We study the cell biology of the protozoan parasites that cause Toxoplasmosis and Malaria, especially the mechanism and control of parasite motility and host cell interaction.
Our long term goal is to define the molecular mechanisms of two-component regulatory systems, which are utilized for signal transduction by bacteria, archaea, eukaryotic microorganisms, and plants. Our current focus is to understand the features that control the rates of self-catalyzed phosphorylation and dephosphorylation of response regulator proteins. The kinetics of these reactions vary dramatically (>40,000x) between different pathways and reflect the need to synchronize biological responses (e.g. behavior, development, physiology, virulence) to environmental stimuli. Member of the Molecular & Cellular Biophysics Training Program
Our lab is interested in the role of chromatin-modifying factors and epigenetics in mammalian development and disease. We are particularly interested in two major areas both of which make use of mouse models: (1) the role of BRG1 and SWI/SNF nucleosome-remodeling complexes in various aspects of hematopoiesis including regulation of globin gene expression and inflammation; (2) the role of dietary fiber and gut microflora on histone modifications, CpG methylation, and prevention of colorectal cancer.
We use the premier model plant species, Arabidopsis thaliana, and real world plant pathogens like the bacteria Pseudomonas syringae and the oomycete Hyaloperonospora parasitica to understand the molecular nature of the plant immune system, the diversity of pathogen virulence systems, and the evolutionary mechanisms that influence plant-pathogen interactions. All of our study organisms are sequenced, making the tools of genomics accessible.
We study Borrelia burgdorferi (the agent of Lyme disease) as a model for understanding arthropod vector-borne disease transmission. We also study the epidemiology and pathogenesis of dengue viruses associated with hemorrhagic disease.
We are interested in uncovering the fundamental systems-wide processes and mechanisms that underlie life, with a human-health focus. We apply a combination of both modern and traditional tools to this pursuit, including bioinformatics, proteomics, microarrays, molecular genetics, bench work, and software development. Current research areas we focus on include: 1) locating the molecular mechanisms that underlie antibiotic tolerance in the bacteria Pseudomonas aeruginosa, to address the threat that drug resistant organisms pose to those with COPD and Cystic Fibrosis; 2) annotation of the human genome with proteomic data, to determine which genes are translated and when, and how those correlate with prevalent diseases such as cancer; 3) development of computational agent-based models of intramolecular pathways and pathogen-host interactions in HIV, to determine how host-pathogen interactions relate to disease progression; 4) development of software tools for analysis of RNA structures, such as the viral HIV genome, to assist with determining how RNA structure impacts function; and 5) developing software for finding post-translational modifications (PTMs) on proteins by integrating proteomic data sets, to determine the role that these play on cellular signaling in healthy and diseased states. We have a wide diversity lab members, from microbiology bench scientists to computer scientists, and would be a great fit for a student looking for a broad, cross-disciplinary training environment focused on either microbiology and/or genomics.
Successful respiratory pathogens must be able to respond swiftly to a wide array of sophisticated defense mechanisms in the mammalian lung. In histoplasmosis, macrophages -- a first line of defense in the lower respiratory tract -- are effectively parasitized by Histoplasma capsulatum. We are studying this process by focusing on virulence factors produced as this "dimorphic" fungus undergoes a temperature-triggered conversion from a saprophytic mold form to a parasitic yeast form. Yersinia pestis also displays two temperature-regulated lifestyles, depending on whether it is colonizing a flea or mammalian host. Inhalation by humans leads to a rapid and overwhelming disease, and we are trying to understand the development of pneumonic plague by studying genes that are activated during the stages of pulmonary colonization. [note: Dr. Goldman will be moving to UNC in Summer 2008]
Our research goal is to understand how bacterial pathogens cause disease on their hosts. We are working with a plant pathogen, Pseudomonas syringae which introduces virulence proteins into host cells to suppress immune responses. Our laboratory collaborates with Jeff Dangl's lab in the UNC Biology Department using genomics approaches to identify P. syringae virulence proteins and to discover how they alter plant cell biology to evade the plant immune system and cause disease.
My lab studies the pathogenic mechanisms of two bacterial pathogens, Haemophilus ducreyi and Francisella tularensis. H. ducreryi, the agent of the sexually transmitted infection chancroid, somehow inhibits the development of an effective immune response
Research in our laboratory is focused on the enzymatic mechanisms and biological roles of DNA helicases. These enzymes provide the primary mechanism by which duplex DNA is converted to single-stranded DNA (ssDNA) for use as a template in DNA replication and repair or as a substrate in recombination. Indeed, these enzymes are essential for DNA replication, repair and to maintain genomic stability in all organisms. Consistent with this idea, defects in genes encoding DNA helicases in human cells have been linked to genomic instability leading to a variety of progeriod disorders and human cancers. The bacterium E. coli and the budding yeast S. cerevisiae provide attractive systems in which to pursue these studies due to the ease of genetic manipulation and the ability to isolate enzymes for biochemical studies. The long-range goal of the research program is to understand, in enzymatic and molecular terms, the mechanism of action of several helicase enzymes, and to define their individual roles in DNA metabolism.
The lab also has an interest in the process of DNA transfer by bacterial conjugation, first observed more than 50 years ago as the unidirectional and horizontal transmission of genetic information from one E. coli cell to another. Today we know that conjugative DNA transfer plays a role in increasing genetic diversity in addition to propagating the spread of antibiotic resistance and microbial virulence factors. Recent work in this laboratory and others has provided a working model of DNA transfer in the F plasmid system. The long-range goal of this research program is to define the function and regulation of the relaxosome, and each protein in this nucleoprotein complex, in conjugative DNA transfer. Based on that information we will begin to establish inhibitors of relaxosome function.
There are two ongoing projects in my lab - mechanism of binding of bacteria to plant surfaces and mechanism of carbohydrate synthesis in bacteria. We are studying the mechanisms of adhesion of the plant pathogenic and symbiotic bacteria Agrobacterium and Rhizobium to plant hosts. This binding involves protein adhesins, pilus adhesins, and carbohydrates. We are also studying the mechanisms of adhesion of the human pathogens E. coli O157 and Salmonella enterica to plant surfaces. The presence of human pathogens on produce and ready to eat fresh food has emerged as a serious concern worldwide. These bacteria bind tightly to the plant surface and can not be removed by washing. Understanding how these bacteria bind to plants is critical to preventing or inhibiting their binding and thus reducing their transmission via this route.
The second project in my laboratory concerns the mechanism of biosynthesis of polysaccharides by bacteria. We are particularly interested in cellulose and curdlan which are synthesized from the same precursor using similar proteins. We would like to understand the differences between these proteins which cause one to catalyze the synthesis of cellulose and the other to catalyze the synthesis of curdlan. We are also interested in the regulation of the biosynthesis of these exopolysaccharides, particularly in the role of cyclic diguanylic acid in this regulation.
Molecular genetic analysis of virulence of Yersinia and Klebsiella: My laboratory uses Yersinia enterocolitica, Y. pestis, and Klebsiella as model systems to study bacterial pathogenesis. The long-term goals of our work are to understand the bacteria-host interaction at the molecular level to learn how this interaction affects the pathogenesis of infections and to understand how these pathogens co-ordinate the expression of virulence determinants during an infection. To do this we use genetic, molecular and immunological approaches in conjunction with the mouse model of infection. [Note: I will be moving my laboratory to UNC-CH in the summer of 2008]
My laboratory has two main interests: 1) P2Y receptor trafficking in epithelial cells. Our laboratory investigates the cellular and molecular mechanisms by which P2Y receptors are differentially targeted to distinct membrane surfaces of
polarized epithelial cells and the role of lipid rafts and caveolae in P2Y receptor function. 2) Antibiotic resistance mechanisms. We are interested in the mechanisms of antibiotic resistance in the pathogenic bacterium, Neisseria gonorrhoeae. Our laboratory investigates how acquisition of mutant alleles of existing genes confers resistance to penicillin and cephalosporin. We also study the biosynthesis of the gonococcal Type IV pilus and its contribution to antibiotic resistance.
Identification of airway epithelial stem cells; innate immunity in the airway; the pathophysiology of post-lung transplant ischemia reperfusion injury and bronchiolitis obliterans syndrome.
The intestine harbors a large and diverse community of microorganisms. This gut microbiota impacts upon many aspects of host biology, including nutrient metabolism, immunity, and epithelial cell renewal. Our lab is using genetic and molecular methods in gnotobiotic zebrafish hosts and in selected members of the gut microbiota, to investigate the mechanisms underlying evolutionarily-conserved host-microbial interactions in the vertebrate digestive tract.
Keywords: intestine, microbiota, bacteria, symbiosis, commensalism, immunity, inflammation, metabolism, obesity, germ-free, gnotobiotics, zebrafish
Our long term goals are to better define mechanisms of chronic intestinal inflammation and to identify areas for therapeutic intervention. Research in our laboratories is in the following four general areas: 1) Induction and perpetuation of chronic intestinal and extraintestinal inflammation by resident intestinal bacteria and their cell wall polymers, 2) Mechanisms of genetically determined host susceptibility to bacterial product,. 3) Regulation of immunosuppressive molecules in intestinal epithelial cells and 4) Performing clinical trials of novel therapeutic agents in inflammatory bowel disease patients.
Topics include gene discovery, genomics/proteomics, gene transcription, signal transduction, molecular immunology. Disease relevant issues include infectious diseases, autoimmune and demyelinating disorders, cancer chemotherapy, gene linkage.
Our research focuses on the mechanisms used by the bacterium Pseudomonas aeruginosa to cause disease. We are interested in identifying signal transduction pathways that regulate the expression of virulence genes in response to the host environment.
