HARVARD SUMMER RESEARCH PROGRAM IN KIDNEY MEDICINE

HARVARD SUMMER RESEARCH PROGRAM IN KIDNEY MEDICINE

HSKP FRONT PAGE

The Harvard Summer Research Program in Kidney Medicine (HSRPKM) will offer a robust and varied introduction to the world of nephrology for the undergraduate college student who is considering a career in science or medicine. The Program will primarily be a research-based experience but will include a core curriculum that addresses the basic science and clinical fundamentals and challenges in the field. The Program will span the nephrology divisions of four Harvard-affiliated hospitals – Brigham and Women’s Hospital (BWH), Beth Israel Deaconess Medical Center (BIDMC), Boston’s Children’s Hospital (BCH) and Massachusetts General Hospital (MGH).

Students have the opportunity to participate in the following labs offered by hospital affiliation:

Brigham and Women’s Hospital

Reza Abdi, MD (Assistant Professor of Medicine,  BWH Renal Division):  Dr. Abdi has a long-standing interest in autoimmune and alloimmune responses leading to type 1 diabetes and allograft rejection, with a special emphasis on the role of dendritic cells and mesenchymal stem cells. Dr. Abdi has trained many individuals in his laboratory, some of whom have assumed academic positions in science and academic medicine. He has been principal investigator on Juvenile Diabetes Foundation Grants and recently received the American Society of Transplantation Basic Science Award, Assistant Professor level.  He was recently awarded an R01 grant with a 6th percentile score.  Three potential projects for trainees are:  1) identifying the immunomodulatory mechanisms of mesenchymal stem cells (MSC) in regulating T1D and to provide vital preclinical data to guide efforts seeking to translate MSC-based therapies to human T1D; 2) Nanodelivery of medications for cancer and transplantation; and 3) examining the mechanism of rejection of allografts in mice

Joseph Bonventre, MD, Ph.D (Professor of Medicine, Chief of BWH Nephrology Division): A major focus of the laboratory has been the study of the pathophysiology of acute renal failure and processes involved with repair. There are many parallels between repair and the normal development of the kidney. While repair is generally considered to be adaptive it can be maladaptive, especially when the acute injury is superimposed on chronic kidney disease. Hence the large effort that has gone into understanding developmental systems will potentially translate into therapeutic approaches to treatment of adult as well as pediatric renal diseases. As a result of our experiments we have placed inflammation at the core of the pathophysiology and are continuing to explore the role of inflammation in the pathophysiology of acute renal injury and ways in which we can interrupt this response and reduce injury. We have found two proteins, KIM-1, an epithelial protein and nmb, a macrophage protein, which we believe play critical roles in the response of the kidney and have created a Kim-1 knockout/Gal4 knockin animal which will potentially allow us to use the characteristics of the promoter region of Kim-1 to express proteins specifically in the S3 segment of the proximal tubule, where most of the injury occurs. In addition we want to understand the factors determining the recovery of the kidney in order to design strategies to enhance and hasten the processes necessary for recovery. These latter goals necessitate multiple experimental approaches. My laboratory carries out whole animal experiments on normal or knockout animals in order to test potential pharmacologic treatments or to test the hypothesis that a particular protein is important to the injury or repair process. More recently we have established models of preconditioning in the mouse in which we have uncoupled exposure to ischemia from the normal functional consequences of ischemia. We are employing genomic approaches to identify genes whose expression patterns might explain the profound protection we can induce in these models. We are using blood and urine proteomic approaches to identify new biomarkers and targets for therapy. Current studies have focused on genetic mouse models and zebrafish and include the role of stem cells in the repair process of the kidney post-ischemia.

 Anil Chandraker, MB, ChB (Associate Professor of Medicine, Medical Director of Kidney Transplantation, BWH Renal Division):  The major focus of the research in Dr. Chandraker’s laboratory the role of T cell co-stimulatory pathways in chronic allograft rejection and transplant tolerance. Dr Chandraker is an active clinical/translational researcher. He has studied the prevalence and the associated causes of anemia in renal transplant patients. He has worked on the problem of polyoma infection in renal transplant patients. BK nephropathy is a relatively common cause of kidney transplant dysfunction in renal transplant recipients. Dr Chandraker initiated collaborations with basic and clinical researchers to show that quinolone antibiotics are effective in vitro and in vivo against this virus through targeting polyoma helicase activity and is currently conducting a placebo controlled randomized clinical study to prospectively confirm the effectiveness of quinolones in kidney transplant recipients.  Potential projects for students working in Dr. Chandraker’s laboratory include 1) analyzing cardiac risk factors in end stage renal disease patients prior to kidney transplantation and 2) characterization of T cells lines from kidney transplant patients with stable and unstable kidney function.

David Charytan, MD, MSc (Assistant Professor of Medicine, BWH Renal Division):  Dr. Charytan studies factors that may account for the high risk of cardiovascular disease and death in patients with renal disease.  He studies outcomes of standard and novel therapies in patients with chronic kidney disease (CKD), underutilization of standard therapies in individuals with chronic kidney disease, and the role of micro-vascular disease in the association of CKD and cardiovascular disease.  Dr. Charytan has a broad background in epidemiology and wet-lab based techniques, which he calls upon in support of this research.  As PI on several foundation and NIH-funded grants, Dr. Charytan has laid the foundation for deeper exploration of these issues, and has excellent resources to support the career development of fellows/trainees.  Dr. Charytan has several projects that would be well-suited for a summer student: 1) association of micro-infarction and CKD using archived left-ventricular specimens of subjects with normal and reduced renal function, and 2) characteristics and predictors of sudden death in diabetic nephropathy using data from the TREAT study.

John Forman, MD, MSc (Assistant Professor of Medicine, BWH Renal Division):  Dr. Forman’s research focuses on the analysis of novel and remediable risk factors for the development of hypertension, diabetes, and cardiovascular disease through epidemiologic research and clinical trials.  Dr. Forman has published multiple prospective reports of risk factors for hypertension and diabetes in large cohorts.  He is currently the PI or Co-PI on three R01 awards, two of which fund randomized trials.  Dr. Forman has a strong commitment to mentoring and is currently mentoring two junior research fellows.  Potential research projects available to an undergraduate student include:  1) examination of the effect of allopurinol on 24-hour urinary calcium and citrate excretion and 2) using data from the Nurses’ Health Study (NHS) cohort, examine whether common genetic variants in circadian control genes are associated with an increase of cardiovascular disease and/or type 2 diabetes.

Anna Greka, MD, PhD (Assistant Professor of Medicine, MGH Nephrology):  Dr. Greka’s laboratory is broadly interested in the biology of calcium signaling.  Calcium has long been recognized as a key regulator of vital cell processes including cytoskeletal remodeling.  Aberrant calcium signaling leading to a disrupted cytoskeleton has been linked to neurologic disorders, heart disease, cancer, and more recently, kidney disease. Dr. Greka has made important observations on TRPC-mediated regulation of the RhoGTPases and the implications of this pathway for kidney disease. Her laboratory uses an interdisciplinary approach, incorporating the tools of molecular biology, cell biology, biological chemistry, advanced imaging techniques, patch clamp electrophysiology and animal models to study the role of TRPC channels in health and disease.  A potential student project in Dr. Greka’s laboratory is performing real time imaging of the dynamic changes of the podocyte actin cytoskeleton in response to upstream signals from various receptor-operated ion channel calcium influx pathways, and how these can be modulated under disease conditions.

Andreas Herrlich, MD, PhD (Assistant Professor, BWH Renal Division):  Using large-scale gene knockdown technology, the Herrlich lab has identified novel genes that selectively regulate ectodomain cleavage of epidermal growth factor (EGF) ligands by acting on the cleaved ligand itself without affecting the metalloprotease. Metalloprotease cleavage of the extracellular domain (ECD) of many transmembrane proteins (“ectodomain cleavage”) such as EGF receptor ligands is life-essential and generates many bioactive molecules from cell-surface precursors. It has been linked to the regulation of many cellular signaling pathways and when dysregulated can cause a number of different diseases, depending on the cleaved substrate involved. Current studies in the lab focus on the study of these genes in tissue culture and mouse disease models and aim at the development of new approaches for substrate-specific inhibition of ectodomain cleavage of EGF ligands that would circumvent current problems with metalloprotease inhibitors. One potential student project would be studying the role of ectodomain cleavage regulators in migration, invasion, and growth factor release of breast cancer and kidney epithelial cells.

Albert Q. Lam M.D. (Instructor, BWH Renal Division): Dr. Lam is an Affiliated Faculty Member of the Harvard Stem Cell Institute.  The focus of his lab is to apply human pluripotent stem cell technologies to the study of kidney regeneration and disease.  Dr. Lam developed strategies to direct the differentiation of human embryonic stem cells and induced pluripotent stem (iPS) cells into populations of kidney progenitor cells.  In addition, he has been using human iPS cells to develop models of hereditary kidney disease.  His current research is aimed at characterizing the nephron progenitor population derived from human pluripotent stem cells and using 3D environments to promote the differentiation of these cells into 3D kidney structures.  Potential projects for students in Dr. lam’s laboratory include: 1) screening factors to optimize the differentiation of nephron progenitor cells and 2) gene expression profiling of nephron progenitor cells.

David Mount, MD (Assistant Professor of Medicine, BWH Renal Division):  Dr. Mount’s research is focused on the molecular physiology of ion and solute transport, and has identified novel members of four transporter gene families.  His laboratory has cloned several new members of the cation-chloride cotransporter gene family, most notably the K-Cl cotransporters KCC3 and KCC4.   Dr. Mount characterized five new members of the SLC26 gene family, including SLC26A6, a multifunctional transporter that is the dominant apical chloride-oxalate exchanger and chloride-base exchanger in the renal proximal tubule.  Apical chloride-formate/base/oxalate exchange mediated by SLC26A6 and basolateral K-Cl cotransport mediated by KCC3 and KCC4 play crucial roles in trans-epithelial salt transport by the renal proximal tubule, with implications for both essential hypertension and edema syndromes.  The Mount lab has also identified the renal sodium-lactate/nicotinate co-transporters that works with SLC22A12 (URAT1) in renal urate absorption; these and other renal absorptive urate transporters are the dominant focus of his current research effort. Potential projects for students in Dr. Mount’s laboratory include:  1) urate transport experiments in Xenopus oocytes, focused on the genetic role of coding polymorphism in SLC2A9 and the effect of GLUT9-interacting proteins on GLUT9-mediated urate transport and 2) using a panel of human kidney (HPCT-05-wt proximal tubular cells), intestine (Caco-2), and other cell lines expressing endogenous SLC2A9, this project will assess for promoter activity of two confirmed promoters, plus and minus co-transfection with downstream enhancer elements identified from ENCODE data transcriptional regulation of SLC2A9.

Vishal Vaidya, PhD (Assistant Professor of Medicine, BWH Renal Division):  Dr. Vaidya directs the laboratory of kidney toxicology and regeneration in the BWH Renal Division.  He has published extensively on the role of biomarkers in assessing kidney injury in animals and humans.  Dr. Vaidya has performed miRNA and mRNA expression analyses in rodent kidneys after injury and have identified candidate genes (fibrinogen) and candidate small RNAs that potentially regulate renal dedifferentiation and repair in animal and humans.  His lab is investigating the critical role of fibrinogen (Aa, Bb and g) in epithelial and endothelial repair using pharmacological inhibitors and genetic manipulation strategies in vitro and in vivo.

Sushrut Waikar, MD, MPH (Assistant Professor of Medicine, BWH Renal Division):  Dr. Waikar is involved in patient-oriented research in acute kidney injury, chronic kidney disease, and hyopnatremia. Active research projects include novel biomarkers of AKI following major vascular and cardiac surgery, critical illness, and nephrotoxin administration; novel biomarkers of chronic kidney disease; the epidemiology of hyponatremia in hemodialysis patients; small solute clearance during continuous renal replacement therapy; two double-blind, placebo controlled randomized trials in patients with or at risk of kidney disease; and mathematical modeling of creatinine kinetics in acute kidney injury. He is a Principal Investigator of the Chronic Kidney Disease Biomarkers Consortium, a NIH-sponsored U01 multicenter study examining biomarkers in cohorts including MDRD, AASK, CRIC, ARIC. He is also the Principal Investigator of Biomarkers of Kidney Pathology, an R01 grant examining biomarkers in patients undergoing kidney biopsy. An example of a project for a student in Dr. Waikar’s laboratory is novel biomarkers of kidney disease in patients undergoing kidney biopsy.

Jing Zhou, MD, PhD (Associate Professor of Medicine; Director, Harvard Center for PKD Research, BWH Renal Division):  Dr. Zhou uses multidisciplinary approaches ranging from human molecular genetics, molecular and cellular biology and biochemistry to developmental biology and mouse genetics to understand the physiology and pathophysiology of polycystins and polycystic kidney disease (PKD).  Her current focus is to understand the downstream signaling events of the two ADPKD proteins.  She is also studying the genetic modifiers that modulate disease severity.  Polycystins are an expanding family with diverse functions in multiple tissues.  Polycystin-2 has recently shown to control the determination of left-right body axis and fertility.  Dr. Zhou also uses multidisciplinary approaches to identify the functions of four new polycystins recently identified in her lab, and the function of autosomal recessive polycystic kidney disease (ARPKD) proteins.  Projects for students working in Dr. Zhou’s laboratory include 1)  studying the role of Pacsin 2 in kidney injury and repair and 2) investigating the role of fibrocystin/polyductin (FPC) in the regulation of the mTOR signaling pathway.

Massachusetts General Hospital

Jodie Babitt, MD (Assistant Professor of Medicine, MGH Nephrology):  Dr. Babitt’s laboratory is focused on elucidating the molecular and cellular mechanisms involved in iron homeostasis. The goal is to identify new treatment strategies for disorders of iron homeostasis including the anemia of CKD and the iron overload disorder hemochromatosis. Dr. Babitt identified that hemojuvelin (HJV)-mediated BMP6 signaling positively regulates hepcidin expression and modulates systemic iron homeostasis in vivo. A biologic agent developed based on this work has now entered phase II clinical trials as a treatment for anemia of kidney disease in human patients, illustrating the translational nature of her work. Dr. Babitt’s laboratory is currently conducting various screening approaches to identify novel modulators of iron balance. One potential project for a student in her laboratory would be to help validate one or more of these candidate modulators using both in vitro approaches and animal models.

Sylvie Breton, Ph.D. (Professor of Medicine, MGH Nephrology):   Dr Breton studies the regulation of transepithelial transport in the kidney and male reproductive tract. Her laboratory uses a multidisciplinary approach combining the utilization of organs in vivo, isolated tissues and cell cultures with three-dimensional imaging by laser scanning and spinning disk confocal microscopy, multi-photon intravital imaging, functional analysis using selective microelectrodes to measure ion fluxes in real time, and a complementary array of other cell molecular and biochemical approaches. These studies aim to better understand the mechanisms underlying transepithelial transport of protons, solutes and water in male reproductive and renal physiology. In the kidney, acid/base transport is central to the maintenance and regulation of blood pH within a very narrow viable range, but the mechanisms by which renal cells, including type A intercalated cells (A-IC), detect and respond to systemic pH deviations remain obscure.  One potential project for a student working in Dr. Breton’s laboratory would be to explore how A-ICs sense and respond to local urinary pH variations by isolating A-ICs from our B1-EGFP transgenic mice to explore purinergic modulation of A-ICs

Dennis Brown, Ph.D. (Professor of Medicine, MGH Nephrology):Dr. Brown’s laboratory combines the use of state-of-the-art imaging techniques with biochemistry and molecular approaches to follow and dissect physiologically-relevant membrane protein trafficking events in epithelial cells. He focuses on water channels (aquaporins – AQP) and proton pumping ATPase function in the kidney. These proteins are central to regulating body fluid homeostasis and systemic acid/base balance, respectively.  Dr. Brown’s work extends from the dissection of critical protein protein interactions at the molecular level, to understanding organ physiology in the whole animal. Using information from his studies, he aims to to develop novel therapeutic strategies that would restore normal function of these proteins in several kidney diseases. His work on the water channel AQP2 has already led to novel strategies to bypass defective vasopressin receptor signaling in diabetes insipidus, and chemical screening is being used to uncover more new drugs for this disease. His other focus is on the proton pumping H+ATPase, an enzyme that acidifies extracellular fluids and intracellular organelles such as endosomes, lysosomes and the Golgi.  It plays a key role in regulating extracellular pH in several organs, including the kidney, where it helps the body secrete acid loads. Acquired or inherited loss or dysfunction of the H+ATPase in humans and animal models causes diseases in many organ systems. Students working in Dr. Brown’s laboratory will work on novel projects aimed at understanding the regulation of renal water or acid/base balance at the protein, cellular and organism level.

Iain Drummond, PhD (Associate Professor of Medicine, MGH Nephrology):  Dr. Drummond’s laboratory established the zebrafish as a relevant model for kidney development and disease.  The current research focus is to identify kidney progenitor cells in zebrafish and jpositional cloning of genes which cause pronephric cysts.  Techniques used include in addition all forms of phenotype analysis such as live imaging in whole living embryos, in situ hybridization, generation of transgenics, histology, in vivo functional assays, and electron microscopy. Expertise also extends to the mouse model including phenotyping, in vivo functional assays, histology, and electron microscopy.  A potential project for a student in Dr. Drummond’s laboratory would be to investigate in vivo calcium signaling in kidney cell development and disease.

Herbert Lin, MD, PhD  (Associate Professor of Medicine, MGH Nephrology):  Dr. Lin’s laboratory studies the role of TGF-b/BMP of signaling pathways in health and disease and how TGF-b/BMP ligands interact with receptors, and role of the RGM/DRAGON family of novel BMP co-receptors in regulation of iron metabolism are areas of active research. Ultimately, by studying this complex but important signaling system, Dr. Lin hopes to shed light on diseases such as ischemic kidney disease, adult polycystic kidney disease, glomeruloscerosis, diabetic neuropathy, inflammatory bowel disease, hemochromatosis and anemia of chronic disease.  Potential projects for students include 1) the role of BMP co-receptors in kidney epithelial cells and 2) soluble hemojuvelin as a biomarker for anemia of chronic disease.

Jenny (Hua) Lu, MD, PhD (Assistant Professor of Medicine, MGH Nephrology):  Dr. Lu’s laboratory is studying the mechanisms of protein and vesicular trafficking using the water channel protein AQP2 as a model. She has discovered a novel role of AQP2 in renal cell migration and tubule formation by modulating the trafficking of integrin inside the cells. She recently established a podocytes specific ablation zebrafish model to examine cellular and molecular mechanism(s) that contribute to podocytes injury and regeneration. Dr. Lu is using a variety of advanced real-time imaging technologies including spinning disk confocal microcopy, FRET and TIRF imaging, and electron microscopy in combination with complex biochemical and molecular biological methods to interrogate cell function, especially during the process of renal tubular injury and repair. Potential projects for students in Dr. Lu’s laboratory include:  1) real time imaging study of polarized trafficking of AQP2 in response to hormonal peptides using 3D culture; 2) Investigate the role of integrin-extracellular matrix signaling on the polarization of AQP2 in epithelial cells; 3) real time imaging study of kidney development and its response to injury in zebrafish; 4) study the mechanism that AQP2 modulates integrin trafficking in cells and 5) study the role of small molecules in regulating AQP2 trafficking, therefore water handling in animals.

Sanja Sever, PhD  (Assistant Professor of Medicine, MGH Nephrology):  Dr. Sever’s laboratory studies the role of the large regulatory GTPase dynamin in podocyte structure and function.  In normal podocytes, dynamin influences actin organization in a GTP-dependent manner.  Induction of a cytoplasmic form of the protease cathepsin L leads to cleavage of dynamin at a conserved site, resulting in reorganization of the podocyte actin cytoskeleton and proteinuria.  Strikingly, proteinuria is avoided in cathepsin L null mice.  The mechanisms that lead to the presence of the cathepsin L in the cytoplasm, as well as the mechanisms by which dynamin regulates structure and function of healthy and diseased podocytes, are currently being investigated.  A second line of investigation explores the role of dynamin in clathrin-mediated endocytosis by testing the hypothesis that dynamin instructs the chaperone machinery to induce conformational changes within the clathrin coat that drive vesicle constriction and fission.  Recently, Dr. Sever’s laboratory has identified direct interactions between dynamin and the actin cytoskeleton.  Research in the laboratory is also focused on the role that dynamin-actin interactions play in the global organization of the actin cytoskeleton in podocytes.  A summer student working in Dr. Sever’s laboratory would join their ongoing study of the role of dynamin oligomerization in the regulation of actin cytoskeleton in podocytes.

Roy Soberman, MD (Associate Professor of Medicine, MGH Nephrology):  Dr. Soberman’s laboratory is focused on understanding signal integration and macromolecular organization in cells of the immune system, and how these processes are linked to control the amplification of the immune response. In inflammatory diseases of the kidney myeloid cells and lymphocytes are exposed to a large number of “kinase-based” signals from cytokines, interleukins, and growth factors.  They are also exposed to signals from G-protein coupled receptors, such as those for leukotrienes and chemokines.  In addition, inhibitory receptors such as CD200R1 on myeloid cells can shift their function by changing their protein associations. Each of these receptors engages a variety of intracellular pathways to allow cells to perform the appropriate function in tissue environments.  A student based in Dr. Soberman’s lab may work on a project focused on how cells integrate signaling responses between these different pathways, with the goal of identifying how cellular organization translates into defined biological phenotypes in health and disease.

Ravi Thadhani, MD (Professor of Medicine, Chief of MGH Nephrology Division):  Dr. Thadhani’s research is focused on two major areas of interest: medical complications of pregnancy, most specifically preeclampsia, and dialysis mortality.  His laboratory has performed several hypothesis-generating observational studies suggesting that therapy with activated vitamin D sterols is associated with improved survival among patients with renal failure.  A possible student project in Dr. Thadhani’s laboratory would be using a prospective study cohort of 10,000 incident hemodialysis patients to examine the relationship between SF36 physical and mental component scores and 1-year outcomes.

Beth Israel Deaconess Medical Center

Seth Alper, MD, PhD (Professor of Medicine, BIDMC Nephrology):  The Alper lab studies ion transport across cell membranes, with a focus on how genetic and acquired dysfunctions of ion transport cause or modify the course of disease.  The Alper lab co-discovered AE1 mutations as a cause of hereditary distal renal tubule acidosis and has made seminal contributions to the understanding of the regulation of the SLC4/AE anion exchange gene family, including identification of a novel regulatory mechanism mediated by ammonium.  Potential projects for students include: 1) genetic modifiers that may predispose patients to nephrolithiasis, 2) cell physiological pathogenesis of autosomal dominant Medullary Cystic Kidney Disease Type 1 secondary to MUC1 mutations and 3) oxalate transporters as risk modifiers of kidney stone disease.

David Friedman, MD (Assistant Professor of Medicine, BIDMC Nephrology):  Dr. Friedman studies several aspects of vascular biology related to kidney disease as well as the genetic basis of CKD.  One area of interest is receptors and enzymes that constitute the purinergic signaling system (P2 receptors, adenosine receptors, and ectonucleotidases) and its role in diabetic nephropathy and in kidney aging.  A second area of interest is the role of APOL1 in chronic kidney disease in African Americans.  Potential research projects for a student in Dr. Friedman’s laboratory include: 1) defining the normal role of the APOL1 protein in the kidney, 2) how the behavior of the risk alleles differs from the wild-type allele, and 3) why some individuals with the high-risk genotype develop kidney disease whereas others do not.  Each of these three questions would translate well into a student project.

S. Ananth Karumanchi, MD  (Associate Professor of Medicine, BIDMC Nephrology):  Dr. Karumanchi is known for his discovery of the cause of pre-eclampsia, and has a major interest in the role of angiogenic factors in the pathogenesis of proteinuric diseases. In addition to his position at BIDMC, Dr. Karumanchi is a clinical investigator at Howard Hughes Medical Institute.  Dr. Karumanchi’s laboratory is evaluating mechanism(s) underlying proteinuria associated with diabetes. Preliminary microarray data generated from podocytes grown in high and normal glucose have revealed several novel targets and pathways. Dr. Karumanchi’s laboratory is also elucidating the molecular mechanisms of uremia related endothelial dysfunction, accelerated atherosclerosis, and cardiovascular deaths in the end-stage renal disease population.  Potential projects for students in Dr. Karumanchi’s laboratory include:  1) analyzing urine proteomics data from diabetic patients with and without nephropathy to identify novel urine markers that predict outcome and 2) characterize the soluble epo receptor and is role in mediating erythropoietin resistance.

Samir Parikh, MD (Assistant Professor of Medicine, BIDMC Nephrology):  Dr. Parikh’s laboratory investigates the role of the Angiopoietin-Tie2 axis in the regulation of endothelial homeostasis and how disruption of tonic signaling through this pathway results in maladaptive molecular, morphologic, and physiologic changes.  Dr. Parikh authored the first paper to suggest a contributory role for Tie2 inhibition in the vascular leakage and inflammation that develops in sepsis.   The laboratory is aggressively investigating the role of the signaling axis as it relates to the pathogenesis of acute kidney injury and diabetic nephropathy.  Dr. Parikh recently reported an in vivo function of PGC-1alpha in the kidney that may lead to new areas for the mechanistic and therapeutic investigation of AKI.  Projects for students in Dr. Parikh’s laboratory include:  1) microvascular inflammation in the ICU: developing new tools to diagnose and treat sepsis, and 2) metabolism in the kidney: how mitochondria impact renal health and disease.

Martin Pollak, MD (Professor of Medicine, Chief, BIDMC Nephrology):  Dr. Pollak’s laboratory studies the genetic and molecular basis of kidney disease in humans using modern genetic tools to identify genes and genetic variation.  His laboratory identified ACTN4, INF2, and APOL1 as human kidney disease genes.  To understand the mechanisms by which specific genetic variation leads to human disease, Dr. Pollak’s laboratory uses a variety of methods – mouse models, cell biology, and biochemistry.  While the major focus of the lab has been the genetic basis of FSGS, he is also collaborating on efforts to study the genetic basis of kidney malformations and on work to understand the function of the calcium-sensing receptor in the kidney.  Potential projects for students working in Dr. Pollak’s laboratory include 1) clinical manifestations of APOL1-associated kidney disease and 2) genetics of urogenital developmental.

Mark Zeidel, MD (Herrman Ludwig Blumgart Professor Medicine, Chief, BIDMC Dept of Medicine):    Dr. Zeidel’s research interests include mechanisms of water and small molecule flux across biological membranes, the cell biology of mammalian bladder epithelium, and the improvement of quality of care in both the inpatient and outpatient settings.  Dr. Zeidel’s laboratory is focused on understanding the structure of membranes as it relates to the ability to block water.  The laboratory’s work on the mammalian bladder epithelium centers around how barrier properties of the bladder are maintained during times of mechanical stress.  As both Chair of the Department of Medicine and a member of the Division of Nephrology at BIDMC, Dr. Zeidel has a strong interest in the research training of physician-scientists, as also demonstrated by the Origins of Renal Physiology course he created and directs yearly at the Mount Desert Island Biological Laboratory in Bar Harbor, Maine.

Boston Children’s Hospital

Friedhelm Hildebrandt, MD (Warren E. Grupe Professor of Pediatrics, Chief, BCH Nephrology):  Dr. Hildebrandt’s laboratory has identified a new class of human renal diseases called ‘ciliopathies’. The laboratory has also identified over 20 novel kidney disease genes as well as genes that are associated with the nephrotic syndrome and congenital malformations of the kidney and urinary tract. Dr. Hildebrandt is internationally renowned for innovation and for his work to identify the genetic basis for disease entities through the ability to efficiently use total human exome capture and parallel sequencing. Dr. Hildebrandt’s laboratory offers experimental mutation analysis for pediatric renal diseases for families worldwide. The laboratory also studies the function of disease-associated genes in disease models leading to the development of in vitro models, in vivo models and extensive studies using mice and zebrafish which allows for the entire realm of exploration. Dr. Hildebrandt is committed to training the next generation of scientists and ensures that trainees in his laboratory are exposed to the spectrum of clinical science research, including contact with patients, genetic phenotyping, cell-based functional studies and in vivo models.  Potential projects for students in Dr. Hildebrandt’s laboratory include 1)  well-defined studies regarding genetic causes of kidney disease and 2) specific aspects of the related disease mechanisms studied in cell-based or animal systems.

 

Jordan Kreidberg, MD, PhD (Associate Professor of Pediatrics, BCH Nephrology):  Dr. Kreidberg is interested in stem cell and progenitor populations in the developing organ and how stem cell biology is regulated by signaling networks.  Specifically, his laboratory is studying integrin cell adhesion receptors and receptor tyrosine kinases to learn how they integrate signals that control gene expression and morphogenetic events during organogenesis.  Dr. Kreidberg has identified Wilms’ tumor-1 target genes of the kidney and is now working to understand how this gene is involved in podocyte-dependent kidney diseases.  Dr. Kreidberg is also interested in PKD and has identified that receptor tyrosine kinases signaling is over active in patients with PKD.  Potential projects for students working in Dr. Kreidberg’s laboratory include: 1) studies on signal transduction in PKD and 2) looking at the mechanisms of transcriptional regulation by the WT1 transcription factor.

Soumitro Pal, PhD (Assistant Professor of Pediatrics, BCH Nephrology):  Dr. Pal’s laboratory is focused on understanding 1) intracellular signals in vascular endothelial cells (EC) and cancer cells that mediate the induced expression of VEGF, 2), the roles of chemokines, chemokine receptors and angiogenesis factors in the development of post-transplantation cancer, and 3), the role of cytoprotective hemeoxygenase-1 (HO-1) in tubular injury during renal inflammation. It is well known that angiogenesis factors are associated with tumor growth, and Dr. Pal’s research has observed that these same factors are increased in expression following transplantation. In addition, Dr. Pal has observed differences in signaling pathways elicited by the two spliced forms of the CXCR3 receptor (called CXCR3A and CXCR3B) and has reported that calcineurin inhibitor immunosuppressive medications increase the relative expression of the pro-proliferative CXCR3A vs. the anti-proliferative CXCR3B isoform on cancer cells.  A potential project for students in Dr. Pal’s laboratory include investigation of expression changes in receptors that result in pro-tumorigenic events including tumor development and growth

Valerie Schumacher, PhD (Assistant Professor of Pediatrics, BCH Nephrology): Dr. Schumacher’s laboratory is studies the localization of cytoplasmic ribonucleoprotein particles (RNPs), RNA granules that store translationally silent mRNAs, within the foot processes of podocytes. mRNAs encoding cytoskeletal proteins can be released from these RNA granules and have been found to function to locally produce nascent cytoskeletal proteins. Damage to the complex podocyte cytoarchitecture is the final common event in many forms of chronic kidney disease. The current treatments for individuals with chronic kidney disease are often not based on an understanding of the molecular basis of the disease, and in many instances these treatments fail to prevent the onset of end stage renal disease and the requirement for dialysis or kidney transplant. One of the key regulators in this process is the RNA binding protein Staufen 2. Dr. Schumacher’s laboratory is currently investigating how RNA granules serve in adaptive repair mechanisms and in the maintenance of the foot process cytoarchitecture. This novel and unique approach to understand podocyte biology may result in evidence-based therapies to prevent or repair foot process architecture and treat glomerular disease.  One potential project for a student working in Dr. Schumacher’s laboratory would be the role of Staufen 2 in regulating podocyte function.