develop chemical imaging strategies to follow DC-SIGN-mediated antigen internalization and dendritic cell migration, and (3) to develop new chemical approaches to explore bacteria-dendritic cell interactions mediated by DC-SIGN. The first specific aim focuses on providing a novel set of inhibitors of DC-SIGN. These also can serve as tools for exploring the consequences of engaging this lectin. The DC-SIGN ligands identified to date are based on carbohydrates, which bind weakly and can interact with other dendritic cell-surface lectins. We envision that non-carbohydrate-based ligands will bind to DC-SIGN with higher specificity and affinity. In Aim 2, we shall use the ligands identified in Aim 1 to explore the consequences of antigen interaction with DC-SIGN. DC-SIGN interacts with a variety of different types of antigens (proteins, viruses, bacteria, and fungi); therefore, it is critical to understand how antigen structure influences internalization and trafficking. We shall use chemical synthesis to vary DC-SIGN ligand structure and to endow these model antigens with fluorogenic reporter groups for imaging. Aim 3 addresses how dendritic cell internalization and processing of organisms is influenced by DC-SIGN engagement. To investigate this process, we shall chemically modify bacteria such that they display specific DC-SIGN ligands. The results of the investigations proposed in Aim 3 can provide insight into the role of DC-SIGN and offer new strategies to explore the role of specific receptors in host-pathogen interactions. Relevance. The carbohydrate-binding protein DC-SIGN is found on the surface of dendritic cells, where it functions in the immune system. In addition to its normal function in humans, DC-SIGN can be used by viruses, like HIV, to facilitate their dissemination, and by some bacteria, like those that cause tuberculosis, to suppress immune responses. Because of its role in facilitating the two diseases that cause the most deaths worldwide, how DC- SIGN works and how to control it is important. This project is aimed at identifying DC-SIGN inhibitors and using compounds that bind to DC-SIGN to study its function
Keywords: AIDS Virus; ATGN; Acquired Immune Deficiency Syndrome Virus; Acquired Immunodeficiency Syndrome Virus; Address; Affinity; Antigen Processing; Antigen Processings; Antigens; Bacteria; Bacterial Infections; Binding; Binding (Molecular Function); Biology; C-Type Lectins; Carbohydrates; Cell Adhesion; Cell Communication; Cell Communication and Signaling; Cell Interaction; Cell Locomotion; Cell Migration; Cell Movement; Cell Signaling; Cell Surface Receptors; Cell surface; Cell-to-Cell Interaction; Cells; Cellular Adhesion; Cellular Migration; Cessation of life; Chemicals; Collaborations; Death; Dendritic Cells; Development; Disease; Disorder; E coli; Escherichia coli; Glycopeptides; Goals; HIV; HIV-1; HIV-I; HIV1; HTLV-III; Health; High Throughput Assay; Human; Human Immunodeficiency Viruses; Human T-Cell Leukemia Virus Type III; Human T-Cell Lymphotropic Virus Type III; Human T-Lymphotropic Virus Type III; Human immunodeficiency virus 1; Human, General; ITX; Image; Immune response; Immune system; Immunity; Immunodeficiency Virus Type 1, Human; Immunologically Directed Therapy; Immunotherapy; Infection; Intracellular Communication and Signaling; Investigation; LAV-HTLV-III; Label; Lead; Lectin; Lectins, C-Type; Libraries; Life; Ligands; Lymphadenopathy-Associated Virus; M. tb; M. tuberculosis; M.tb; M.tuberculosis; MR Imaging; MR Tomography; MRI; Magnetic Resonance Imaging; Magnetic Resonance Imaging Scan; Man (Taxonomy); Man, Modern; Mediating; Mediator; Mediator of Activation; Mediator of activation protein; Medical Imaging, Magnetic Resonance / Nuclear Magnetic Resonance; Methods; Microbe; Modeling; Molecular; Molecular Interaction; Monitor; Motility; Motility, Cellular; Mycobacterium tuberculosis; NMR Imaging; NMR Tomography; Nuclear Magnetic Resonance Imaging; Organism; Pb element; Play; Process; Proteins; Reagent; Receptor Protein; Receptors, Cell Surface; Reporter; Research; Role; Route; S Period; S Phase; S phase (cell cycle); Signal Transduction; Signal Transduction Systems; Signaling; Solid; Specificity; Structure; Surface; Synthesis Period; Synthesis Phase; T-Cells; T-Lymphocyte; TIL4; TLR protein; TLR2; TLR2 receptor; Thymus-Dependent Lymphocytes; Toll-Like Receptor 2; Toll-like receptors; Toll/Interleukin 1 Receptor-Like 4; Toll/Interleukin 1 Receptor-Like Protein 4; Tuberculosis; Variant; Variation; Veiled Cells; Viral; Viral Gene Products; Viral Gene Proteins; Viral Proteins; Virus; Virus-HIV; Viruses, General; Work; Zeugmatography; antigen processing; bacterial disease; base; biological signal transduction; body system, allergic/immunologic; carbohydrate binding protein; cell motility; chemical synthesis; combat; design; designing; disease/disorder; disseminated TB; disseminated tuberculosis; experiment; experimental research; experimental study; fluorophore; fungus; gene product; heavy metal Pb; heavy metal lead; high throughput screening; host response; human T cell leukemia virus III; human T lymphotropic virus III; imaging; immune therapy; immunogen; immunoresponse; inhibitor; inhibitor/antagonist; insight; living system; migration; mimetics; novel; organ system, allergic/immunologic; pathogen; prevent; preventing; receptor; research study; response; small molecule; social role; thymus derived lymphocyte; tool; trafficking; tuberculous spondyloarthropathy; tumor; uptake; vaccine effectiveness; virus protein
Project start date: 2009-09-30
Project end date: 2011-08-31
Budget start date: 30-SEP-2009
Budget end date: 31-AUG-2011
PFA/PA: PA-07-070
3R01GM049975-15S1 (2009): $41000
THE CHEMISTRY AND BIOLOGY OF GALACTOFURANOSE RESIDUES
Laura L Kiessling
University Of Wisconsin Madison, 21 N. Park Street, Suite 6401, Madison, Wi 53715-1218
Grant 2R01AI063596-05A1 from National Institute Of Allergy And Infectious Diseases
Abstract: Galactofuranose (Galf) residues have been implicated in the virulence or viability of many microbes, including mycobacteria. The goal of the proposed research is to understand the mechanisms underlying Galf residue incorporation into the mycobacterial cell wall. We shall investigate the structure, catalytic mechanism, and function of two key enzymes in this process the flavoenzyme uridine-5´-diphosphate (UDP)-galactopyranose mutase (Glf or UGM) and the galactosylfuranosyltransferase GlfT2. The three Specific Aims of this application follow. Aim 1 is to understand the mechanism of the flavoenzyme UGM. Elucidating the catalytic mechanism UGM will enhance our understanding of the diverse chemistry of the flavoenzymes, provide insight into the chemistry underlying cell wall biosynthesis, and guide the generation of inhibitors of this essential enzyme. Aim 2 is to generate potent and cell-permeable inhibitors of UGM that can be used as probes of cell wall biosynthesis and as leads for the development of new antimycobacterial agents. Aim 3 is to investigate the enzyme GlfT2, which catalyzes the synthesis of a galactan polymer composed of alternating 1,5- and 1,6-linked Galf residues. We shall test whether the polymerization is processive, explore how a single enzyme generates two regioisomeric sugar linkages, and determine how polymer length is controlled. These investigations will illuminate the mechanisms underlying galactan biosynthesis in mycobacteria and the biosynthesis of polysaccharides, in general. In pursuing these Aims, we shall employ methods and ideas from organic chemistry, glycobiology, carbohydrate chemistry, chemical enzymology, structural biology, microbiology, and chemical biology. Significance The results of the proposed research will provide new insights into the assembly of the galactan polymer, an essential component of the mycobacterial cell wall. They also will address the fundamental question of how biological systems control polymer length in the absence of a template. This knowledge will be applied to develop small molecules that block mycobacterial cell growth. Such agents will serve as valuable probes of mycobacterial cell wall biosynthesis and as leads for the development of new antimycobacterial drugs. This research project is focused on understanding essential steps in the biosynthesis of the mycobacterial cell wall. Mycobacteria cause a number of diseases, including tuberculosis (TB). TB causes about 1.7 million deaths each year, and current therapies are failing. The goal of this project is to understand key steps in mycobacterial cell wall biosynthesis that are not targeted by any current drugs and find inhibitors from which new types of drugs could be developed
Keywords: Address; Anabolism; Anti Mycobacterial Agents; Antimycobacterial Agents; Assay; Bioassay; Biochemical; Biogenesis; Biologic Assays; Biological Assay; Biology; Carbohydrate Chemistry; Carbohydrates; Catalysis; Cell Wall; Cells; Cellular Expansion; Cellular Growth; Cessation of life; Chemicals; Chemistry; Chemistry, Organic; Complex; D-Galactose; Data; Death; Development; Diphosphates; Disease; Disorder; Drugs; Enzymatic Biochemistry; Enzymes; Enzymology; Flavins; Foundations; Galactans; Galactopyranose; Galactopyranoside; Galactose; Generations; Genus Mycobacterium; Glycans; Glycobiology; Glycoconjugates; Goals; Grant; Intramolecular Transferases; Investigation; Ions; Knowledge; L-arabinofuranose; Length; Ligands; Link; Mediating; Medication; Methods; Microbe; Microbiology; Mutase; Mycobacterial Infection; Mycobacterium; Mycobacterium Infections; New Agents; Organic Chemistry; Origin of Life; Parasites; Pharmaceutic Preparations; Pharmaceutical Preparations; Polygalactoses; Polymers; Polysaccharides; Process; Property; Property, LOINC Axis 2; Pyrophosphates; R01 Mechanism; R01 Program; RPG; Research; Research Grants; Research Project Grants; Research Projects; Research Projects, R-Series; Role; Science of Chemistry; Science of Microbiology; Spectroscopy; Spectrum Analyses; Spectrum Analysis; Structure; Testing; Tuberculosis; UDP; Urd; Uridine; Uridine 5`-(trihydrogen diphosphate); Uridine Diphosphate; Uridine Pyrophosphate; Virulence; adduct; antimycobacterial; arabinofuranose; arabinogalactan; base; biological systems; biosynthesis; cell growth; cofactor; covalent bond; design; designing; disease/disorder; disseminated TB; disseminated tuberculosis; drug/agent; frontier; fungus; inhibitor; inhibitor/antagonist; insight; mycobacterial; polymerization; public health relevance; pyranose; small molecule; social role; structural biology; sugar; tuberculous spondyloarthropathy
Relevance: This research project is focused on understanding essential steps in the biosynthesis of the mycobacterial cell wall. Mycobacteria cause a number of diseases, including tuberculosis (TB). TB causes about 1.7 million deaths each year, and current therapies are failing. The goal of this project is to understand key steps in mycobacterial cell wall biosynthesis that are not targeted by any current drugs and find inhibitors from which new types of drugs could be developed
Project start date: 2005-03-15
Project end date: 2014-12-31
Budget start date: 1-JAN-2010
Budget end date: 31-DEC-2010
PFA/PA: PA-07-070
2R01AI063596-05A1 (2010): $359610
Laura L Kiessling
University Of Wisconsin Madison
Project start date: 2003-04-15
Project end date: 2013-11-30
SYNTHETIC LIGANDS FOR MODULATING B-CELL RESPONSES
Laura L Kiessling
Department/ Educational Institution Type:
Grant 5R01AI055258-07 from National Institute Of Allergy And Infectious Diseases
Keywords: ing; Address; Affect; Affinity Chromatography; affinity purification; Antibodies; antibody biosynthesis; Antibody Formation; Antibody Production; Antibody Response; Antigen Presentation; antigen processing; Antigen Processing; Antigen Processings; Antigen Receptors; Antigens; ATGN; Attenuated; Autoimmune Diseases; autoimmune disorder; Autoimmune Responses; Autoimmune Status; Autoimmunity; B blood cells; B cell receptor; B-Cell Activation; B-Cells; B-Lymphocytes; balance; balance function; base; Binding; Binding (Molecular Function); biological signal transduction; Biology; BL-CAM; body system, allergic/immunologic; Bursa-Dependent Lymphocytes; Bursa-Equivalent Lymphocyte; CD22; CD22 gene; Cell Communication and Signaling; cell imaging; Cell Signaling; Cell surface; Cells; cellular imaging; Chemicals; Chemistry; Chromatography, Affinity; Closure by Ligation; Complex; Data; design; designing; EC 2.7; Equilibrium; experiment; experimental research; experimental study; fluorophore; gene product; glycosylation; Goals; heavy metal lead; heavy metal Pb; host response; imaging modality; Immune response; Immune system; Immunity; immunogen; immunoglobulin biosynthesis; immunoresponse; Intracellular Communication and Signaling; Investigation; Kinases; Lead; Life; Ligands; Ligation; Link; living system; lymph cell; Lymphocyte; Lymphocytic; Mass Spectrum; Mass Spectrum Analysis; Metabolic Glycosylation; Methods; Molecular; Molecular Interaction; Monitor; new approaches; new therapeutics; next generation therapeutics; novel approaches; novel strategies; novel strategy; novel therapeutics; Oligosaccharides; organ system, allergic/immunologic; Organism; pathway; Pathway interactions; Pb element; Peptides; Phosphorylation; Phosphotransferases; Photometry/Spectrum Analysis, Mass; Play; Polymer Chemistry; Population; Process; Protein Phosphorylation; Proteins; receptor; Receptor Activation; receptor internalization; Receptor Protein; Receptor Signaling; Receptors, Antigen, B-Cell; Research; research study; response; Role; Sampling; Science of Chemistry; self recognition (immune); SIGLEC2; Signal Transduction; Signal Transduction Systems; Signaling; social role; Specific qualifier value; Specified; Spectrometry, Mass; Spectroscopy, Mass; Spectrum Analyses, Mass; Spectrum Analysis, Mass; Structure; Surface; Synthetic Antigens; T cell response; T-Cells; T-Lymphocyte; Testing; thymus derived lymphocyte; Thymus-Dependent Lymphocytes; tool; trafficking; Transphosphorylases; vaccine development
Relevance: B cells are important components of the immune system because they can be activated by foreign (non-self) molecules to produce antibodies; however, B cells that become activated by self molecules (molecules within the organism) can give rise to autoimmune diseases. Compounds designed to result in B cell activation can promote immune responses (e.g., for vaccine development), and those that block B cell activation could lead to tolerance (e.g., for treating autoimmune diseases). The goal of this proposal is to synthesize new compounds that can be used to control B cell responses
Project start date: 2003-04-15
Project end date: 2013-11-30
Budget start date: 1-DEC-2010
Budget end date: 30-NOV-2011
PFA/PA: PA-07-070
5R01AI055258-07 (2011): $330784
Laura L Kiessling
University Of Wisconsin Madison
Project start date: 1997-06-01
Project end date: 2015-07-31
Sponsored Links Excellgen http://Excellgen.com
GLYCOPEPTIDES AND OTHER NON-NATURAL VARIANTS: PROBES OF CARBOHYDRATE FUNCTION
Laura L Kiessling
University Of Wisconsin Madison, 21 N. Park Street, Suite 6401, Madison, Wi 53715-1218
Grant 5R01GM049975-16 from National Institute Of General Medical Sciences
Keywords: No Project Terms available
Project start date: 1993-07-01
Project end date: 2011-11-30
Budget start date: 1-DEC-2009
Budget end date: 30-NOV-2010
PFA/PA: PA-07-070
5R01GM049975-16 (2010): $329440
SYNTHETIC LIGANDS FOR MODULATING B-CELL RESPONSES
Laura L Kiessling
University Of Wisconsin Madison, 21 N. Park Street, Suite 6401, Madison, Wi 53715-1218
Grant 5R01AI055258-06 from National Institute Of Allergy And Infectious Diseases
Keywords: ATGN; Address; Affect; Affinity Chromatography; Antibodies; Antibody Formation; Antibody Production; Antibody Response; Antigen Presentation; Antigen Processing; Antigen Processings; Antigen Receptors; Antigens; Attenuated; Autoimmune Diseases; Autoimmune Responses; Autoimmune Status; Autoimmunity; B blood cells; B cell receptor; B-Cell Activation; B-Cells; B-Lymphocytes; BL-CAM; Binding; Binding (Molecular Function); Biology; Bursa-Dependent Lymphocytes; Bursa-Equivalent Lymphocyte; CD22; CD22 gene; Cell Communication and Signaling; Cell Signaling; Cell surface; Cells; Chemicals; Chemistry; Chromatography, Affinity; Closure by Ligation; Complex; Data; EC 2.7; Equilibrium; Goals; Immune response; Immune system; Immunity; Intracellular Communication and Signaling; Investigation; Kinases; Lead; Life; Ligands; Ligation; Link; Lymphocyte; Lymphocytic; Mass Spectrum; Mass Spectrum Analysis; Metabolic Glycosylation; Methods; Molecular; Molecular Interaction; Monitor; Oligosaccharides; Organism; Pathway interactions; Pb element; Peptides; Phosphorylation; Phosphotransferases; Photometry/Spectrum Analysis, Mass; Play; Polymer Chemistry; Population; Process; Protein Phosphorylation; Proteins; Receptor Activation; Receptor Protein; Receptor Signaling; Receptors, Antigen; Receptors, Antigen, B-Cell; Research; Role; SIGLEC2; Sampling; Science of Chemistry; Signal Transduction; Signal Transduction Systems; Signaling; Specific qualifier value; Specified; Spectrometry, Mass; Spectroscopy, Mass; Spectrum Analyses, Mass; Spectrum Analysis, Mass; Structure; Surface; Synthetic Antigens; T-Cells; T-Lymphocyte; Testing; Thymus-Dependent Lymphocytes; Transphosphorylases; ing; affinity purification; antibody biosynthesis; antigen processing; autoimmune disorder; balance; balance function; base; biological signal transduction; body system, allergic/immunologic; cell imaging; cellular imaging; design; designing; experiment; experimental research; experimental study; fluorophore; gene product; glycosylation; heavy metal Pb; heavy metal lead; host response; imaging modality; immunogen; immunoglobulin biosynthesis; immunoresponse; living system; lymph cell; new approaches; new therapeutics; next generation therapeutics; novel approaches; novel strategies; novel strategy; novel therapeutics; organ system, allergic/immunologic; pathway; receptor; receptor internalization; research study; response; self recognition (immune); social role; thymus derived lymphocyte; tool; trafficking; vaccine development
Relevance: B cells are important components of the immune system because they can be activated by foreign (non-self) molecules to produce antibodies; however, B cells that become activated by self molecules (molecules within the organism) can give rise to autoimmune diseases. Compounds designed to result in B cell activation can promote immune responses (e.g., for vaccine development), and those that block B cell activation could lead to tolerance (e.g., for treating autoimmune diseases). The goal of this proposal is to synthesize new compounds that can be used to control B cell responses
Project start date: 2003-04-15
Project end date: 2013-11-30
Budget start date: 1-DEC-2009
Budget end date: 30-NOV-2010
PFA/PA: PA-07-070
5R01AI055258-06 (2010): $334125
Glycopeptides And Other Non-Natural Variants: Probes Of Carbohydrate Function
Laura L Kiessling, Professor
Chemistryuniversity Of Wisconsin Madison
Grant 5R01GM049975-15 from National Institute Of General Medical Sciences IRG: ZRG1
Project start date: 1993-07-01
Project end date: 2011-11-30
SOLUTION STRUCTURES OF LEWISA And LEWISX BASED SELECTIN LIGAND ANALOGS
Laura L Kiessling, Professor
University Of Wisconsin Madison Suite 6401 Madison, Wi 537151218
Grant 5P41RR002301-130049 from National Center For Research Resources
Keywords: arthritis, biological product, biomedical resource, carbohydrate, immunology, lymphatic system
BIOORGANIC STUDIES OF CARBOHYDRATE FUNCTION
Laura L Kiessling, Professor
Chemistryuniversity Of Wisconsin Madison
21 N. Park Street, Suite 6401
madison, Wi 537151218
Grant 5R29GM049975-04 from National Institute Of General Medical Sciences IRG: BNP
Project start date: 1993-07-01
Project end date: 1998-06-30
5R29GM049975-04 (1996): $100449