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Marion Merrell Dow Missouri Professor and Head
Ph.D., Iowa State University
Office: 505 BSB
Phone: (816) 235-2235
E-mail: carlsongm
Laboratory Research Staff and Graduate Students.
Current Interests
Phosphorylase kinase (PhK), an enzyme of the cascade activation of glycogen breakdown, is among the most complex and largest enzymes known. Of its 1.34 million Da mass, 90% has a regulatory role. Through allosteric sites on its 3 regulatory subunits, PhK integrates metabolic (ADP), hormonal (cAMP and Ca2+) and neural Ca2+) signals, resulting in large changes in its activity. This activity change in response to diverse physiological signals allows for the tight control of glycogenolysis, and subsequent energy production, e.g. in skeletal muscle PhK activation by Ca2+ couples contraction with energy production to sustain contraction.
We are determining, using a variety of approaches, the mechanisms for how these different signals alter intersubunit interactions and activity of PhK. Two-hybrid genetic screening, protein crosslinking and synthetic peptides are used to identify interacting regions of adjacent subunits. Immunoelectron microscopy with monoclonal antibodies is used to localize regions of subunits within PhK's overall tetrahedral structure. Immunochemistry and chemical modification are used to identify regions of the protein that are influenced by the allosteric effectors. Site-directed mutagenesis is used to define interacting residues between subunits and to introduce report groups.
This work will help define the relationship between quarternary structure and control of activity for this important regulatory enzyme of mammalian energy production.
Research Support
This research is supported by a grant from the National Institutes of Health.
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Associate Professor
Ph.D., University of California-Los Angeles
Office: 407 BSB
Phone: (816) 235-2243
E-mail: bamek
Laboratory Research Staff.
Current Interests
My research uses genetic and biochemical techniques to study the catabolism of heparan sulfate proteoglycans in Chinese hamster ovary (CHO) cells. Proteoglycans are complex macromolecules found at the cell surface which act as receptors, are involved in cell-cell interactions, and promote or inhibit cell growth. Heparan sulfate proteoglycans at the cell surface are internalized, and the glycosaminoglycan chains are removed from the protein core and cleaved into smaller pieces by heparanases. Most of the cleaved glycosaminoglycans are completely degraded; however, some are secreted from the cell or are transported to other cellular locations, suggesting that, in addition to its role in proteoglycan degradation, chain cleavage may produce biologically active glycosaminoglycans.We have purified three different heparanase activities from CHO cells, suggesting that there may be a family of these enzymes responsible for heparan sulfate catabolism. We are now purifying the activities from rat liver to generate the quantities of protein necessary for sequencing, and use this information to clone the heparanase gene(s) from CHO cells. The ultimate goal of these experiments is to express the heparanase protein so that we can characterize the reaction mechanism.
Research Support
This work is supported by the National Science Foundation, the University of Missouri Research Board, and Repligen Corp.
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Assistant Professor
Ph.D., Johns Hopkins University
Office: 416 SCB
Phone: (816) 235-2565
E-mail: crawforddo
Laboratory Research Staff.
Laboratory HomePage 
Current Interests
My research can be divided into two broad projects: (1) evolutionary variation in glycolysis: phylogenetic analyses of enzyme expression and its effect on metabolic flux and (2) analyses of promoter function and how natural sequence variation affects transcription.
We are quantifying the concentration of all ten glycolytic enzymes in heart ventricles from the different Fundulus populations and species and determining how this variation affects cardiac glycolytic flux. We then experimentally alter enzyme expression to quantify how this variation affects metabolism. These projects, combining phlyogenetic analyses of a physiological trait (glycolysis) with experimental assays, are an example of how my laboratory combines functional and evolutionary analyses.
Variation in mRNA transcription is an important evolutionary adaptation. My laboratory is interested in the molecular mechanisms responsible for this variation and are focusing our efforts on the Ldh-B promoter. There is considerable sequence variation in Ldh-B proximal promoter. Molecular analyses of this variation indicate that specific substitutions affect transcription processes. Evolutionary analyses indicated that the proximal promoter, specifically the nucleotide that affects transcription, is evolving by directional selection. This research has provided insights into the regulation of gene transcription that are not available from the study of standard laboratory organisms or synthetic promoters.
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Associate Professor
Ph.D., University of Wisconsin-Madison
Office: 311 BSB
Phone: (816) 235-2537
E-mail: gorskij
Laboratory Research Staff.
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Associate Professor and Associate Dean
Ph.D., University of Wisconsin- Madison
Office: 012 BSB
Phone: (816) 235-2596
E-mail: hirschbergr
Laboratory Research Staff.
Current Interests
I am a microbiologist-molecular biologist. My research interests focus around two general themes: unusual bacteria and regulation of gene expression.
The primary research project in my lab is "Pilin Genes and Their Role in Pathogenesis of Eikenella corrodens." This organism is associated with periodontal diseases. We would like to understand the role pili may play in attachment of the organism in the mouth and generation of subsequent problems. We are using a combination of molecular genetic, immunological, and animal studies to address these questions.
We have also identified cytotoxic effects produced by this organism. In the future we want to study this and investigate its role in pathogenesis. I am also interested in oral spirochetes.
Research Support
This research is supported by a grant from the National Institutes of Health (National Institute of Dental Research).
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Associate Professor
Ph.D., UCLA
Office: M3-202
Phone: (816) 235-2582
E-mail: huangc
Current Interests
In the expanding elderly population, falls and movement-related accidents diminish sharply the quality of their lives and impose serious medical and economical consequences onto our society. Hip fracture in US alone is estimated at 6-10 billion dollars a year and is a major contributing factor leading to death in older people. Precise causes of motor function deterioration are multiple and complex but many lines of evidence have implicated the decline of central motor control as a major factor. Our overall aim is to advance understanding of this neurodegeneration. Specifically, we are investigating the age-related loss of cerebellar motor function.
In the cerebellar cortex, synapses between granule cells and Purkinje cells are strategic elements in its neuronal circuitry. These synapses, however, are vulnerable while exposed to mitochondrial oxidative stress, glutamate neurotransmission, and nitric oxide -- all recognized risk factors of age-related neurodegeneration. Our lab was among the first to document the dramatic vulnerability of cerebellar synapses during aging, which is more severe than most other brain structures. We anticipate future studies will lead to elucidation of underlying mechanisms as well as the design of rational therapeutic means for intervention.
Our research emphasizes both technology and concepts, employing a variety of interdisciplinary approaches. Interested students should expect training in a broad spectrum of theoretical as well as practical aspects of independent research.
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Professor
Ph.D., University of London
Office: 214 BSB
Phone: (816) 235-2575
E-mail: huttfletcher
Laboratory Research Staff and Graduate Students.
Current Interests
Long standing research interests are in virus cell interactions, virus pathogenesis and immune responses to viruses. The major focus of current work is on the pathogenesis and virology of Epstein-Barr virus (EBV), a ubiquitous human herpesvirus that establishes persistent infections in almost 100% of the world's population. Most people are infected subclinically with EBV in childhood. However, the virus also causes infectious mononucleosis and oral hairy leukoplakia and is strongly implicated in the pathogenesis of Burkitt's lymphoma, nasopharyngeal carcinoma, immunoblastic lymphomas of the immunosuppressed and some types of Hodgkin's Disease. We are studying how EBV enters and traffics between cells by determining the biochemical and functional characteristics of the virus proteins involved. Most recently we have determined that EBV uses HLA class II as a second receptor for entry into B cells and have identified the virus glycoprotein that is responsible for this interaction. A major effort is underway to derive viruses deleted for the expression of individual glycoproteins to explore the role(s) of each and to identify those which are essential for either entry into or egress from different cell types.
Research Support
This research is supported by the National Institutes of Health.
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Associate Professor
Ph.D., University of Navarre, Spain
Office: 422 SCB
Phone: (816) 235-2259
E-mail: iriartea
Laboratory Research Faculty, Research Staff and Graduate Students.
Current Interests
Our research interests are focused on the analysis of protein folding mechanisms, protein structures in their native state, and the structural consequences of introducing alterations at selected regions in a protein. In this manner, strategic regions of a protein can be investigated as to their influence in maintaining protein structural stability and function as well as on its folding into the proper native conformation. We have
selected for our studies proteins which are well characterized structurally, the two isoenzymes of aspartate aminotransferase. The mechanisms of recognition, binding and translocation of proteins across biological membranes are also being investigated using as model the mitochondrial precursor of this protein. Our main interest resides on the study of the precursor structural requirements for import into mitochondria and the events associated with the initial interaction of the translocated protein with the membrane. The role of
certain heat shock proteins working as "molecular chaperones" in this translocation process as well as in the proper folding and assembly of the two isozymes is also being investigated.
Research Support
This research is supported by grants from the National Institutes of Health.
Professor
Dean, School of Graduate Studies
Vice-Provost for Research
Ph.D., University of Oregon
Office: 342 AC
Phone: (816) 235-1301
E-mail: macquarrie
Professional HomePage
Current Interests
The major research project in this laboratory is concerned with the mechanisms of signal transduction across biological membranes. It is well established that cyclic processes of synthesis and degradation of membrane
phospholipids occur in response to certain physiological stimuli, including some which are initiated by hormones, neurotransmitters and growth factors. These processes originate with stereospecific binding to receptors on the
cell surface, followed by the release of potent regulators (second messengers) within the cell. These regulators include diacylglycerol, arachidonic acid, inositol triphosphate and lysophospholipids, all of which have diverse
effects on cellular activities. The long-range plan of this project is to elucidate the molecular details of the relationship between phospholipid metabolism and the transmission of these signals across the membranes.
Studies are underway to determine the properties and control of phospholipases and acyltransferases, which catalyze key reactions in the sequence of events leading to a cellular response. Some of these enzymes have been isolated and their properties studied and correlated with the known characteristics of biological membranes. Other aspects of this project are designed to determine how these enzymes are linked to the action of cell-surface receptors, and to determine the mechanism by which phospholipid-derived second messengers influence cell functions.
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Assistant Professor
Ph.D., University of Notre Dame
Office: 421 SCB
Phone: (816) 235-2258
E-mail: mattinglyj
Laboratory Research Staff.
Current Interests
Macromolecular interactions, particularly the mechanisms of protein folding and the basis for molecular chaperone selectivity in facilitating intracellular protein folding.
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Professor
Ph.D., University of California-Santa Barbara
Office: 314 BSB
Phone: (816) 235-2587
E-mail: morganwt
Laboratory Research Staff.
Current Interests
The transport of heme by hemopexin to tissues like liver is a specific, membrane receptor-mediated process. As a result, biologically useful iron is conserved and the accumulation of toxic heme is prevented. Our ultimate aim is to delineate the biochemical mechanisms of heme transport by hemopexin from initial binding of heme in the circulation to the specific interaction of hemopexin with its plasma membrane receptor. To attain this goal, a basic approach is being taken in which the hemopexin molecule and its receptor are being characterized in detail using physical, immunochemical and molecular biological techniques, e.g. site-directed mutagenesis of hemopexin and molecular cloning of the receptor.
Histidine-proline-rich glycoprotein (HPRG) is distinguished by its ability to interact with a variety of molecules involved with blood clot formation and breakdown. HPRG binds heparin and fibrinogen and modulates the activation of plasminogen by tissue plasminogen activator. The biological function of HPRG in hemostasis is being defined using physical, immunochemical and molecular biological techniques to characterize the ligand-binding functional domains of HPRG and to define its mechanisms of action in hemostasis. The current paradigm is that HPRG acts in plasminogen activation at the surfaces of endothelial cells, platelets or fibrin aggregates, and that HPRG is regulated by localized changes in pH, such as occur in ischemia or hypoxia. This information should aid the development of improved diagnostic and therapeutic measures in blood clotting.
Research Support
This work is supported by grants from the National Institutes of Health, the American Heart Association, and the University of Missouri Research Board.
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Professor
Ph.D., Neurological Sciences, Stanford Medical School
Office: 412 BSB
Phone: (816) 235-2592
E-mail: sjmorris
Laboratory Research Staff.
Laboratory HomePage
Current Interests
Besides typical cell biology methodology, we rely upon visualization of vital dyes in living cells using digital video microscopy. There are three main projects:
Research Support
This work is supported by grants from the National Science Foundation, the American Heart Association, and the Loeb Charitable Foundation.
Assistant Professor
Ph.D., Moscow State University, Russia
Office: SCB 415
Phone: (816) 235-2595
E-mail: popovk
Current Interests
To survive, all living organisms have to burn some respiratory fuels. In humans, the average modern diet provides about 45-50% of total fuel mix in the form of carbohydrates, 33-43% as fat and 13-17% as protein. In well-oxygenated tissues the major determinant of carbohydrates oxidation seems to be the activity of the mitochondrial pyruvate dehydrogenase complex (PDC), which commits carbohydrates to further catabolism. This reaction is heavily regulated by a variety of nutritional and hormonal stimuli and two dedicated enzymes--pyruvate dehydrogenase kinase (PDK) that phosphorylates and inactivates PDC and pyruvate dehydrogenase phosphatase (PDP) that dephosphorylates and re-activates PDC. Thus the amount of active, dephosphorylated PDC in any particular tissue is coordinated. To complicate matters even further, it appears that, in humans, there are multiple isoenzymes of PDK and PDP and almost every tissue has its own subset of isoenzymes that differ in their properties and regulation. The objectives we currently pursue are: 1) to understand how both PDK and PDP function at the atomic level and how they manage to integrate a variety of metabolic stimuli; 2) to understand the molecular mechanisms responsible for regulation of kinase and phosphatase activities by hormones; and 3) to evaluate the molecular basis for abnormal regulation of PDC observed in diabetes, ischemia and sepsis.
Research Support
This research is supported by a grant from the National Institutes of Health.
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Associate Professor
Ph.D., Arizona State University
Office: 215 BSB
Phone: (816) 235-2065
E-mail: riderv
Laboratory Graduate Students.
Current Interests
Estrogen and progesterone are steroid hormones that regulate a variety of cellular processes in target tissues by altering the rates of specific gene transcription. Current interests in the laboratory are focused on the mechanisms involved in hormone action at the cellular and molecular levels.
Progesterone is the only steroid hormone that is essential for the establishment of pregnancy in all mammalian species studied, but its mechanisms of action on target cells are poorly understood. The main focus of my laboratory is to provide greater insight into the question of how progestins control proliferation in normal target cells. Increased knowledge about the mechanisms of progesterone action will impact human, domestic animal and vertebrate wildlife reproduction.
Systemic lupus erythematosus (SLE) is an autoimmune disease that occurs more frequently in women of childbearing age (9:1 compared to men). We are studying the role of sex hormones in promoting immunological-inflammatory responses in autoimmune diseases using SLE as the model system. Recently we showed that calcineurin, a key player in T cell activation, increases significantly in response to estradiol in cultured lupus T cells but not in T cells from normal healthy women. Estradiol-dependent increases in calcineurin expression are postulated to alter the transcription of proinflammatory cytokine genes and molecules involved in T-B cell interactions
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Assistant Professor
Ph.D., Texas A&M University
Office: 213 BSB
Phone: (816) 235-2573
E-mail: schaeferm
Laboratory Research Staff and Graduate Students.
Current Interests
Light is a critical environmental factor for photosynthetic organisms. In addition to driving photosynthesis, it provides the information necessary for acclimation and development in response to changes in ambient conditions. Most photosynthetic organisms can modulate their photosynthetic capacity to accommodate fluctuations in light availability. Often, genes that encode components of the photosynthetic apparatus are under the control of wavelength-specific photoreceptors that initiate light-responsive signal transduction pathways. Although photoregulation of gene expression is well documented for different phototrophs, the molecular mechanisms by which photoreceptors communicate with the regulatory machinery of cells are not.
We seek to define the photoregulatory mechanism controlling chromatic adaptation by the cyanobacterium Fremyella diplosiphon. Chromatic adaptation is the process by which this organism senses changes in light quality and responds by altering the protein and pigment composition of the light-harvesting phycobilisome. Two approaches are being used to identify genes involved in chromatic adaptation. Both approaches are based on a collection of pigment mutants characterized by aberrant chromatic adaptation or altered phycobilisome structure. The first approach involves complementation of the different pigment mutants with a wild-type genomic DNA library. The second approach involves transposon-tagging of chromatic adaptation genes with endogenous transposon Tn5469. By characterizing the identified genes, a molecular framework for the chromatic adaptation photosensory and signaling mechanisms can be established.
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Associate Professor
Ph.D., University of London, U.K.
Office: 313 BSB
Phone: (816) 235-2579
E-mail: smithan
Laboratory Research Staff.
Current Interests
Transferrin and hemopexin are a specific class of endocytotic systems where the transport protein recycles and the ligands, iron and heme, respectively, are bound to specific membrane proteins to facilitate the intracellular transport of these chemically-reactive, water-insoluble molecules. Hemopexin-mediated heme transport and sequestration of heme to minimize heme-mediated oxidative damage are important in the liver, placenta, eye, regenerating nerves and the central nervous system.
Most recent studies using micromolar concentrations of heme-hemopexin as a model for intravenous heme released in hemolysis, trauma and ischemia-reperfusion injury show a transient increase in cellular oxidation state associated with heme transport. The N-terminal c-Jun kinase also known as stress activated protein kinase (JNK/SAPK) is activated and hemopexin also induces the cyclin inhibitor p21WAF/CIP1/SDI1 and the tumor suppressor p53 causing partial G2/M arrest not necrosis or apoptosis.
The emerging picture is that hemopexin is a cell survival factor leading also to the nuclear translocation of the transcription factor NFkB involved in the innate immune response. The hemopexin system is being used to define at the molecular level the pathway from the plasma membrane to the nucleus for protective gene regulation in response to this extracellular signal of danger via the hemopexin receptor.
Research Support
This work is supported by grants from the National Institutes of Health.
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Assistant Professor
Ph.D., Simon Fraser University
Office: 216 BSB
Phone: (816) 235-2599
E-mail: thomaske
Laboratory Research Staff and Graduate Students.
Laboratory and
Personal HomePage
Current Interests
Our research investigates evolution at the molecular level with the goal of elucidating relationships among organisms and understanding the processes of genome evolution.
Recently, we have begun to employ the nematode (C. elegans) as a model organism for studies in evolution. C. elegans has become a useful model system for many areas of biology (e.g. reproduction, development, morphogenesis, neurobiology and genome organization). One of the first goals of our research is to determine the relationship of this famous nematode to other animals and provide a valuable evolutionary framework upon which our ever increasing knowledge of C. elegans can be placed. The phylum Nematoda, also called roundworms, is comprised of the most abundant, ubiquitous and genetically diverse multicellular organisms in the world. However, fundamental studies of evolution, ecology and biodiversity are dramatically impeded by an often inefficient system for the identification of individual nematodes and a vastly incomplete taxonomic inventory. One of the goals of this laboratory is to develop molecular tools for species identification.
Another area of investigation focuses on the role of genes important for controlling the rate of mutation and genome evolution, specifically, the mismatch repair genes and their role in maintaining replication fidelity in microsatellite loci.