Faculty: G–Q

The major goal of this laboratory is to understand the molecular mechanisms that lead to the polymerization of the microtubule-associated protein tau into pathological structures observed in Alzheimer's disease and other neurodegenerative disorders. Current interests include the effects of phosphorylation on this process and the mechanism of fatty acid binding to the tau protein.

Ribonuclease P (RNase P) is the enzyme responsible for cleaving the 5'-leader sequence from precursor tRNA molecules. In bacteria, the catalytic subunit of RNase P is an RNA molecule or ribozyme ~400 nucleotides long; and in all other organisms studied, the enzyme also contains a catalytically-required RNA subunit. In contrast, we find that RNase P from plant chloroplasts appears to be a single protein. We are currently pursuing protein chemistry and genetic approaches to identify the chloroplast enzyme, and we are investigating whether other groups surrounding the scissile bond help bind metal ions during the RNase P reaction. Our lab is also investigating how structural interactions among the subunits of chloroplast ATP synthase generate its novel allosteric and regulatory properties.

Intracellular protein and membrane trafficking is an essential process for the morphogenesis and proper functioning of all eukaryotic cells. The specificity of cargo sorting and targeting demands unique regulatory and structural proteins at each transport step, and many of these proteins have been identified and extensively characterized. However, the branching of transport routes has complicated studies of the late (post-Golgi) secretory pathway, and the molecular machinery required for exocytic cargo sorting and exit from the Golgi and endosomes is largely unknown. Our research is focused on delineating the membrane transport pathways and the mechanisms of cargo packaging and vesicle formation in the late secretory pathway using the yeast Saccharomyces cerevisiae as a model system.

Chlamydia spp. include human pathogens which have an immense impact on public health. These obligate intracellular bacteria are maintained through a unique biphasic developmental cycle that is linked with its ability to cause disease. My primary interest is to elucidate developmental cycle regulatory mechanisms to gain a better understanding of Chlamydia-host interactions and generate new therapeutic strategies.

The research programs in our group focus on the applications of theoretical/computational methods to chemical and physical problems in biology and material science.

Cytokines are small secreted proteins responsible for mediating cell-cell communication. The encoding of multiple functions in a single cytokine has confounded attempts to understand—and manipulate—cell–cell signaling. My lab is working towards building up a map of cytokine-receptor interactions using computational structure-based docking, with experimental validation of predicted interactions in vitro and in vivo. We utilize this structural dissection of cytokine-receptor interactions to design and test proteins and small-molecules that attenuate certain cytokine functions while leaving others intact. This research will extend the current understanding of cell-cell communication, and will stimulate novel therapeutic approaches for human conditions ranging from cancer to allergic inflammation.

Intracellular signaling mechanisms regulate synaptic transmission and synaptic plasticity. Mechanisms controlling synaptic transmission are believed to be critical for learning and memory in humans. We are answering key questions about molecular/cellular mechanisms responsible for short- and long-term changes in synaptic transmission in the mammalian brain. We examine the role of postsynaptic calcium, protein kinase and phosphatase pathways in controlling synaptic transmission in the hippocampus, a brain region important for learning in humans. We have discovered many reliable ways to enhance synaptic transmission by specific manipulations of intracellular signaling pathways.

Computer simulations provide a wide range of information about molecular behavior, enabling the description of motions of individual atoms, but the practical application of simulations is limited by the accuracy of the approximations, the difficulty in relating simulations to observable properties, and the insufficient length of feasible simulations relative to biochemically interesting time scales. My studies include simulations of conformational thermodynamics and dynamics in peptide and protein systems to correlate simulations with experimental data as well as between flexibility and reactivity of peptide drugs; use of free energy simulation methods to investigate effects of point mutations in proteins, including influence on ligand binding, oxidation, hydrophobic interactions, macromolecular solvation and aggregation; and rational design of receptors that will efficiently and specifically bind cationic ligands, which can be used for environmental waste remediation. The work involves both using existing simulation programs and development of new methods and algorithms for molecular modeling.

Using X-ray crystallography and a variety of other biochemical and biophysical techniques, my laboratory will investigate how bioinorganic chemistry has an impact on human health and disease. Specifically, the major goal of this laboratory is to understand the enzymes of the iron-uptake pathways of Pseudomonas aeruginosa. The proteins involved in these pathways are potential drug targets in the fight against early mortality in Cystic Fibrosis patients.

My lab is concerned with the molecular signaling events that underlie cellular morphogenesis. We use the nematode Caenorhabditis elegans to identify and characterize genes involved in neuron development and axon guidance. Current interests include signaling to the actin cytoskeleton via the actin-binding UNC-115 protein and regulation of axon development by the Rac family of signal transduction molecules.

The primary goal of the lab is to understand the genetic basis of complex polygenic traits. We are interested in identifying and characterizing the precise genetic polymorphisms that contribute to trait variation both within and between species. To accomplish this we combine the powerful genetic and molecular tools available for the Drosophila model system, with a variety of genomic and bioinformatic approaches.

The long-range goal of this laboratory is to reveal the underlying mechanisms for growth control of normal intestinal tissue, explaining how disruption of this normal state leads to tumor formation. Using cultured colon cells and mouse models, we study the tumor suppressor protein adenomatous polyposis coli (APC) to understand how loss of this particular protein leads to colon carcinogenesis. Our lab has demonstrated that nuclear-cytoplasmic shuttling of APC is critical for its function and we are now further defining both upstream triggers and downstream consequences of nuclear APC.

Our research centers on the investigation of neural mechanisms that regulate heart and blood vessel function. We are particularly interested in identifying endogenous chemicals that stimulate sensory nerves from organs such as the heart or lung. Following identification of these chemicals, we seek to understand the cellular mechanism that allows these chemicals to stimulate sensory nerve endings. Understanding the mechanism of nerve stimulation will allow us to manipulate these events during abnormal or pathological conditions.

We are exploring the molecular mechanisms by which bacterial pathogens elicit disease. The model systems currently in use in our laboratory are: 1) investigating the structure-function relationships for the secreted virulence proteins of Shigella flexneri; and 2) studying the protein-membrane interactions that occur for cholera toxin.