| HOST-PATHOGEN INTERACTIONS/INFLAMMATION
Host Pathogens/Inflammation
The broad focus of our research is gastrointestinal epithelial pathobiology. Included under this umbrella are molecular mechanisms and chemoprevention of colorectal and liver cancer, host-pathogen interactions/inflammation in the intestine, and intestinal transport in health and disease. These particular areas of focus are of monumental importance to the field of gastrointestinal health and disease. The primary symptom of enteric infection is diarrhea, it is crucial to understand the mechanisms underlying normal physiology of intestinal transport as well as pathogen-induced alterations in this process. Digestive Disease Host-Pathogen Researchers
Gail Hecht, MD: The focus of Dr. Hecht's work is on the interactions between enteric bacterial pathogens and host intestinal epithelial cells. She is specifically interested in the related organisms enteropathogenic and enterohemorrhagic E. coli (EPEC and EHEC, respectively). The overall goal of the laboratory is to understand the mechanism by which these organisms alter the physiological functioning of the host cells including tight junction barrier function, intestinal ion transport, and stimulation of the inflammatory cascade. Both of these organisms exert their pathogenic effects by actively delivering effector molecules into host cells through a type III secretion system, which has been compared to a “molecular syringe”. Several of the projects in the laboratory revolve around identifying how specific effector molecules, EspB, D, F, and G, disrupt host cell physiology. Host cell interactors of some of these proteins have already been identified through yeast 2-hybrid analyses and more in depth studies are underway to understand how such interactions influence host cell physiology.
Lyn Sue Kahng, MD: Dr. Kahng's research focuses on understanding the role of multiple chromosomes in pathoge nic enteric bacteria. She is also studying the effects of DNA methylation on the replication and virulence of the cholera bacterium. Dr. Kahng was a recipient of VA REAP funding and has several grant applications pending.
Thomas Layden, MD: Dr. Layden's res earch involves determining the production and clearance rate of the hepatitis C virus (HCV). This virus is present in 1 to 3 percent of the population and presents a significant health care risk. Treatment with interferon and other agents has not been adequate in that less than 20% of patients respond to therapy. Dr. Layden's group has utilized sophisticated mathematical modeling techniques in order to provide a method for assessing the kinetics of the virus after exposure to various drugs, thereby providing data on how this drugs should be used. These ongoing studies involve active use of the UIC Clinical Research Center and collaborations with mathematicians at UIC and elsewhere.
V.K. Viswanathan, PhD: Dr. Vishwanathan's research concentrates on EPEC virulence factors. EPEC is a predominant cause of enterocolitis worldwide and carries a high mortality rate. Through a type III secretion system, EPEC injects bacterial proteins (effector molecules) into host cells. These proteins signal transduction pathways. The hypothesis of his studies is that EPEC activation of specific signal transduction pathways is responsible for the changes in intestinal epithelial functions including active ion transport, tight junction barrier function, and gene expression, in particular for cytokines that direct the transepithelial migration of neutrophils. Dr. Viswanathan's research focuses on a specific EPEC protein, EspF, and its interactions with host cell proteins. Additional UIC Researchers
Stephen J. Ackerman, PhD: Dr. Ackerman's research centers on the molecular biology and function of human eosinophil proteins in health and disease pathogenesis. Ongoing research projects focus on the: (1) molecular biology, biochemistry and biologic actions of granule and cytosolic enzymes and cationic cytotoxins expressed by eosinophils, and their roles in the effector functions of this granulocyte in disease pathogenesis, (2) structural biology (structure-activity relationships) of eosinophil granule-associated cytotoxins and enzyme mediators of inflammation, (3) cytokine regulation and mechanisms of eosinophil terminal differentiation, activation and secretion, including cytokine-activated signal transduction pathways, and (4) the roles of eosinophils and their mediators in normal tissue remodeling and pathological tissue fibrosis.
John Christman, MD: The theme of Dr. Christman's research is regulation of acute inflammation at epithelial surfaces. He is interested in the role of the NF- k B pathway in host defense. His model systems primarily utilize lung but his questions and technical approaches are applicable to the intestine as well.
Oscar Colamonici, MD: Dr. Colamonici is currently working on the characterization of the structure of the interferon alpha receptor (IFN R) and cytokine signaling. The research projects ongoing in his laboratory can be summarized as follows: 1) characterization of the structure of the IFN receptor and the interaction with kinases of the JAK family which are responsible for the activation of the system; 2) characterization of interaction of the beta Long subunit of the IFN alpha receptor with transcription factors Stat 1 and 2. The hypothesis of his work is that Stat factors do not always require tyrosine phosphorylation of receptor subunits for docking to the receptor Jak kinase complex.
James Cook, MD: Dr. Cook's laboratory focuses on understanding the regulation of mammalian cell responses to different types of proapoptotic injuries in the context of viral gene expression or bacterial infection. One project involves studies of viral gene regulation of mammalian cell responses to injuries inflicted by cellular components of the innate immune response. The other project involves studies of the role of macrophages in the host response to anthrax infection and anthrax lethal toxin-induced shock syndrome.
Giamila Fantuzzi, PhD: Dr. Fantuzzi's research focuses on the study of leptin as a regulator of immunity and inflammation. Her lab also studies the effects of cytokines in inflammation, particularly colitis and pancreatitis.
Bin He, PhD: The research in Dr. He's laboratory focuses on the viral response to cellular antiviral defenses. Current efforts are directed towards the g 1 34.5 protein of herpes simplex viruses (HSV), a viral factor that blocks host antiviral defense mediated by the interferon-induced double-stranded RNA-dependent protein kinase (PKR). He is also interested in the ebola protein VP35 and its role in pathogenesis. His long-term goal is to identify components involved in virus-host interaction and define their roles in viral pathogenesis.
Thomas Hope, PhD: Dr. Hope's lab focuses on studies of viral post-transcriptional regulatory elements with a goal of understanding the novel mechanism of the stimulation of heterologous gene expression by the WPRE. Understanding WPRE function will allow the development of even more efficient gene expression for a variety of applications from gene therapy to large scale protein production. His lab also studies the cell biology of HIV with emphasis on imaging techniques which hope to revolutionize our understanding of the process of fusion, uncoating, nuclear localization, and other aspects of the life.
Linda Kenney, PhD: Dr. Kenney is studying the tw o-component regulatory system EnvZ/OmpR. EnvZ is a sensor kinase located in the inner membrane and OmpR, can function as a transcriptional activator and a repressor. Her most recent work focuses on how OmpR regulates genes on Salmonella pathogenicity island 2 that are required for systemic infection in mice. OmpR activates a two-component regulatory system SsrA/SsrB. SsrB, in turn, activates many genes inside and outside of SPI-2. The mechanism of activation at this locus is unusual compared to other known activation sites. Despite an X-ray crystal structure of the C-terminal domain of OmpR, little is currently known about how OmpR interacts with DNA to stimulate or inhibit transcription. A combination of biophysical and molecular approaches, including FRET, limited proteolysis, cross-linking, mass spectrometry, over-expression of mutant proteins and in vitro transcription assays are currently employed to elucidate the details of this signaling pathway. Asrar Malik, PhD: Dr. Malik's research is focused on three related areas. One is to understand the regulation of the barrier properties of the endothelial and epithelial cells. Another objective of the laboratory is to develop and to test novel strategies for drug and gene delivery. He is interested in targeting specifically the cells of the vessel wall which are critical in the pathogenesis of variety of inflammatory diseases, atherosclerosis and cancer metastasis. Last, his laboratory is studying the expression of the adhesion molecule ICAM-1 at the level of gene transcription. In particular, he is interested in how certain cytokines and oxidants induce the expression of the ICAM-1 gene at the level of its promoter, the intra-cellular signalling pathways regulating ICAM-1 expression, and how gene activation is regulated by the redox state of the cell.
Bellur Prabhakar, PhD: Dr. Prabhakar has long studied the immunology of various clinical entities including Graves' disease and pemphigus. He has identified a role for Yersinia proteins in the development of graves disease. In collaboration with Dr. Layden's group, Dr. Prabhakar also studies at the molecular level the immunological mechanisms responsible for chronic hepatitis C viral infection. As Chair of the Department of Microbiology and Immunology, Dr. Prabhakar has been responsible to the recent faculty additions of Dr. He and Rong, and whose work also directly address hepatitis C infection.
Lijun Rong, PhD: Research in Dr. Rong's laboratory focuses on the molecular mechanisms of enveloped viral entry. This lab uses an integral approach of molecular, biochemical and structural techniques to dissect the essential features of the viral receptor protein and the viral envelope protein required for viral/host membrane fusion and viral penetration. These studies will provide important insights for molecular and cellular understandings of viral infection of retroviruses and other enveloped viruses. Currently Dr. Rong's lab focuses on two different enveloped viruses. (1) Rous sarcoma virus. Dr. Rong's laboratory studies this virus as a model system to investigate how retroviruses mediate membrane fusion and viral entry in general. (2) Hepatitis C virus. Members of Dr. Rong's lab are in the process of developing an in vitro system of hepatitis C virus to study the host tropism and pathogenesis of this virus.
David Ucker, PhD: Dr. Ucker's lab focuses on d efining death and the innate physiological cell death process. C ell death is a ubiquitous physiological process that serves a critical role in organismal development and in homeostasis. In particular, it plays a pivotal role in shaping and maintaining functional cellular repertoires, including a non-autoreactive and self-limiting immune system and an appropriately interconnected and outwardly targeted neuronal network. The purpose of the physiological cell death process, then, is the elimination of functionally inappropriate cells in a manner that does not elicit a pathological or inflammatory response. His lab has focused on a molecular dissection of two critical aspects of the physiological cell death process: the cell-autonomous death effector mechanism, including the point of irreversible death commitment, and the process of corpse recognition leading to non-inflammatory phagocytic clearance.
William E. Walden, PhD: The research interest of Dr. Walden's lab is on the post-transcriptional regulation of genes of iron transport, storage and utilization, and on the regulation of iron homeostasis in eukaryotes. He is also interested in the mechanisms of translational regulation, specifically translational control via sequence specific RNA binding proteins. His major focus has been the regulation of ferritin synthesis in response to changing iron. Ferritin is the major iron storage protein in animal cells and its synthesis is coordinated with cellular iron status. Iron excess causes a stimulation in ferritin synthesis by activating pre-existing, repressed ferritin mRNA. Iron limitation enhances repression of ferritin mRNA. This process of regulating ferritin mRNA is mediated by a small family of sequence specific RNA binding proteins, called Iron Regulatory Proteins (IRP). IRP mediate regulation of ferritin mRNA metabolism by binding to a cis-acting element within ferritin mRNAs, called Iron Responsive Element (IRE). IREs consist of 28 nucleotides and can fold into a conserved stem and loop structure. IREs have been found in several other mRNAs, and it is now known that IRP/IRE interactions mediate regulation of the synthesis of a number of proteins involved with iron metabolism. Thus IRP are central regulators of iron in animal cells. Peter Williamson, MD, PhD: This clinical mycology laboratory focuses on molecular mechanisms of pathogenesis of mycoses, particularly, the AIDS-related pathogen, Cryptococcus neoformans. The incidence of fungal diseases, such as cryptococcosis has risen dramatically since the onset of the HIV-1 epidemic and increased immunosuppression related to chemotherapy. Recently, the genomic sequences of important strains of C. neoformans have been obtained and are actively being investigated. In the post-genome era, identification and organization of regulatory and biosynthetic networks related to virulence are essential to the understanding of how the pathogen responds to the host environment to effect virulence. This laboratory has studied the gene responsible for the copper-dependent virulence factor laccase, CNLAC1, which protects the fungus from oxidative defenses of the host. Molecular characterization of mutants of this factor have identified several genes important to the biosynthesis and regulation of laccase, including a vesicular ATPase and a vesicular chloride channel, both of which appear to be important to the metaliation of laccase and laccase regulators. Mutation of the vesicular ATPase results in a severe attenuation in virulence that suggest that vesicular pumps may make ideal drug targets. In addition, they are investigating the role of a regulatory cascade that receives input from multiple signal cascades and integrates the signal to regulate the mRNA stability of laccase transcription factors. Studies are ongoing to characterize such regulatory cascades and identify additional virulence determinants that may be useful for the design of new anti-fungal targets.
Richard Ye, MD, PhD: Research in Dr. Ye's laboratory focuses on how G protein-coupled receptors (GPCR) are activated, and how the binding signal is transduced to trigger cellular functions. One of his major interests is to understand how chemoattractants activate phagocytes and generate various cellular responses such as directed cell migration and degranulation. He investigates the interactions of chemoattractant receptors, a subgroup of GPCR, with different G proteins and cytoskeletal elements. His studies use several approaches including molecular cloning, bioinformatics, confocal microscopy, and biophysical measurements of real-time changes of intracellular signaling molecules. Another research project aims at understanding how G proteins regulate transcription. The primary interest is to delineate the signaling pathways that link G protein activation to nuclear signaling, particularly events that lead to activation of nuclear factor kappa B (NF-kappa B). Recently, they found that G proteins activate NF-kappa B through different signaling mechanisms that converge to I kappa B degradation and nuclear activation of the transcription factor. He is in the process of defining the functions of several serine/threonine kinases and GTPases that are involved in transcription activation.
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