Dr. Richard Quigg studies the immunopathogenesis of renal diseases through the use of animal models of these disorders. These include glomerular disorders such as membranous nephropathy and mesangial proliferative glomerulonephritis; nephropathy occurring in type 1 and 2 diabetes; lupus nephritis with its glomerular, tubular and vascular manifestations; acute renal failure occurring from ischemia-reperfusion and sepsis; and, chronic renal disease that can be modeled by ureteral obstruction and experimental nephrotic syndrome. Besides animal studies, a diversity of renal and non-renal cell lines are used to model pathophysiological events in culture systems. A longstanding interest in the role of complement activation and its regulation in these diseases, and the therapeutic potential of interrupting this system guides some of the research. A diversity of techniques are utilized to understand disease pathogenesis and to suggest and implement strategies to favorably alter disease course, which might ultimately be used as treatment in the human diseases. In addition to the use of standard tools to describe disease, contemporary approaches are used. These include transcriptional profiling using microarrays and identifying the underlying genetic bases for disease susceptibility or resistance, which are carried out in studies in the University of Chicago Functional Genomics Facility that Dr. Quigg directs. Additional approaches include the production and use of a variety of transgenic and gene targeted mouse strains; the use of renal and bone marrow transplantation to identify sites of action of relevant protein mediators; design and production of recombinant proteins, including those that can be targeted to sites of injury; and, confocal imaging of specific renal cells in vitro and in vivo using transgenic approaches to selectively express sensors in specific kidney cell types. Finally, translational studies are also performed using the section’s large patient base in diseases such as lupus nephritis, membranous nephropathy and diabetic nephropathy, and includes attempts to correlate findings in the experimental animal with human diseases and the use of novel therapeutic approaches.

Dr. Patrick Murray studies renal and systemic effects of vasoactive agents in critically ill subjects (in collaboration with investigators from the Critical Care sections of the Departments of Anesthesia and Medicine), and approaches to prevent, treat, and provide renal replacement therapy for acute renal failure.

Dr. Fredric Coe studies the pathogenesis and treatment of kidney stones in close collaboration with Dr Elaine Worcester. Protocols involving data mining from an extensive database of laboratory and clinical materials collected over three decades have helped to create a coherent sense of the disease for physicians world wide, and have complemented more basic studies in providing a clinical rationale. Recent discoveries have included first convincing evidence that stone forming patients are hypertensive as a population. Human experimental protocols, in the CRC or outpatient setting are aimed at understanding the pathogenesis of genetic hypercalciuria, and the naturally occurring inhibitors of crystallization in kidneys and urine. The former have been in close collaboration with Dr Murray Favus. Animal experiments at this institution performed in collaboration with Drs Glenn Gerber and Gene Chang, and have led to the development of a promising model of enteric hyperoxaluria with nephrocalcinosis. Collaboration with Dr David Bushinsky (U Rochester) have focused on an inbred strain of hypercalciuric stone forming rats, that exhibit abnormal vitamin D receptor abundance in intestine, kidney and bone. Collaborations with Profs Andrew Evan and James Lingeman (Indiana University) involve study of papillary and deep medulla biopsies from stone forming patients obtained during percutaneous nephrolithotomy. This work has led to the discovery that renal stone disease begins as apatite plaque in the basements of thin loops of Henle, and to characterization of the physiological factors that control plaque formation. In addition to the above-mentioned scientists, I collaborate with Drs and John Asplin (Medicine), and Dr Ronald Thisted, Dept of Health sciences, and have collaborated with Dr Michelle Josephson (Medicine) in preparing a grant proposal to study kidney stone formers as transplant donors.

Dr. Pradeep Kadambi is the co-Investigator for the Correction of Hemoglobin and Outcomes in Renal Insufficiency (CHOIR) study which is a Multi-center Phase IV Trial designed to test the hypothesis that the level of anemia correction with once weekly dosing of Procrit (Erythropoietin) in patients with chronic kidney disease will decrease mortality and cardiovascular morbidity. The recruitment focuses on patients with anemia secondary to Chronic Renal Insufficiency.

Dr. Elaine Worcester research is focused on achieving a better understanding of the processes that lead to kidney stone formation, and ways to provide better prevention and treatment of stones, in collaboration with Dr. Fredric Coe. This includes studies of patients with stones to better understand the absorption and renal excretion of minerals involved in stone formation, as contrasted with normal individuals, and studies of the clinical characteristics of patients with differing types of stones, as well as the effect of stone formation on renal function and blood pressure. We are also developing a model of stone disease in rats that is similar to that found in humans with bowel disease, which will allow us to better understand the physiological derangements that lead to stones, and develop better treatments, in collaboration with investigators from the sections of Urology and Gastroenterology.

Dr. Mary Hammes studies chronic renal failure, vascular access with emphasis on infectious hematologic complications.

Dr. Michelle Josephson studies medical complications of transplantation and donation including post transplant bone disease and BK nephropathy. Current research examines the prevention of BK nephropathy and the appropriateness of kidney donation among those with kidney stones.

Dr. Nicole Stankus studies use of Vitamin D preparations and calcimimetrics in secondary hyperparathyroidism.

Dr. F. Gary Toback is characterizing a novel protein that stimulates growth, migration, and cytoprotection of epithelial cells, and is seeking molecular mechanisms by which the protein acts. Studies now in progress are aimed at: (1) defining mechanisms by which a peptide fragment of the protein stimulates accumulation of tight junction and adherens junction proteins in epithelial cell monolayers and in vivo, (2) determining the role of heat shock proteins (hsps) in epithelial cell cytoprotection mediated by the novel peptide, and (3) defining specific signaling mechanisms that mediate its effect, such as the p38 MAP kinase/hsp27/actin microfilament pathway. The methods used in these projects include: immunoblotting confocal microscopy, northern blotting, gene expression, PCR, ELISA, immunocytochemistry, cell culture, measurements of paracellular permeability, and mouse models of epithelial cell injury. Collaborates with: Margaret Walsh-Reitz (Senior Research Associate), Sreedharan Kartha (Senior Project Professional), Eugene Chang and Mark Musch (Digestive Diseases Research Core Center), Terence Martin (Molecular Genetics and Cell Biology), John Alveredy and Richard Wu (Surgery), and John Hart (Pathology).

Dr. Robert Hoover is focused on regulation of the thiazide-sensitive Na-Cl cotransporter (rNCC). The rat thiazide-sensitive Na-Cl cotransporter is expressed in the mammalian renal distal convoluted tubule and is the side of action of an important class of antipertensive agents, the thiazide diuretics. In my lab I utilize techniques such as the Xenopus laevis oocyte expression system, confocal microscopy, tissue culture, PCR, site directed mutagenesis, and other techniques of molecular biology to investigate regulation of the cotransporter. I am presently investigating the pathways of regulation of the cotransporter by kinases and second messengers. I have recently identified the glycosylation sites for the cotransporter, demonstrated the key role of glycosylation my transport of the protein to the membrane an established that gylcosylation greatly alters the binding of thiazde diuretics.

Dr. Patrick Cunningham studies the pathogenesis of sepsis-induced acute renal failure through the use of animal models. Specific areas of interest include the roles that renal apoptosis, renal neutrophil accumulation, cytokines such as TNF, and oxidative damage play in this syndrome. Main methods used include analysis of kidney tissue with light microscopy, immunohistochemistry, TUNEL staining, ligase-mediated PCR, immunoblotting, ELISA, and purification of RNA for northern blotting, real-time PCR, and microarray analysis, as well as the use of murine kidney transplantation to localize the influence of various mediators.

Dr. Bharathi Reddy studies chronic kidney diseases and hemodialysis. Projects include:nasal mupirocin, a catheter associated bacteremia in hemodialysis patients and anticoagulation during hemodialysis.

Dr. Orly Kohn is the Director of our Peritoneal Dialysis Unit and is the Principal Investigator for the Family Investigation of Nephropathy in Diabetes (FIND) Minority Recruitment Center at The University of Chicago. FIND is a multicenter consortium established by the National Institutes of Diabetes, Digestive and Kidney Diseases to identify the gene(s) responsible for diabetic nephropathy. Our recruitment focuses on minority populations including African Americans, Mexican Americans and Asians. Other research interests include Quotidian Dialysis (Home Dialysis) and its affects on clearance and inflammatory markers and factors which improve technique survival in peritoneal dialysis.

Dr. Daniel Levy studies accessory-subunit modulation of potassium channels by the family of integral membrane proteins, the MinK-Related Proteins (MiRPs). Recent work has been on the characterization of the biochemical and electrophysiologic interaction of MiRP-3 and the potassium channel, MaxiK. MiRP-3 appears to modulate MaxiK in intercalated cells of the cortical collecting duct by increasing the energy required for channel opening. This effect would attenuate flow-dependent and pH-dependent potassium secretion from these cells, and Dr. Levy hypothesizes that MiRP-3 expression upregulated by rising serum potassium levels. The electrophysiological characterization of ion channels is performed with two-electrode voltage clamp of Xenopus oocytes and patch-clamp recordings of cultured mammalian cells. As necessary, channels and accessory subunits are modified via site-directed mutagenesis. Finally, protein interactions are evaluated by immunopurification and other basic biochemical techniques.

Dr. Tipu Puri studies the pathogenesis of renal fibrosis and progression of renal disease. It is widely held that chronic kidney disease such as diabetic, hypertensive, and other nephropathies, progress through a final common pathway resulting in fibrosis and culminating in end stage renal disease. His current work is focused on developing a novel animal model in which to apply microarray techniques to identify genetic factors that confer susceptibility or resistance to more rapid progression of renal disease. In vitro models of key mediators of renal fibrosis are also being developed in which to further study factors identified by animal studies.

Dr. Jian Zhang studies molecular mechanisms of T cell activation and apoptosis and their potential roles in autoimmunity. The signaling threshold of antigen receptors and costimulatory receptors determine immunity or tolerance to self-proteins. A major costimulatory receptor, CD28, is required for induction of autoimmunity in several mouse models. CD28 costimulation amplifies early and late TCR-mediated signaling events, and may lower the threshold needed for T cell activation. Dr. Zhang’s lab has shown that Cbl-b, an adaptor protein and ubiquitin ligase, is one of the key signaling molecules involved in both CD28- and CTLA-4-mediated T cell costimulation. His group is currently trying to identify novel proteins regulated by Cbl-b, to evaluate whether and how Cbl-b regulates CD28-mediated formation of immunological synapse, and to investigate the potential role of Cbl-b in regulating CD28-dependent autoreactive T cell activation in autoimmune diseases. Activation-induced cell death (AICD) of T cells is also one of the major mechanisms of peripheral tolerance. Dr. Zhang’s lab has studied the molecular mechanisms that underlie AICD and the potential role of AICD in autoimmune diseases. He has shown that IL-4 can regulate T cell susceptibility to AICD via an IL-2-dependent mechanism. Currently, his lab is investigating how cytokines, especially IL-4, regulate AICD in autoimmune arthritis in vitro and in vivo. Understanding of the signaling mechanisms of Fas-mediated AICD will provide new therapeutic targets for designing novel agents to cure autoimmune diseases including autoimmune arthritis.