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Pathobiology | Investigators/Teams

Guojun Bu, Ph.D., Unit Leader  

Our laboratory is interested in studying biogenesis, intracellular trafficking and biological functions of members of the low-density lipoprotein (LDL) receptor family. Our studies have been focused primarily on a large endocytic receptor, the LDL receptor-related protein (LRP), which binds over 30 ligands. We are particularly interested in how LRP plays a role in the pathogenesis of Alzheimer's disease. We are also studying another large member of the family, called LRP1B, which was discovered as a putative tumor suppressor and exhibits the slowest endocytosis rate.

Carolyn L. Cannon, M.D., Ph.D.  

Our laboratory seeks to understand the pathobiology of host-bacterial interaction in the genesis of the pulmonary infections that plague cystic fibrosis (CF) patients. The protein defective in CF, the cystic fibrosis transmembrane regulator (CFTR), subserves numerous functions in respiratory epithelium including that of a sensor for bacteria that colonize the lungs of patients with CF. Using both in vitro and animal models of infection, we are studying the interaction of pathogenetic organisms with CFTR and the downstream pathways that are activated.

F. Sessions Cole, M.D.  

Our laboratory hopes to elucidate the genetic basis of lung disease in newborns. Our studies focus on analysis of polymorphisms in a critical lung protein, surfactant protein-B, in causing respiratory difficulty in both term and preterm newborns.

Dennis J. Dietzen, Ph.D.  

Our laboratory investigates the cell biology of cholesterol and sphingolipid-rich domains within the plasma membrane, referred to as lipid rafts. The goal of our research is to define the role that these membrane domains play in both normal and pathologic physiology. We are actively studying the influence of the membrane environment on the first step of the coagulation cascade, factor VIIa/tissue factor, and its inhibition by tissue factor pathway inhibitor (TFPI).

Allan Doctor, M.D.  

Thomas Ferkol, M.D.  

The respiratory epithelium is the first line of defense in the lung, and it is constantly exposed to innumerable inhaled pathogens, aeroallergens and other noxious agents. Innate host defenses have evolved to prevent acute pulmonary injury, relying on complex interactions that occur between effector cells present in the respiratory tract. Research in our laboratory has focused on developing cell and animal models to study pulmonary inflammation characteristic of cystic fibrosis, and developing novel therapies to better treat the pulmonary manifestations of this disorder.

Anthony R. French, M.D., Ph.D.  

Our laboratory is focused on elucidating the in vivo responses of natural killer (NK) cells during viral infections as well as on characterizing the evasion of these responses by large DNA viruses such as murine cytomegalovirus (MCMV), HSV-1, and vaccinia. We are particularly interested in understanding the factors driving and controlling NK cell proliferation and expansion during viral infection as well as the subsequent homeostasis of NK cells following resolution of the infection.

Aaron Hamvas, M.D.  

David B. Haslam, M.D.  

Our laboratory is investigating how bacterial toxins damage human cells. In particular, we are investigating the mechanisms by which some toxins transit the endoplasmic reticulum (ER) on their way to the host cell cytoplasm. Most of our studies are focused on shiga toxin, the agent responsible for hemolytic uremic syndrome in children. In these studies, we identified a novel ER-localized chaperone, and are investigating its role both in toxin trafficking and normal cell biology.

Keith A. Hruska, M.D.  

Our laboratory studies mechanisms of chronic kidney disease progression and its complications. We have discovered that the critical renal morphogen, bone morphogenetic protein (BMP)-7, is expressed in the adult kidney and reduced by renal injuries. Moreover, BMP-7 exhibits therapeutic potential against renal fibrogenesis and diabetic nephropathy. Other members of the bone morphogenetic protein family differentially affect lineage allocation of mesenchymal stem cells. Our studies in basic bone cell biology are focused on the role of these proteins in lineage commitment of mesenchymal stem cells and novel mechanisms of osteoclast cytoskeletal regulation.

David A. Hunstad, M.D.  

We utilize tissue culture systems and the murine cystitis model to study two major questions in bacterial pathogenesis. First, we are investigating how Gram-negative bacteria, in particular uropathogenic Escherichia coli, modulate host immune responses during infection. Second, we are studying the functions of the conserved periplasmic chaperone SurA in virulence, aiming to target this protein with anti-infective strategies.

Jeffrey S. McKinney, M.D., Ph.D.  

Our laboratory is interested in the pathogenesis of bacterial infections and is using novel techniques of bacterial gene regulation to dissect host-pathogen interactions. The laboratory is investigating the effects of dynamically modulating virulence gene expression in E. coli and pathogenic Salmonella, using these bacteria as models of Gram-negative pathogens responsible for a wide range of serious infections. To modulate gene expression, the lab employs a system of inducible gene product disruption, involving RNA molecules called external guide sequences that target specific mRNA for cleavage by cellular RNase P.

Alan L. Schwartz, Ph.D., M.D.  

Our laboratory focuses on the cellular and molecular biology of intracellular protein targeting and degradation. Specifically, we have defined two areas of concentration that are closely integrated. First, we study the molecular mechanisms of protein processing and degradation within the endosomal/lysosomal pathway and in the cytoplasm. Second, we continue to evaluate the cell and molecular biology of receptor-mediated endocytosis and its regulation.

Fei Fang Shih, M.D., Ph.D.  

Phillip I. Tarr, M.D., Unit Leader  

Our laboratory is focused on several projects related to the human intestinal microbiota. First, we maintain a surveillance network in the Pacific Northwest, where we identify children who are infected with Escherichia coli O157:H7, and study the progression of their illness into the hemolytic uremic syndrome (HUS), or to spontaneous resolution. Second, we are determining the etiology of unexplained diarrhea in urban and rural populations in the Pacific Northwest in a unique case-control study. Third, we are attempting to determine the risk factors for acquisition of reportable enteric infections in urban and rural populations in the Pacific Northwest. Fourth, we are attempting to determine the evolutionary basis for acquisition of virulence loci by diarrheagenic E. coli O157:H7 and other Shiga toxin-producing pathogens. Finally, we are beginning to explore microbial precipitants of inflammatory bowel disease in children.