Jeffrey H. Miner, PhD, professor of medicine   Cover Illustration J Cell Sci 121:2008 (Miner Laboratory) George Jarad MD, instructor in medicine.

Highlights of research currently being conducted in the Division - including that by postdoctoral fellows - follows. Some of the investigators have primary appointments in other divisions within the Department of Internal Medicine or in other departments, reflecting the wide network of collaborative pursuits. George M. O'Brien Center: Washington University Center for Kidney Disease Research Between 1992-2003 (P50: Renal Genes, Growth Factors, Development and Disease) and again in 2007 [P30: The Center for Kidney Disease Research (CKDR)] the Washington University Renal Division was named recipient of a George M. O'Brien Center by NIDDK. The CKDR consists of an administrative core and three scientific cores; Renal Organogenesis Core; Renal Disease Models Core; and Kidney Translational Research Core. The first two are international in scope. The third is a regional St. Louis City-wide Core based at Washington University and including St. Louis University. The principal investigator for the Center is Dr. Marc Hammerman. To access the Washington University George M. O'Brien Center for Kidney Disease Research , please click on WU George M. O'Brien Center Frequent Hemodialysis Clinical Trials In 2003, the Washington University Renal Division was named a participating Center in the National Institutes of Health - sponsored study evaluating nocturnal hemodialysis, Frequent Hemodialysis Clinical Trials. The principal investigator for the Center is Dr. Brent Miller. Hemodialysis Vascular Access Clinical Trials Consortium In 2002, the Chromalloy American Kidney Center was named one of 5 participating Centers for the Hemodialysis Vascular Access Clinical Trials Consortium by the NIH. The Washington University Center will test the efficacy of dipyridamole as an agent to decrease the need for intervention and prolong the survival of PTFE grafts. Dr. James Delmez, medical director of the center, is the principal investigator. Drs. Daniel Coyne, Brent Miller, Marcos Rothstein and David Windus also participate.

Daniel W. Coyne, MD, professor of medicine, director of hemodialysis and outpatient clinics     Cover Story: Embryonic Donor Organs and Renal Organogenesis. Organogenesis 1:1 2004 (Hammerman laboratory)   Pig beta cells (red) in rhesus macaque lymph node (Xenotransplantation 14:591-602, 2007)

Institutional NIH Training Grants: Renal Disease In 1961 and again in 1974, the Division was awarded an institutional training grant by the NIH to prepare selected candidates for full-time careers in academic medicine. Since that time, the postgraduate education of a large number of physicians and renal scientists has been supported by this grant. Most trainees have remained in academic medicine and many have gone on to head renal divisions in the United States, Canada, Europe, and Asia or to assume other important academic scientific and administrative positions. Drs. Neal Bricker and Saulo Klahr have served as principal investigators for this award. Dr. Marc R. Hammerman is the present principal investigator. Renal Division-Biotechology Interactions Rarely has there been a time when universities and industry have sought closer alignment than today. The biotechnology revolution that has transformed and continues to change the landscape of health care began at the benches of university scientists. It became a reality, however, through partnerships with visionary companies that understood the enormous potential of biotechnology. The Renal Division interacts with a number of biotechnology companies through research agreements, licensing agreements and clinical trials. Transplantation of Developing Organs - Organogenesis of Kidney or Endocrine Pancreas Marc R. Hammerman, MD Human kidney or pancreas transplantation (or islet transplantation) is limited by organ availability. Use of porcine donors (xenotransplantation) is a possible alternative. One problem with the use in humans of developed porcine organs such as kidney or pancreas, is that humoral rejection is directed against antigens present on the vascular endothelium. Organ primordia (kidneys or pancreas) can be transplanted in 'cellular' form so that they develop in situ and become vascularized by the host obviating humoral rejection. If transplanted with its ureteric bud attached, a renal primordium (metanephros) transplanted into the mesentery enlarges and differentiates into a functional kidney that can maintain life for a time in otherwise anephric hosts following ureteroureterostomy between transplant and host. If transplanted at a sufficiently early stage of development, pancreatic primordia undergo selective endocrine differentiation post-transplantation such that exocrine components are not present at all. Embryonic pig pancreatic primordia transplanted into rats with type 1 (streptozotocin) or type 2 (ZDF) diabetes or into non-human primates with streptozotocin diabetes engraft and differentiate into functioning beta cells without the need for host immunsuppression. Glucose tolerance is normalized in rats with type 1 or type 2 diabetes within weeks after transplantation of pig pancreatic primordia.

Retro-peritoneal dissection of E15 rat embryo showing mesonephroi & metanephroi (Am. J. Physiol. 262:F523-F532, 1992)

Alex Brown, PhD, research associate professor Cover illustration, Kidney International 54:1, 1998 (Hammerman laboratory)   Cover illustration, Genomics 61:2, 1999 (Miner laboratory)   Cover illustration, Am. J. Physiology: Renal Physiology 48:1, 2000 (Hruska laboratory) David Ornitz MD PhD, Alumni endowed professor and chair, developmental biology

Vitamin D, Phosphate, and PTH Interactions in Health and Chronic Renal Failure Eduardo Slatopolsky, MD The major focus of our group is the evaluation of the factors involved in the pathogenesis of secondary hyperparathyroidism and bone disease in chronic renal failure. Our research examines the effect of dietary phosphate on the development of secondary hyperparathyroidism and, using the rat model of chronic renal failure, regulation of PTH secretion and pre-pro-PTH mRNA expression. In addition, new non-calcemic analogs of calcitriol are being investigated as regulators of PTH secretion and parathyroid gland growth in chronic renal failure. We are also interested in characterizing the mechanisms involved in the selective action of vitamin D analogs in vivo. The basic research in the field of secondary hyperparathyroidism is complemented by a series of clinical projects. Regulation of Renal Vitamin D Metabolism Alex J. Brown, PhD Activation of vitamin D occurs predominantly in the kidney. The active form of the vitamin, 1,25-(OH)2D3(calcitriol), is a hormone that binds to a cellular receptor similar to those for the steroid hormones. Calcitriol receptors have been found in more than two dozen tissues and mediate a variety of responses, but the most important actions of calcitriol are in the intestine, bone, kidney and parathyroid glands where it plays a critical role mineral homeostasis. There are several requirements for vitamin D analogs used in the treatment of secondary hyperparathyroidism. First, the analog has to have a reasonable affinity for the VDR. This requires the presence of a hydroxyl group in the 1[alpha] position. Second, the analog needs to be substantially less calcemic than the parent compound. Despite a high affinity for the VDR, many analogs have significantly less calcemic activity than 1,25-(OH)2D3. An example of this is 19-nor-1, 25-(OH)2D2, which is approximately 10 times less calcemic than 1,25-(OH)2D3. The decreased calcemic activity of 19-nor-1,25-(OH)2D2 cannot be attributed to decreased VDR binding. Finally, the analog has to be able to suppress PTH in vivo. Although some analogs are effective in suppressing PTH in vitro, when tested in vivo, they are rapidly metabolized and not effective in treating secondary hyperparathyroidism. Four analogs are currently used are 19-nor-1,25-(OH)2D2 (paricalcitol, Zemplar) and 1[alpha]-(OH)D2 (doxercalciferol, Hectorol), in the United States, and 22-oxa-calcitriol (OCT) and 1,25-(OH)2-26,27F6 D3 (falecalcitriol), in Japan. Fibroblast Growth Factor Expression and Action David Ornitz, MD, PhD Fibroblast growth factors (FGFs) are essential molecules for mammalian development. FGFs also are important regulators of angiogenesis, wound healing, and when inappropriately expressed, cancer. Engineered mutations in the genes encoding several FGFs and FGF receptors results in developmental defects and/or embryonic lethality in the mouse. FGF receptor 3 is expressed in developing bone, the central nervous system and in the organ of Corti of the inner ear. We have disrupted the gene encoding FGF receptor 3 in mice and have observed defects in both bone and inner ear development. We are studying the developmental role of FGF receptor 3 in this context. In a similar fashion, we have disrupted the gene encoding FGF-9. Preliminary data suggests a role in pulmonary and cardiac development. Currently we are analyzing the expression patterns of several new members of the FGF family.

2005 KIDNEY TRANSPLANTATION AT Barnes-Jewish Hospital/Washington University

Michele Cabellon MD, assistant professor of medicine   Brent W. Miller, MD, associate professor of medicine   Matthew Lambert, MD, postdoctoral fellow   Georges Saab, MD, assistant professor of medicine

Research in Renal Transplantation Daniel C. Brennan, MD The renal transplantation program is a mutual service between medicine and surgery. We collaborate closely with the other solid organ transplant programs such as liver, small bowel, heart and lung, which provide sufficient patients for us to engage in both clinical and basic research. We are currently investigating several areas. Cytomegalovirus (CMV) disease is one of the major causes of morbidity and mortality in organ transplant recipients and is one of our primary areas of research activity. Although there is no consensus on prophylaxis, treatment or monitoring strategies, our investigations use the polymerase chain reaction to monitor CMV and determine treatment and prophylaxis strategies. Using the USRDS/HCFA database as well as our internal database, we are determining the impact of the pretransplant CMV donor and recipient status and post-transplant infection rate on long-term outcome and chronic rejection in renal transplant recipients. We also participate in several multicenter clinical trials of investigational immunosuppressive agents. Molecular and Cellular Regulation of Potassium Channels Colin G. Nichols PhD A unique class of potassium channels (KATP) are inhibited by ATP and link metabolic state to electrical activity. A major question has been: What is the nature of the ATP-binding site on this channel? Ultimately, the answer requires knowledge of the channel structure, and we have long been involved in efforts to clone the channel. KATP channels are blocked by sulfonylurea drugs, and we have now purified and cloned the sulfonylurea receptor (SUR) and reconstituted KATP channel activity by coexpression of SUR with a pancreatic K channel subunit. A class of K+ channels that are structurally related to KATP channels are called inward rectifiers and have a steep voltage-dependence of conductance (rectification). We cloned a novel strong inward rectifier K channel and demonstrated that rectification requires soluble factors, which we subsequently identified as polyamines. This work has renewed interest in the phenomenon of inward rectification. It is now clear that polyamines also underlie inward rectification of receptor activated K+ channels in the heart and several glutamate receptor channels in nerve cells. For additonal information Dr. Nichols' website is www.nicholslab.wustl.edu/nichols.htm. Nocturnal (Frequent) Dialysis Modalities Brent W. Miller, MD The Frequent Hemodialysis Network trial will evaluate frequent or ‘nocturnal’ hemodialysis. We were one of the early adapters of nocturnal hemodialysis in the United States and one of the first to use a form called “single-needle nocturnal hemodialysis” which improves patient safety and acceptance of the dialysis procedure.

Anitha Vijayan, MD, associate professor of medicine     David Windus, MD, professor of medicine

Acute and Chronic Renal Failure and Transplantation Clinical Trials Anitha Vijayan, MD Acute kidney injury is the most common kidney-related problem in hospitalized patients, accounting for as many as 5% of hospitalizations. Mortality for this condition in patients remains high. My laboratory is concerned with identifying biomarkers that will permit early diagnosis and define regenerative events in acute kidney injury. In additon we are conducting clinical trials to determine the best way to treat acute kidney injury in hospitalized patients. Medicine in Emerging Countries - Eritrea and Bhutan David W. Windus, MD Our work in Bhutan and Eritrea is conducted in conjunction with a team of nurses and diabetes educators and sponsored by Pathologists Overseas. The goals the Pathologists Overseas projects are improved physician education in management of chronic adult diseases and improved utilization of laboratory services. Specifically, we have developed productive working relationships with local physicians and other healthcare professionals, consulted on patients both in outpatient and inpatient settings, and organized continuing medical education courses for physicians in the areas of hypertension, diabetes, and kidney disease. In 2004, we organized and delivered the majority of lectures during a three day symposium on diabetes care for practicing physicians in Eritrea. Subsequent to his symposium there was a demonstrable improvement in diabetes control as evidence by a significant fall in hemoglobin A1C values. In recognition of this success, we were invited back to Eritrea by the Minister of Health. In June 2006 we directed an intensive two-week course in kidney, cardiovascular and endocrine diseases for 2nd and 3rd year medical students. This included lectures as well as small group problem solving and case-study related material.

RET-mediated PLC-gamma activation ensures that only a single ureteric bud is formed.

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Feng Chen PhD, assistant professor of medicine Piyush Tripathi PhD, postdoctoral fellow

Calcineurin in the Development of the Excretory System Feng Chen, PhD Congenital obstructive nephropathy is the most common cause of renal failure in infants and children. Hydronephrosis is a frequent complication. Experimental surgical animal models for obstructive nephropathy have been useful in characterizing the pathophysiology of obstruction, but less informative about defining the molecular and cellular defects that lead to the disease. Calcineurin is a calcium-dependent serine/threonine phosphatase composed of a catalytic subunit CnA and a regulatory subunit, CnB. The disruption of calcineurin function in mice carrying a CnB mutant allele results in vascular developmental defects and embryonic lethality. To avoid the lethality and permit functional evaluation of the role for CnB later in development, a floxed CnB allele has been produced. We have generated a strain of mice in which the CnB gene is deleted in the developing neural crest and other cells by Pax3-Cre-mediated recombination. These mice have deletion of CnB from the excretory system and die from renal failure resulting from congenital hydronephrosis. Our mice provide an animal model for non-surgical congenital obstruction.

FY 2005 NIH FUNDING

Stanley Misler, MD, PhD, associate professor of medicine   Helen Liapis, MD, professor of pathology and medicine Alex Argoudeles MD, postdoctoral fellow Yinqui Wang PhD, postdoctoral fellow Jeremiah J. Morrissey, PhD, research professor of medicine

Stimulus-secretion coupling in insulin-secreting Pancreatic Islet Cells Stanley Misler, MD, PhD My laboratory has a longstanding interest in the mechanisms, dynamics and modulation of glucose-induced insulin secretion from pancreatic beta cells, in addition to acetylcholine-induced catecholamine release from adrenal chromaffin cells. In the past decade we have pioneered the use of single cell assays for exocytosis. This is done via electrical tracking of small changes in plasma membrane surface area and electrochemical detection of synchronized release of packets of epinephrin and serotonin. Using this technique we can examine the dependence of quantal secretion of these hormones on the timing of electrical activity and the rate of entry of extracellular calcium. In addition we can define modulation of these parameters by paracrine hormones, cyclic nucleotides, neurotoxins and stimulators of intracellular calcium release stores. In collaboration with Dr. Kenneth Polonsky, my laboratory has been investigating the roles of the developmental regulatory gene PDX-1 and cytosolic calcium on the regulation of apoptosis in adult beta cells under conditions of metabolic stress. Our studies have implications both for the secretory defects as well as progression of diabetes mellitus, a major cause of renal failure. Signal Transduction in Kidney and Bone Keith A. Hruska, MD The research focus of our laboratory is signal transduction in kidney, bone and endothelial cells. We have demonstrated that matrix proteins such as osteopontin when coupled to avb3 integrin, induce immediate cell signals such as activation of phosphatidylinositol 3-hydroxyl kinase and the proto-oncogene c-src. The regulation of the cytoskeleton through matrix protein/integrin interaction and cellular mechanical stimulation are current foci of activity in the laboratory. Another area under investigation is the role that bone morphogenetic protein 7 (BMP7) deficiency resulting from renal failure plays in the progression of kidney disease, disordered bone remodeling and susceptibility to vascular calcification. Using a rat model, we have determined that exogenously administered BMP 7 is broadly therapeutic in the setting of kidney disease. Renal Vasoactive Peptides Jeremiah J. Morrissey, PhD In a wide variety of kidney diseases there are alterations in the synthesis of several cytokines that contribute to the development and progression of tubulointerstitial fibrosis. The effect of these cytokines on kidney fibrosis can be ameliorated by treating experimental animals with inhibitors of angiotensin II (AII) synthesis or AII action. In addition, the amino acid arginine, given as a supplement in the drinking water, blunts many of the factors contributing to renal fibrosis. We have found that inhibitors of AII formation or action in addition to arginine downregulate transcription factor NF-kappa B activation during experimental kidney disease. Furthermore, each of these treatments significantly reduces monocyte infiltration of the kidney during disease. In related studies, we have found that AII and tumor necrosis factor-a (TNF-a) operate in an autocrine reinforcing loop within the kidney. A central mediator in this reinforcing loop which exacerbates AII and TNF-a formation is the transcription factor NF-Kappa B.

Fused podocyte foot process in mice with a targeted mutation in the laminin beta 2 gene.

Chimeric mice. Embryos destined to become white mice were aggregated with embryos destined to become black mice   Cover Illustration JASN 18:8:2007 (Miner Laboratory)   Masato Hoshi PhD, postdoctoral fellow

Studies of Extracelular Matrix Jeffrey H. Miner, PhD My laboratory is interested in the role of basement membrane components in development, function, and disease of the kidney, with particular emphasis on the glomerular basement membrane (GBM). Several genetic and acquired diseases of the kidney affect the GBM, causing thinning or thickening. We are focusing on the laminin and type IV collagen components of the GBM and have identified a novel laminin chain that is present in all renal basement membranes. We have produced a set of "knockout" mice lacking this and other GBM components to determine their functions in the kidney and elsewhere. Some of these mutant mice serve as models for human diseases, including Alports syndrome and minimal change nephrotic syndrome. Molecular Studies of Glucose Transport Mike Mueckler, PhD We use the methods of molecular biology to study the structure, biosynthesis and regulation of the mammalian facilitated-diffusion glucose transporters (GT). Glucose transport across the plasma membrane is carried out by a family of glycoproteins that are expressed in a tissue-specific manner in mammals. One such GT is expressed specifically in muscle and fat, where its activity is increased in response to insulin. A disruption in the normal sensitivity of this transporter to insulin is a principal feature of type II diabetes, and one of our goals is to define this defect at molecular levels and to understand the mechanism of insulin action on glucose transport. Current specific areas of investigation include: 1) isolation and characterization of GT genes; 2) construction of transgenic mouse models and gene disruption by homologous recombination to study the physiologic role of different transporters; 3) regulation of the GT hormones, growth factors and oncogenes; 4) transfection and expression of human GT cDNAs in cultured cell lines, in conjunction with in vitro mutagenesis of the cDNA, in order to define informational sequences within the GT molecule necessary for its proper intracellular targeting and response to insulin; 5) structure-function studies involving expression of GT mRNAs in Xenopus oocytes; and 6) use of the GT as a model to study the mechanism of insertion of complex membrane proteins into the rough endoplasmic reticulum.

Sections of rat kidney stained for alpha 1 & 2 and alpha 4 chains of type IV collagen.

Sanjay Jain MD PhD, assistant professor of medicine and pathology   Cover Illustration Biol. of Reproduction 74:2:2006 (Jain Laboratory) Adriana Dusso, PhD, research associate professor Raphael Kopan, PhD, professor of molecular biology, pharmacology and medicine Jianghui Hou PhD, assistant professor of medicine.   Matt Coussens PhD, postdoctoral fellow

Role of RET in development and diseases of the urinary tract Sanjay Jain, MD, PhD Congenital renal and urinary tract abnormalities are one of the most common causes of renal failure in children and include a fairly complex array of phenotypes such as ureterocele, megaureter, hydronephrosis, hypoplasia/hypodysplasia, multicystic kidneys and renal agenesis. GDNF-RET signaling is crucial for renal development and is necessary for ureter maturation, ureteric bud induction and branching morphogenesis. These events rely on reciprocal interactions between the RET expressing ureteric bud epithelium that are also the precursors for the collecting ducts, and the GDNF expressing metanephric mesenchyme where the tubules and the glomeruli are formed. Identifying how RET regulates these diverse processes in kidney and ureter development will allow us to answer fundamental questions in renal development, understand pathogenesis of renal anomalies in patients and develop animal models of human kidney diseases. Regulation of Vitamin D Metabolism Adriana Dusso, PhD 1-hydroxylase, the enzyme responsible for the synthesis of 1,25-(OH)2D3, is a single gene product expressed mainly in renal proximal tubular cells but is also expressed in macrophages. Dr. Dusso has shown that a common transcription factor C/EBPb is responsible for the induction of 1-hydroxylase gene expression by cAMP/PKA in renal cells and by IFN-gamma in macrophages. Dr. Dusso is seeking to identify the mechanisms underlying: 1) the induction of C/Ebb Tran activation of the 1-hydroxylase gene by camp and IFN-gamma; 2) the diverse control by 1,25-(OH)2D3 of C/Ebb transcriptional responses in renal cells and macrophages; and 3) the advantage of local vs. systemic 1,25-(OH)2D3 synthesis in 1,25-(OH)2D3 control of its own metabolism and immune function.Elevated levels of parathyroid hormone (PTH) cause osteitis fibrosa, bone loss and cardiovascular complications. Hyperplasia of PTH-producing cells is a major cause of high serum PTH levels. Dr. Dusso’s is characterizing the antagonistic interactions between vitamin D and TGF-alpha/EGFR and their relevance in the pathogenesis of parathyroid hyperplasia and vitamin D resistance in shronic kidney disease as well as in EGFR-driven carcinomas. Notch signaling in Kidney Raphael Kopan, PhD The Notch pathway regulates differentiation during development by mediating short range intercellular signals. Mutations resulting in partial loss of the Notch ligand, jagged 1, impact upon renal function (Alagille Syndrome). Our laboratory has developed a pharmacological approach for Notch loss in renal anlagen in order to identify Notch controlled transcriptional changes in the metanephric kidney. In addition we are using conditionally activatable Notch alleles coupled with organ culture methods to evaluate the nephrogenic potential of the mutants and test the hypothesis that constitutive Notch activation will alter the distribution of cell fates in metanephric blastema. Claudin 16 and claudin 19 function, interaction, and modulation of ion selectivity of tight junction Jianghui Hou, PhD The renal handling of magnesium and calcium in the thick ascending limb (TAL) of Henle’s loop is primarily through the paracellular pathway. Claudin-16 and claudin-19 are found in TAL of the nephron, and mutations in claudin-16 or 19 have been linked to the human hereditary disease, familial hypomagnesemia with hypercalciuria and nephrocalcinosis (FHHNC). Our previous efforts have elucidated the channel functions of claudin-16 and claudin-19 (in epithelial cells such as MDCK and LLC-PK1), their interaction and synergy, and the in vivo role of claudin-16 in renal handling of magnesium and calcium. Continuing efforts to generate transgenic RNAi mouse models of claudin-19 and claudin-16/19 double knockdown will define the role of the TAL paracellular pathway in TAL ion and water homeostasis, define in vivo interaction and synergy between claudin-16 and -19 and provide a platform for drug screening.

Andrew Siedlecki MD, instructor in medicine Prashanth Podaralla MBBS MPH, postdoctoral fellow

Prevention of Complications in Patients with Chronic Kidney Disease James A. Delmez, MD Renal osteodystrophy is a universal complication of renal failure and is a major cause of morbidity in the 300,000 patients undergoing dialysis in the United States. High turnover bone disease (osteitis fibrosa) is the most common form of renal osteodystrophy and is due to excessive rates of parathyroid hormone (PTH) secretion. Complex abnormalities of calcium, phosphorus and calcitriol metabolism in renal failure stimulate PTH secretion. We are investigating the clinical utility of new compounds that bind phosphorus in the bowel to avoid hyperphosphatemia. Calcitriol suppresses parathyroid secretion indirectly by increasing levels of calcium and directly by decreasing gene transcription of pre-pro PTH mRNA. Little is known of the effect of calcitriol in preventing the development of parathyroid glandular hyperplasia. This is being studied in a randomized, controlled trial of early use of intravenous calcitriol in hemodialysis patients. The mortality rate of hemodialysis patients in the United States is substantially higher than that in Europe or Japan. We have shown that this is, in part, due to widespread under-dialysis of patients. We are evaluating factors that contribute to the impaired delivery of hemodialysis treatments in patients with acute and chronic renal failure.

Andrey S. Shaw, MD, professor of pathology and immunology.

Congenital Nephrotic Syndrome in Mice Lacking CD-2 Associated Protein Andrey S. Shaw, MD CD2-associated protein (CD2AP) is an 80-kilodalton protein that is critical for stabilizing contacts between T cells and antigen-presenting cells. In CD2AP deficient mice, immune function is compromised. The mice die at 6 to 7 weeks of age from chronic renal failure. In the kidney, CD2AP is expressed primarily in glomerular epithelial cells. Knockout mice exhibit defects in epithelial podocytes, as well as mesangial cell hyperplasia and abnormal extracellular matrix deposition. Supporting a role for CD2AP in the slit diaphragm, CD2AP is associated with nephrin, the primary component of the diaphragm. Recently we have shown that mice heterozygous for CD2AP deficiency develop glomerular disease that is characterized by mesangial expansion and electron-dense deposits in subendothelial, subepithelial and mesangial locations. CD2AP heterozygous mice are also more susceptible to glomerular injury than their wild-type littermates.

Electron microscopy of glomeruli wild-type (A) and CD2 AP KO (B) mice shows foot process effacement in KO mice.

Dwight Towler MD, PhD, professor of medicine   Bala Sankar MD, postdoctoral fellow Scott Boyle PhD, postdoctoral fellow WU School of Medicine Celebrated its 100th Year in 1991   The BJC Institute of Health will open in 2009. It will house BioMed21.

Active Remodeling of Calcified Tissues Dwight Towler MD,PhD Abnormal vascular calcification is a major cause of morbidity and mortality in end-stage renal disease. The molecular mechanisms whereby the osteoblast nucleus integrates transcriptional responses to morphogenetic, metabolic and mechanical cues are poorly understood. Msx2, Runx2 and Osx have emerged as key regulators osteoblast- and odontoblast-dependent bone formation. Runx2/Cbfa1 and Osx are necessary for proper intramembranous as well as endochondral bone formation. Msx2, by contrast, appears to function primarily to regulate intramembranous ossification and tooth development during craniofacial skeletogenesis. The osteocalcin (OC) promoter has proven useful for identifying and characterizing transcription factors that control osteoblast differentiation and maturation. We have identified a regulatory region in the OC promoter that entrains expression to activated fibroblast growth factor receptor 2 (FGFR2) signaling and to the osteoblast homeoprotein Msx2 (OC inhibitor). Of note, during aortic vascular calcification, specific osteogenic transcription factors are recruited by atherogenic diets during disease initiation—including the ectopic vascular expression of Msx2 and osteopontin (OPN) in adventitial myofibroblasts. By studying Msx2 action, Dr. Towler has identified cell-autonomous and paracrine Wnt/Dkk signaling cascades that may contribute to heterotopic mineralization by promoting the osteogenic lineage allocation of multipotent, vascular mesenchymal progenitors. St. Louis Children's Hospital Dr. Keith Hruska directs the Division of Pediatric Nephrology at Washington University and St. Louis Children's Hospital. Drs. Beck and Hmiel, also members of the Division, are interested in calcium metabolism and renal pharmacology respectively. The Division of Biology and Biomedical Sciences The Division of Biology and Biomedical Sciences (DBBS) was organized in 1973. DBBS is a graduate educational consortium that includes faculty affiliated with 20 basic science departments in the School of Medicine and the College of Arts and Sciences. DBBS programs are designed to provide a broad interdisciplinary approach to graduate education, emphasizing investigation of important questions in biology. Doctoral programs currently operating within the Division include: developmental biology, evolutionary and population biology, immunology, molecular biophysics, molecular cell biology and biochemistry, molecular genetics, molecular microbiology and microbial pathogenesis, neurosciences and plant biology. DBBS directs one of the largest and most successful Medical Scientist Training Programs offering a combined MD/PhD. BioMed 21 To any list of momentous dates in the history of life sciences at Washington University, 2003 must now be added as the year in which BioMed 21 was initiated. From the 1909 visit of Abraham Flexner that fueled a redefinition of American medical education through the completion of the Human Genome Project in 2002, few events will have the impact of BioMed 21. It is an intiative that will reshape university culture over the next decade to catalyze and support emerging forms of bioresearch and rapidly convert the knowledge of the genetic blueprint into effective individualized treatments for patients. As a first stage three new Institution-wide research units will be established: The Center for Genomics and Human Genetics; The Division of Clinical Sciences; and the Center for Biological Imaging. BioMed 21 is also a building program that will establish new spaces to house the emerging interdisciplinary basic and clinical research programs. Beginning in 2009, many BioMed 21 activities will take place in a new 250,000 square foot building, the BJC Institute of Health, that will serve as both a literal and figurative bridge between basic and clinical sciences on the Medical Campus.

Renal Division Department of Internal Medicine Washington University School of Medicine