Regulatory Mechanisms of the Cod-Y Protein of Staphylococcus aureus
Low G+C Gram-positive bacteria, including Staphylococcus aureus, are metabolically versatile and can interact with hosts in diverse ways. They can reside in and on our bodies in a commensal state or can cause life-threatening infections. Genetic switches, controlled in part by transcription factors that bind key intracellular metabolites, govern the reconfiguration of physiology that mediates the shift between commensal and pathogenic lifestyles. Despite observations that the expression of virulence genes often correlates with the exhaustion of available nutrients, there is limited knowledge about how the signaling of nutrient status and the resulting physiological responses are coordinated.
We are studying the integrated regulation of metabolism and pathogenesis in S. aureus, an important hospital- and community-acquired infectious disease agent responsible for significant morbidity and mortality. We are currently examining in depth the role of the global regulatory protein CodY in altering the activities of multiple metabolic pathways when faced with changing levels of nutrient depletion, and how this response is coupled to the production of virulence factors. A deeper understanding of cellular mechanisms underlying bacterial disease will reveal new ways to prevent the switch from harmless to harmful lifestyles that lead to potentially life-threatening infections.
Elena Casey, see Elena Silva
Development of the neurons in the inner ear
The long-term goal of the research in the Coate laboratory will be to define the signaling mechanisms underlying neural development within sensory systems and how synaptic connections can be reestablished in cases of damage or disease. In the field of developmental neuroscience, we are now at an exciting time where we can take multi-faceted approaches to understanding (with excellent temporal and spatial resolution) the mechanisms by which precise cell types coordinate appropriate axon guidance decisions and synapse formation. In our research, we aim to understand the mechanisms by which spiral ganglion neurons (SGNs) make functional connections with mechanosensory hair cells in the mouse cochlea. We are currently addressing how secreted Semaphorins, which activate Neuropilin/Plexin co-receptors, control SGN axon guidance decisions in the cochlear sensory epithelium. We are also investigating how the transcription factor Pou3f4 controls the expression of axon guidance factors in the developing cochlea (such as ephrins and Eph receptors) and how those factors control cochlear innervation. The cochlea provides an excellent model for discovering how circuits assemble within a complex organ system, as it is composed of an array of cell types and structures precisely arranged to detect a range of sound frequencies.
Cerebral cortex development
The Donoghue Laboratory examines the development of the cerebral cortex, the largest and most complex portion of the mammalian forebrain. A battery of molecular, cellular, biochemical, and organismal approaches is used to examine the forces that shape the proper formation of the cortex. For example, current studies focus on how the proliferation of cells in immature cellular zones is controlled in development so that the mature cortex contains the appropriate number of cells. In addition, once cells have stopped dividing, we are interested in the regulatory programs that control their subsequent differentiation in more mature compartments. Together, we are interested in the coordination of cell genesis and cell differentiation in order to produce an integrated neural structure that has the proper cells present in the proper proportions. Mouse models (mutant, transgenic) are used for examining the function of particular genes in vivo and in vitro.
Giardia lamblia is one of the most prevalent intestinal protozoan pathogens worldwide. In the U.S., infections are most common among campers and children in daycare centers. After ingestion of the infective cyst stage by the host, the parasite differentiates in the lumen of the small intestine and its presence often results in severe gastrointestinal symptoms, including diarrhea, vomiting and weight loss. In addition to its medical importance, Giardia is also a representative of one of the earliest diverging eukaryotic lineages. Our laboratory focuses on two main questions: transcriptional regulation and cytoskeleton control of swimming and attachment behavior.
Neural regeneration and neuron-glia interactions
The goal of my research is to understand how glial cells regulate neuronal function in the mammalian central nervous system (CNS). We focus on oligodendrocytes, a type of glia, whose cellular processes engage with and enwrap CNS axons, and form the lipid-rich myelin membranes required for rapid, saltatory axonal conduction. Oligodendrocyte loss or dysfunction has profound impact on brain development, homoeostasis and aging, and has been implicated in many neurological disorders including certain leukodystrophies, multiple sclerosis (MS), cerebral palsy, Alzheimer’s disease, schizophrenia, and autism.
We are currently investigating the mechanisms by which oligodendrocytes interact and communicate with axons, and how their interactions might promote axonal integrity and survival. We are also investigating the mechanism of CNS regeneration, with a focus on how oligodendrocytes regenerate from endogenous neural progenitor cells to replace myelin during homeostatic turnover or after demyelination. We use primary oligodendrocyte/neuron co-cultures, transgenic mice, and models of experimental CNS injury and demyelination, combined with molecular biology and imaging tools to address these questions.
Transcriptional control in the yeasts Saccharomyces and Candida
Research in my laboratory is focused on elucidating the mechanisms that yeast cells use to sense external conditions - such as nutrient abundance and host status - and how these cells alter gene expression in response to these conditions. We are studying expression of the enzymes that comprise the purine nucleotide biosynthetic pathway in Saccharomyces cerevisiae. In Candida albicans, we are investigating how filamentation is controlled at the genetic level.
My laboratory is focused on two major areas of cell biology – cell fusion and the control of meiosis. Many of the genes required for cell fusion and meiosis have close homologs in all eukaryotic organisms; it is likely that their functions are deeply conserved.
Cell Fusion: One of the most fundamental events in eukaryotic biology is the fusion of two cells to produce a single cell. Although fertilization is the basis of sexual reproduction, cell fusion also plays important roles during development. For example, muscle fibers are formed by the fusion of precursor cells. We are using the yeast Saccharomyces cerevisiae to identify genes and proteins responsible for the two major steps in mating; cell fusion and nuclear envelope fusion.
Control of Meiosis: Recent work from many laboratories has revealed the complexity of the regulation of meiosis. My lab is actively studying how one key regulator, Kar4p, affects both transcriptional and translational regulation during yeast meiosis.
protein trafficking and ion homeostasis
The Rosenwald laboratory investigates a number of different aspects of life at the microbial level, including membrane traffic, cell wall biosynthesis, and ion homeostasis in Saccharomyces cerevisiae (Baker's yeast) and its close but pathogenic relative, Candida glabrata. We use approaches that combine classical techniques of biochemistry, cell biology, and genetics, but more recently have also included bioinformatics and genomics in our arsenal of tools.
Neural induction in Xenopus leaves
The goal of the Silva lab is to understand the transcriptional regulation of a class of genes involved in the formation of the early vertebrate body plan. Patterning events such as the establishment of neural tissues require a series of signal transduction events that lead to the transcription of a set of genes. Few of the details of transcriptional regulation in vertebrate development have been deciphered. However the ability to generate transgenic frogs has revolutionized the field, allowing rapid analysis of promoter function in a large number of embryos. This technique, along with embryology, traditional biochemical and molecular assays, and expression screens now enable us to define the factors required for regulation of genes involved in early vertebrate development.
Mucosal Immunity and Giardiasis
My research centers on the protozoan parasite, Giardia lamblia. Giardia replicates in the small intestines of many species of mammals and is a major cause of human diarrheal disease throughout the world. In the U.S., Giardia infections are mainly found in campers and hikers who forget to treat their water, as well as in day care and nursing home situations. Although Giardia is a significant cause of diarrhea, the majority of infections are actually sub-clinical. Indeed, recent data suggest that Giardia infection may actually reduce the severity of diarrhea due to other pathogens. We are studying immune responses against this parasite in humans and mice in order to understand how these responses contribute to the variety of clinical outcomes observed. For example, do immune responses against Giardia reduce the severity of infections by other pathogens? And how do these immune responses contribute to intestinal cramps and nutrient malabsorption that are the hallmarks of giardiasis?