Summer Research Opportunities

Markus Bitzer, MD, Assistant Professor of Nephrology, Department of Internal Medicine
MicroRNAs are small non-coding RNAs that regulate expression post-transcriptionally. We have identified microRNAs that exhibit good correlation of expression in glomeruli of patients with diabetic nephropathy and albuminuria. To begin to explore the function of these microRNAs, we plan to inhibit or overexpress these microRNAs with anti-sense oligonucleotides or overexpression plasmids, respectively, in cultured glomerular cells (mesangial and podocyte cell lines) and the effect on cell survival, proliferation, extra-cellular matrix production and cytoskeleton structure will be assayed. The localization of the albuminuria-associated microRNAs and their relevant target genes will be determined using in situ hybridization and immunohistochemistry in kidney tissue. Future project may further determine the function of these microRNAs in animal models.

Neal Blatt, MD, Ph.D. Assistant Professor of Pediatric Nephrology, Department of Pediatrics
For patients with advanced chronic kidney failure, the two most common causes of death are from heart disease and infections, which both have their origins in alteration of immune function.  The goal of my research is to understand how kidney failure impacts immune function via study of macrophages and T-lymphocytes, cells that are key players in the innate and adaptive immune systems. For these studies, macrophages and lymphocytes will be isolated from a mouse model of chronic kidney failure, and then stimulated in tissue culture to understand how kidney failure alters their function.

Frank Brosius, MD, Professor and Division Chief of Nephrology
The Brosius lab works primarily on basic and translational research into the most common cause of chronic kidney disease, diabetic nephropathy.  The student project would encompass an 8 week study of one of our engineered “humanized” mouse models of diabetic nephropathy to determine effects of treatment on progressive kidney disease.  Aspects of this work would involve systems biological approaches to investigating molecular responses to treatment.

Greg Dressler, PhD, Collegiate Professor of Pathology Research
The Dressler lab studies the embryonic development and the genes that control cell fate determination.  How embryonic genes are reactivated and impact disease is also of interest.  Much of the work focuses on kidney and renal epithelial cells.  We have discovered several new genes and pathways which can be manipulated to suppress renal injury and to enhance recovery.  Student can contribute to ongoing projects in genetically engineered mouse models of kidney disease using biochemical, immunological, and cell biological methods to address function.

Puneet Garg, MD, FASN, Assistant Professor of Nephrology, Department of Internal Medicine
Over the past decade, identification of human diseases with podocyte-specific gene mutations and observations from animal models and cell culture studies have led to intense scientific interest in the role of podocytes in glomerular diseases.  Nephrin and Neph1 are cell adhesion molecules of the Ig superfamily that are specifically targeted to podocyte intercellular junctions. When deleted in human inherited disease or in mouse genetic mutant models, absence of Nephrin or Neph1 result in a developmental phenotype in which podocyte tertiary process formation and podocyte intercellular junction is dramatically disrupted, suggesting that these proteins are required for normal podocyte patterning. Investigation of the signaling mechanisms by which nephrin and neph1 influence podocyte process patterning and cell junction formation revealed their ability to assemble a protein complex that can regulate actin cytoskeletal dynamics. My lab is interested in the signaling mechanisms responsible for Nephrin phosphorylation and regulation of podocyte actin dynamics. We are also interested in studying mechanisms by which endocytosis of membrane proteins including Nephrin influences podocyte homeostasis. As Nephrin is also expressed in pancreas, we are investigating its role in insulin vesicle secretion in the pancreas by generating a mouse model where Nephrin will be conditionally deleted in the pancreatic beta cells.

Ken Inoki, MD, PhD, Assistant Professor of Molecular & Integrative Physiology and Nephrology, Department of Internal Medicine
The Inoki lab is investigating the function and regulation of nutrients-sensing kinases such as mTOR(target of rapamycin) and AMPK (AMP-activated kinase) in the development of kidney diseases, metabolic disorders, and cancer using biochemical and genetic approaches.

Wenjun Ju, PhD, Research Assistant Professor, Nephrology, Department of Internal Medicine
Chronic kidney diseases (CKD) affect 13% of adult population in the United States. Patients with CKD can progress into end-stage renal disease (ESRD) requiring dialysis and renal replacement therapy, associated with high cost, morbidity and mortality. Disease progression can be delayed or halted and patient outcomes can be improved if early detection and treatment becomes possible. By applying systems biology approach in CKD, we are able to pinpoint the candidate non-invasive biomarkers, whose expression in kidney is able to predict kidney function and kidney disease progression. Our current research focuses are: validation of the candidate non-invasive markers in the urine samples of a large cohort of CKD patients; determination of the pathophysiology role of validated biomarkers in disease initiation and progression; and exploring novel therapeutic strategies for disease altered pathways.

Matthias Kretzler, MD, Professor of Nephrology, Department of Internal Medicine,  and Computational Medicine & Bioinformatics
The research in Dr. Kretzler’s team focuses on the analysis of molecular mechanism of glomerular failure. Using integrated biology approaches the group defines transcriptional networks in human glomerular diseases and integrates them with complex clinical data sets and other large-scale data sets. The NEPTUNE network offers the unique opportunity to analyze a prospective cohort of glomerular disease patients with high-resolution clinical and molecular phenotyping.  An international multi-disciplinary research team will enable large scale data integration across the genotype-phenotype continuum of glomerular failure with carefully monitored environmental exposures, genetic predispositions, epigenetic markers, transcriptional networks, proteomic profiles, metabolic fingerprints, digital histological biopsy archive and prospective clinical disease characterization.
Opportunities for bioinformatics graduate student rotations include integrative analyzes across species along the genotype-phenotype continuum in an interdisciplinary research team.

Possible projects include work on strategies for (1) integrating systems information into genetic association analyses, (2) identifying molecular subsystems affected by multiple candidate genetic variants, and (3) identifying shared mechanisms across tissues, species, or phenotype.

Expansion of the project into a Ph.D. thesis is possible and funds for support might be available. 
Background in analysis of large-scale data sets is preferred; basic concepts of molecular biology, statistics and programming are preferred; and ability to function and interact in a multidisciplinary team is essential.

Ben Margolis, MD, Professor of Nephrology, Associate Dean for Research
The Margolis laboratory uses tissue culture models to study the basis of cilia formation. Insights into cilia structure and function are relevant to many diseases including polycystic kidney disease and retinitis pigmentosa.  We examine cilia formation using molecular biology, biochemistry and microscopy techniques.

Rajiv Saran, MD, MS, MRCP, Associate Professor of Medicine, Division of Nephrology, Associate Director, UM Kidney Epidemiology and Cost Center (UM-KECC)
The Centers for Disease Control and Prevention(CDC) funded, Chronic Kidney Disease (CKD) Surveillance System is a one of a kind project designed to continually monitor many aspects of CKD in the United States. The eventual goal is to slow down the growing burden of this devastating disease.  Our multidisciplinary team at the UM-Kidney Epidemiology and Cost Center (located in the UM-School of Public Health) is engaged in examining mulitple national (e.g., National VA data or NHANES) and regional data sources (e.g., Managed Care Data) to paint a national picture of CKD, and produce regular updates to a soon to be activated CDC website. We constantly produce reports and research papers on this subject to inform both the scientific world as well as public policy in this area

Matthew Sampson, MD, MSCE, Assistant Professor of Pediatric Nephrology, Department of Pediatrics
Genetics of Gene Expression in Nephrotic Syndrome: Nephrotic syndrome is a common disease in children and adults. Etiologies for this condition are diverse, with the common final lesion being injury to the glomerulus, resulting in massive proteinuria, with the loss of important proteins in the blood, such as coagulation factors and immunoglobulins.Patients suffer from edema, increased susceptibility to infection, and venous thromboembolism.  In addition, there is significant morbidity from the nonspecific medications used to treat this disease.

My interest is in discovering new genes, biological pathways, and signaling networks that are important in nephrotic syndrome's (1) etiology and (2) progression of poor clinical outcomes. By discovering these, we can aid in diagnosis, prediction of natural history, and identification of targets for drug development that can help improve the outcomes of this disease.   My approach to answering these questions is to first understand how genetic variation (rare mutations and more common polymorphisms) affects expression of genes within the kidney tissue of patients with nephrotic syndrome.  The establishment of the Nephrotic Syndrome Study Network (NEPTUNE) gives us a unique opportunity to do this, as it is collecting DNA and renal biopsy tissue (for gene expression analysis) in each of the subjects enrolled.  Each patient will have whole genome genotyping data and whole genome gene expression profiles generated.  The summer project will involve applying population-based genetics approaches to discover relationships between genetic variants and gene expression (measured by RNA-Seq) in the diseased kidneys of NEPTUNE enrollees.  We will then use functional annotation and network analysis approaches to understand the biological functions and pathways underlying these disease-specific relationships. 

Sivaraj Sivaramakrishnan, PhD, Assistant Professor of Cellular and Developmental Biology
Myosin VI is a molecular motor that enables the appropriate localization of the sodium-proton antiporter (NHE3) in the proximal tubule cells of the kidney. The localization and transport function of NHE3 is essential for maintenance of sodium levels in the blood. Our laboratory uses a model system that combines biophysical and biochemical approaches to study the cooperative behavior of molecular motors. In collaboration with Dr. Joel Weinberg we are interested in studying the collaborative movement of myosin VI coated membrane vesicles. The long-term goal of this project is to develop novel therapeutics that combat renal hypertension.

Deneen Wellik, Ph.D., Associate Professor of Molecular Medicine and Genetics
We have generated a new conditional allele of Hoxd11 and are interested in pursuing conditional ablation of the Hox11 group genes to explore their function in the development and maintenance of the ureteropelvic junction and the neprhogenic mesenchyme.  A fellow would learn a great deal about mouse developmental genetics.

Roger C. Wiggins, MB, BChir, Professor of Internal Medicine, Division of Nephrology
The Wiggins laboratory has played a major role in defining podocyte depletion as the key mechanism that drives progressive glomerulosclerosis causing progression to End Stage Kidney Disease (ESKD) and accounting for >80% of all ESKD in man.  A major focus of the laboratory is to use model systems to define conditions under which podocyte depletion can be initiated by the interplay of normal growth, environmental and dietary factors, underlying genetic predispositions and disease mechanisms; to understand how podocyte injury and loss from glomeruli can be amplified by common pathways triggered by the initial podocyte injury and loss; and to develop therapeutic approaches to prevent podocyte loss and replace podocytes so as to stabilize glomeruli and prevent progression to ESKD. A second focus is the development and testing of non-invasive biomarkers based on these insights that can be used to monitor and guide treatments for people with progressive kidney diseases.

Weibin Zhou, PhD, Research Investigator, Department of Pediatrics
DNA repair damage response (DDR) deficiencies  have been implicated in pathogenesis of a variety of human diseases. Recently, we have identifed deleterious mutations in Fanconni Anemia associated nuclease1 (FAN1) that impair DDR function as genetic causes of karyomegalic nephritis in human.  In order to understand the role of DDR in human kidney diseases and search for potential therapies, we are investigating a number of zebrafish models for DDR-related genes (FAN1, ruvbl1, ruvbl2) and testing therapeutic agents using the animal models.