Zhu Lab:Research

Our research interests span the broad areas of gastroenterology

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Ongoing research projects include:

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•Mechanism and regulation of gastric acid secretion Abnormal acid secretion is the reason of many GI diseases including GERD, gastric, duodenal and esophageal ulcers. The spending in treating these conditions is substantial. The gastric parietal cell, lining the lumen of the stomach, is responsible for the secretion of isotonic HCl (0.15M) into stomach. One ATP is consumed for every proton secreted into the stomach lumen and a lot of proton pump (H,K-ATPase, the alpha and beta subunits of this enzyme were discovered in 1967(1) and 1990(2)) is required for this job. To accommodate these many proton pumps, the apical plasma membrane, in the resting state, is expanded in the form of numerous invaginations which express relatively short microvilli, and a large compartment of cytoplasmic membranes, commonly called tubulovesicles, fully loaded with proton pumps. Upon stimulation by hismatine initiated PKA signaling, these tubulovesicles traffic to and fuse with apical membrane, forming densely packed microvilli comparable to those found on the brush border membrane of small intestine. This intracellular trafficking and fusion events bring proton pumps to their post for active acid secretion. In time, these proton pumps are brought back into the cytoplasm (by way of endocytosis) for a reliable mechanism to turn off acid secretion. Although the membrane recycling theory was raised long time ago(3), there are still many major gaps in the understanding of the mechanism for the regulation of acid secretion, which are the research interests of our laboratory. Techniques employed include isolation and primary culture of gastric parietal cells, measurement of acid secretion, fractionation of different membranes by differential and gradient centrifugation.

Figure 1, Schematic representation of the parietal cell in resting and stimulated states. Drastic morphological change occurs with stimulation. In the resting state the apical canaliculi extend into the cell presenting short microvilli. Tubulovesicles containing cargo H,K pumps (red) abound in the cytoplasmic space. There are also many mitochondria. •Using gastric parietal cell model to study general cell biological questions: how membrane trafficking is regulated by small G-proteins, how filamentous actin supports the dynamic change of microvilli on apical membrane. Parietal cell has a remarkable large volume of intracellular membrane trafficking adapted to the elegant mechanism for the regulation of acid secretion. This means that this cell is abundant in those protein machineries required for membrane trafficking and fusion, exocytosis and endocytosis. For instance, no other cell types express the amount of syntaxin3 found in parietal cell. Therefore, parietal cell is the top choice for elucidating many of the core questions in cell biology. Techniques used to attack these questions include immunoabsorption, differential ultra-centrifugation, IMAC, 2D-electrophoresis, Western blot analysis, LC-MSMS, immunofluorescence and confocal microscopy.

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•Pathogenesis of Nonalcoholic Steatohepatitis (NASH)

NASH research is funded by the Peter and Tommy Fund. NASH is a disease of the liver that is associated with obesity and adult onset, or type II, diabetes. NASH is not a benign disease. Many people with NASH have a shortened life expectancy than those who do not have NASH. NASH is associated with cirrhosis and is the third most common reason for liver transplantation in adults. No one knows what causes NASH, but it is known that in obese people there is increased fat in the liver. In addition to fat, cells that cause inflammation are found in the liver in patients with NASH. It is thought that these inflammatory cells may cause liver damage that results in fibrosis, cirrhosis and ultimately liver failure. The purpose of this research is to understand the relationship among obesity and the molecular factors that control inflammation so the interaction of the two can be better understood and treatments developed.

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•Pathogenesis of Inflammatory Bowel Diseases (IBD) This is an investigator-initiated research, sponsored by the Pharmaceutical Industry. The etiology of IBD is unknown, but a body of evidence from clinical and experimental observation indicates a role for intestinal microflora in the pathogenesis of this disease. An increasing number of both clinical and laboratory-derived observations support the importance of luminal components in driving the inflammatory response in Crohn's disease. A growing amount of evidence indicates that the intestinal flora plays a pathogenic role in IBD: hence, the use of anti-bacterial agents as ancillary treatment in patients with ulcerative colitis, or Crohn's disease. The rationale of antibiotic therapy in the treatment of IBD is to decrease the bacterial load that act as an antigen that triggers an immune response. Numerous antibiotics have been used for several years in the treatment of intestinal diseases, most are members of the class of aminoglycosides. These are effective against gram-positive and some gram-negative bacteria, above all aerobes, and do not therefore cover the entire range of microorganisms responsible for intestinal infections. With these antibiotics, moreover, it is not possible to exclude intestinal absorption, which can lead to serious side effects. Ciprofloxacin and metronidazole are the two most widely studied antibiotics proved effective therapy for patients with active ileo-colonic and colonic Crohn's disease, but with known side effects attributed to systemic absorption. Rifaximin is a rifamycin analogue with a broad spectrum of activity similar to that of rifampin; however, because it is poorly absorbed through the gastrointestinal tract, it's development was focused for intestinal infections and diseases. The primary objective of this study is to evaluate the subject's disease activity response as measured by the pediatric Crohn's disease activity index (PCDAI) that includes a questionnaire, physical exam and blood work with the treatment of oral rifaximin for 21 days in mild to moderate Crohn's disease flare-up in pediatric patients, 12 to 18 years of age, inclusive. The secondary objective of the study is to evaluate the amount of time the subject's disease activity response remains improved post 21 days of treatment of rifaximin. We hypothesize that oral rifaximin treatment for 21 days will be an effective treatment modality for patients with confirmed Crohn's disease presenting with mild to moderate disease flare up. Members of the Toll-like receptor family are key regulators of both innate and adaptive immune responses. These receptors bind molecular structures that are expressed by microbes but are not expressed by the human host. Activation of these receptors initiates an inflammatory cascade that attempts to clear the offending pathogen and set in motion a specific adaptive immune response. Defects in sensing of pathogens or mediation of the inflammatory cascade may contribute to the pathophysiology of disease and injure the host by activating a deleterious immune response, such as in inflammatory bowel disease. The focus of this research is to identify possible abnormalities in toll-like receptors and their roles in the development of inflammatory bowel disease.