The Johns Hopkins Center for Epithelial Disorders focuses on research into the physiology and pathophysiology of epithelial cells (cells that line the cavities and interior surfaces of the body) of the gastrointestinal (GI) tract, liver, pancreas and kidney. Specifically, the center’s research seeks to: -Understand the mechanisms regulating the activity of transport proteins (including channels) of epithelial cells Characterize the mechanisms by which polarity of epithelial cells are maintained -Investigate the mechanisms controlling transcription of epithelial-specific genes Understand the pathophysiological basis of GI and renal diseases that involve the preceding three components -The center also provides a framework for training fellows in gastroenterology and hepatology to become independent investigators. The center is funded primarily through individual investigator-initiated extramural research grant support from the National Institutes of Health (NIH) as well as multi-investigator grants including RO1, PO1, UO1 and R24.

The Zhu lab is focused on characterizing the activities of large collection of proteins, building signaling networks for better understanding the mechanisms of biological processes, and identifying biomarkers in human diseases and cancers. More specifically, our group is interested in analyzing protein posttranslational modifications, and identifying important components involved in transcription networks and host-pathogen interactions on the proteomics level, and biomarkers in human IBD diseases.

The David Graham Lab studies the consequences of HIV interactions with the immune system, the resulting pathogenesis and how to sabotage these interactions. We apply advanced technologies like mass spectrometry to dissect processes at the molecular level. We are also actively involved in cardiovascular research and studies the ways proteins are organized into functional units in different cell types of the heart. Major projects in our lab are organized into three major areas: (1) H/SIV pathogenesis and neuropathogenesis, (2) Cardiovascular disease, and (3) High technology development

Current projects include: The evaluation of mechanisms of immune tolerance to cancer in mouse models of breast and pancreatic cancer. We have characterized the HER-2/neu transgenic mouse model of spontaneous mammary tumors. This model demonstrates immune tolerance to the HER-2/neu gene product. This model is being used to better understand the mechanisms of tolerance to tumor. In addition, this model is being used to develop vaccine strategies that can overcome this tolerance and induce immunity potent enough to prevent and treat naturally developing tumors. More recently, we are using a genetic model of pancreatic cancer developed to understand the early inflammatory changes that promote cancer development. The identification of human tumor antigens recognized by T cells. We are using a novel functional genetic approach developed in our laboratory. Human tumor specific T cells from vaccinated patients are used to identify immune relevant antigens that are chosen based on an initial genomic screen of overexpressed gene products. Several candidate targets have been identified and the prevelence of vaccine induced immunity has been assessed . This rapid screen to identify relevant antigenic targets will allow us to begin to dissect the mechanisms of tumor immunity induction and downregulation at the molecular level in cancer patients. More recently, we are using proteomics to identify proteins involved in pancreatic cancer development. We recently identified Annexin A2 as a molecule involved in metastases. The analysis of antitumor immune responses in patients enrolled on vaccine studies. The focus is on breast and pancreatic cancers. We are atttempting to identify in vitro correlates of in vivo antitumor immunity induced by vaccine strategies developed in the laboratory and currently under study in the clinics.

Work in the William B. Guggino Lab focuses on the structure of the cystic fibrosis transmembrane conductance regulator (CFTR) and water channels; the molecular structure of transport proteins in epithelial cell membranes; and gene therapies to treat cystic fibrosis (CF) patients. We are also working to identify CF’s specific defect in chloride channel regulation. One recent study showed that insulin-like growth factor 1 (IGF-1) enhances the protein expression of CFTR.

Work in the Wei Dong Gao Lab primarily focuses on heart failure and defining molecular and cellular mechanisms of contractile dysfunction. We use molecular biology and proteomic techniques to investigate the changes that myofilament proteins undergo during heart failure and under drug therapy. We're working to determine the molecular nature of nitroxyl (HNO) modification of tropomyosin.

Research in the Wilson Lab focuses on three components of nuclear lamina structure: lamins, LEM-domain proteins (emerin), and BAF. These three proteins all bind each other directly, and are collectively required to organize and regulate chromatin, efficiently segregate chromosomes and rebuild nuclear structure after mitosis. Mutations in one or more of these proteins cause a variety of diseases including Emery-Dreifuss muscular dystrophy (EDMD), cardiomyopathy, lipodystrophy and diabetes, and accelerated aging. We are examining emerin's role in mechanotransduction, how emerin and lamin A are regulated, and whether misregulation contributes to disease.

Ion channels are pore-forming membrane proteins gating the flow of ions across the cell membrane. Among their many functions, ion channels regulate cell volume, control epithelial fluid secretion, and generate the electrical impulses in our brain. The Qiu Lab employs a multi-disciplinary approach including high-throughput functional genomics, electrophysiology, biochemistry, and mouse genetics to discover novel ion channels and to elucidate their role in health and disease.

The Landon King Lab studies aquaporins water-specific membrane channel proteins. We hope to understand how these proteins contribute to water homeostasis in the respiratory tract and how their expression or function may be altered in disease states.

The O’Rourke Lab uses an integrated approach to study the biophysics and physiology of cardiac cells in normal and diseased states. Research in our lab has incorporated mitochondrial energetics, Ca2+ dynamics, and electrophysiology to provide tools for studying how defective function of one component of the cell can lead to catastrophic effects on whole cell and whole organ function. By understanding the links between Ca2+, electrical excitability and energy production, we hope to understand the cellular basis of cardiac arrhythmias, ischemia-reperfusion injury, and sudden death. We use state-of-the-art techniques, including single-channel and whole-cell patch clamp, microfluorimetry, conventional and two-photon fluorescence imaging, and molecular biology to study the structure and function of single proteins to the intact muscle. Experimental results are compared with simulations of computational models in order to understand the findings in the context of the system as a whole. Ongoing studies in our lab are focused on identifying the specific molecular targets modified by oxidative or ischemic stress and how they affect mitochondrial and whole heart function. The motivation for all of the work is to understand • how the molecular details of the heart cell work together to maintain function and • how the synchronization of the parts can go wrong Rational strategies can then be devised to correct dysfunction during the progression of disease through a comprehensive understanding of basic mechanisms. Brian O’Rourke, PhD, is a professor in the Division of Cardiology and Vice Chair of Basic and Translational Research, Department of Medicine, at the Johns Hopkins University.