Summer Research Opportunities

Celine Berthier, PhD, Assistant Research Scientist, Nephrology, Department of Internal Medicine
As member of Dr. Kretzler lab, the major research interest of Dr. Berthier is lupus nephritis, one of the main complications of systemic lupus erythematosus (SLE). She works in closed collaboration with Dr. Kahlenberg, rheumatologist at the University of Michigan, whose research interest is skin lesions in lupus patients. Their common goals are to understand the biological mechanisms leading to lupus skin disease and the events driving the associated kidney disease. Among others, some data from treated/untreated keratinocytes from control and lupus patients should be available for analyses in summer 2016. The student in charge of the analyses will learn how to process and analyze microarray data using systems biology tools, as well as build hypotheses from the results.

Markus Bitzer, MD, Associate Professor of Nephrology, Department of Internal Medicine
Glomerular hypertrophy and podocytes stress lead to decreased podocytes density and are hallmarks of many glomerular diseases, in particular diabetic nephropathy and age-associated glomerulosclerosis. My research is focused on understanding the underlying molecular mechanisms of podocytes stress. We are integrating morphometric and transcriptomic data from human and mouse kidneys and validate our findings in tissue culture and animal models of kidney disease and injury. A particular focus is on non-coding RNAs including microRNAs, which are small non-coding RNAs that regulate expression post-transcriptionally and can be targeted with small molecules. We have identified specific microRNAs for which the expression in glomeruli is significantly associated with clinical outcomes and morphometric parameters of glomerular injury in patients with diabetic nephropathy and age-associated glomerulosclerosis. To explore the function of these microRNAs, we inhibit or overexpress these microRNAs in cultured glomerular cells (mesangial cells and podocytes) and determine the effect on cell survival, proliferation, extra-cellular matrix production and cytoskeleton structure.

Charles Burant, MD, PhD, Professor of Metabolism, Endocrinology and Diabetes (MEND), Department of Internal Medicine
The Burant lab is studying the development of diabetic kidney disease in both rodents and humans. We are studying the relationship between increased blood glucose and changes in cellular metabolism, including changes in mitochondrial function through modifications of proteins. We use metabolomic profiling to determine the changes in the flux of metabolites through various pathways. We also use computational tools to understand the changes in intermediary metabolism in diabetes.

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.

Evan Farkash, MD,PhD, Assistant Professor, Department of Pathology

Antibody mediated rejection (AMR) is a major cause of late graft loss after kidney transplantation, but the existing criteria for AMR diagnosis suffers from poor sensitivity.  Recognizing patients who are at risk for graft failure would permit improved targeting of patients for therapy or recruitment into clinical trials.  Using targets identified in molecular expression analysis, we are developing new tissue-based biomarkers for AMR, testing the utility of computer aided-diagnosis using digital morphometric analysis and comparing them with primary and secondary clinical endpoints.  Possible translational projects for students include collecting manual morphometric data, digital morphometry, and/or multivariate analysis to identify biomarkers associated with AMR and poor outcome.  Students will be mentored in renal pathology and the use of database/statistical software, and will become familiar with renal histology and patterns of renal transplant rejection.

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.

Debbie Gipson, MD, MS, Associate Professor of Pediatric Nephrology, Department of Pediatrics
Kidney disease will affect up to 1 in 9 North Americans during their lifetime. When prevention, early diagnosis and treatments fail, kidney failure may occur which requires life-saving therapies with dialysis or kidney transplantation. Our research team studies one of the leading causes of kidney failure, namely glomerular diseases. Opportunities for summer projects included use of an electronic health record data set to evaluate the prevalence, therapies and health outcomes of children and adults with glomerular disease at UM and participate in the linkage of these data with 2 other large academic health systems in the USA.

Jeff Hodgin, MD, PhD, Assistant Professor, Department of Pathology
Computer-assisted and automated image analysis of the kidney biopsy. The Hodgin lab focuses on the molecular and cellular features of glomerular disease. The glomerulus is a complex, specialized filtration unit made up of three cell types – endothelial cells, mesangial cells, and podocytes. Qualitative and semi-quantitative assessment of injury in kidney biopsies through evaluation of structural and cellular alterations in glomeruli has been a crucial part in the diagnosis and treatment decisions in patients with glomerular disease. Our lab is working to improve this by adding quantitative pathology through the use of image analysis software designed by information technology specialists in the Department of Pathology. For example, podocyte loss has been identified as a driving force in disease progression across nearly all glomerular diseases. In collaboration with the Wiggins lab, we are designing methods to measure podocyte density in kidney biopsies fast enough to be a part of the clinical workflow. We are also analyzing cellular features of glomeruli in a cohort of patients with lupus nephritis to determine clinically useful parameters. A student project would help design and validate cutting-edge software algorithms to quantitate cellular and structural characteristics of diseased glomeruli. In addition, quantitative kidney pathology data will be analyzed in larger patient cohorts with glomerular transcriptomic data to identify key molecular pathways in the progression of glomerular disease.

Ken Inoki, MD, PhD, Associate Professor of Life Sciences Institute, 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 (mechanistic/mammlian target of rapamycin) and AMPK (AMP-activated protein kinase) in the development of kidney diseases such as diabetic nephropathy. Both mTOR and AMPK sense intracellular nutrient levels to control essential anabolic (i.e. protein and lipid biosynthesis) and catabolic (i.e. autophagy) processes. We have recently identified that aberrant activation of mTORC1 in podocytes (glomerular epithelial cells) occurs in both type1 and type2 diabetic kidney in human and animal models. Aberrant activation of mTOR or insufficient activation of AMPK leads to podocyte injury and contributes to the development of diabetic nephropathy. However, the molecular mechanisms by which mTORC1 is up-regulated and mTORC1 activation causes podocyte injury under diabetic conditions remains elusive. Using biochemical and genetic approaches, our research focuses on investigating signal transductions from nutrients (i.e. glucose and amino acids) in cultured podocytes and the roles of these signals in the development of podocyte injury and diabetic nephropathy using mouse models.

Wenjun Ju, PhD, Associate Research Scientist, Nephrology, Department of Internal Medicine, Departiment of Computational Medicine and Bioinformatics (DCMB) and Michigan Diabetes Research and Training Center
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 can predict kidney function and kidney disease progression (for more information: http://stm.sciencemag.org/content/7/316/316ra193). Our current research focuses are: validation of the candidate non-invasive markers in the urine samples of international large cohorts of CKD patients; determination of the pathophysiology role of validated biomarkers in disease initiation and progression; and developing novel therapeutic strategies to prevent CKD progression.

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.

Laura Mariani, MD, Assistant Professor of Nephrology, Department of Internal Medicine
Nephrotic Syndrome is caused by several diseases that result in a similar patient presentation of massive proteinuria, edema, hypoalbuminemia and hyperlipidemia. The complications that patients experience result not only from the disease process (kidney failure, clotting and edema) but also side effects from the immunosuppressive therapies that we give them. Unfortunately, even within a particular pathologic disease, such as focal segmental glomerulosclerosis (FSGS), there is tremendous heterogeneity in patient presentation, response to therapy and prognosis. My research interest is in helping to evaluate whether novel clinical features, biomarkers or gene expression patterns can better help inform patient prognosis and response to therapy by identifying clinically relevant subgroups.

The summer project will leverage the Nephrotic Syndrome Study Network (NEPTUNE), a unique, multi-center, prospective cohort of 500 patients with minimal change disease, membranous nephropathy and focal segmental glomerulosclerosis who are enrolled at the time of diagnostic kidney biopsy. Using a broad dataset which includes clinical information, tissue gene expression, urinary biomarkers and pathology descriptors, we will evaluate potential predictors of disease progression and response to therapy.

Anna Mathew, MD.  Assistant Professor of Nephrology, Department of Internal Medicine.
11% of the adults in United States have kidney disease. Cardiovascular disease is present in 40% of all kidney patients and risk increases 10 to 30 fold in kidney patients compared to the general population. Thus, even though we are able to prolong patient’s life after their kidneys fail with dialysis or kidney transplant, these patients ultimately die of accelerated heart disease. Our work examines the causes and mechanisms behind the disproportional risk of heart disease in kidney patients. Since traditional risk factors like gender, body mass index, smoking history, family history and cholesterol levels are unable to completely explain the aggressiveness of the heart disease in kidney patients, we propose to use a very sensitive and state of the art platform called mass spectrometry to detect these changes in patients with increased heart disease and kidney disease. We are specifically looking at High Density Lipoprotein (HDL) and its modification by the enzyme Myeloperoxidase (MPO) that causes HDL dysfunction and promotes cardiovascular disease.  We will use human samples from kidney patients with and without heart disease. This project will generate a mechanism that explains the high rate of heart disease in kidney patients. Once clearly defined, this pathway will help us identify a prognostic risk factor, develop diagnostic testing and therapeutic strategies to prevent the burden of heart disease in this high risk group of patients. Students will learn separating lipid fractions and basics of mass spectrometer based metabolomics and proteomics. Working knowledge of biochemistry, basic statistics and lab experience will be gained throughout the course of the work under the mentorship of experienced lab personnel. All work performed towards completion of this project will be credited in the form appropriate authorship in the final product. There will be opportunity to expand on this project based on the student’s interest and performance.

Jeffrey L. Platt, MD, Professor of Surgery, and Microbiology and Immunology
Cellular and Molecular Pathogenesis of Accommodation and Renal Cell Carcinoma - For nearly one hundred years, systemic immune and inflammatory reactions have been known to target the kidney, leading to, among other conditions, acute and chronic glomerulonephritis, diabetic nephropathy, transplant rejection and renal cell carcinoma. In the course of research directed at understanding the distinct properties of immune and inflammatory reactions that evoke renal disease, Dr. Platt and members of his laboratory discovered that far from being a passive target, the kidney (and other organs) can acquire resistance to immune and inflammatory reactions, a condition Dr. Platt named accommodation. Today, Dr. Platt and members of his laboratory investigate the cellular and molecular mechanisms engendering accommodation in renal transplants; asking especially whether some diseases of the kidney and kidney transplants might be best understood as loss of accommodation to immune and inflammatory reactions and whether these reactions and/or accommodation explain the genesis of epithelial tumors of the kidney and other organs.

Bruce Robinson, MD, MS, Vice President for Research, Arbor Research, Adjunct Clinical Assistant Professor of Internal Medicine, Division of Nephrology
o Dr Robinson is Principal Investigator of the Dialysis Outcomes and Practice Patterns Study (DOPPS) Program at Arbor Research. Now in 20+ countries, the DOPPS Program includes our longstanding international prospective cohort study of hemodialysis patients (DOPPS, since 1996), and our newer cohort studies in peritoneal dialysis (PDOPPS) and advanced chronic kidney disease (CKDopps). Research focuses on characterizing practice variation and identifying practices associated with the best patient outcomes, with the goal of improving patient longevity, quality of life, and other outcomes. Supervised research activities will focus on data analysis and critical review, and can also include participation in design and implementation of our new international projects.

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. 

Deneen Wellik, Ph.D., Professor of Internal Medicine, Molecular Medicine and Genetics
My laboratory uses mouse genetics to understand the role of Hox genes in many aspects of organogenesis. Using recently generated fluorescent insertion alleles and conditional alleles, we are pursuing questions regarding the function of Hox10 and Hox11 genes in the development and maintenance of the ureteropelvic junction, neprhogenic mesenchyme and cortical stroma. A fellow would learn a great deal about mouse developmental genetics, molecular genetics and kidney development.

Roger C. Wiggins, MB, BChir, Emeritus 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. The general approach has been to use model systems to define the underlying mechanisms and then to translate these insights to human glomerular diseases. The current focus of model systems is now on developing therapeutic strategies to prevent progression to ESKD including dietary and targeted molecular approaches building on recent discoveries. The focus for human studies is in testing quantitative approaches for measuring podocyte number, size and density in glomeruli and the rate of podocyte detachment into the urine to diagnosing and monitoring glomerular diseases. The goal is to provide improved tools to the clinic to facilitate preventing progression and testing new drugs.

Weibin Zhou, PhD, Assistant Professor, Department of Pediatrics
Renal glomeruli are the filtration apparatus in a functional nephron in kidneys across species. Damage or injury of renal podocytes that are essential for the maintenance of glomerular filtration barrier is underlying many glomerular diseases. The highly conserved role of podocytes in zebrafish renders this aquatic animal a useful and relevant model for podocyte disease. Therefore we have exploited this simple yet powerful animal model to study genes involved in normal podocyte function as well as podocyte injury using genome-editing technology and high-throughput chemical compound screening, aiming to generate zebrafish models of human glomerular diseases and to identify small molecule compounds that may modulate podocyte function and its response to induced injury. We have also been working on zebrafish models of diabetes and kidney regeneration. Our ultimate goal is to understand the pathomechanism of kidney disease and discover novel therapies.