Basic research faculty

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Joseph V. Bonventre, MD, PhD, Professor of Medicine, Harvard Medical School; Director, Division of Health Sciences, Harvard Medical School-MIT; and the Director, Renal Division, Brigham and Women's Hospital, Boston, Mass

Research interests: Mechanisms of cell injury and repair, tissue regeneration, signal transduction, biomarkers of renal dysfunction.

Summary: Dr. Bonventre's research focuses primarily on the study of kidney injury and repair and signal transduction, with a special emphasis on the role of inflammation, biomarkers and stem cells. The laboratory has three major areas of study: 1)Pathophysiology of Kidney Tubular Injury and Chronic Fibrosis: 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. 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. We 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. 2) Kidney Stem Cells: The kidney possesses the intrinsic capacity for repair after injury but whether adult kidney stem cells are responsible for epithelial regeneration is unresolved. During nephrogenesis, renal epithelia develop from precursors located in the metanephric mesenchyme that condense to form the nephron. Persistence of such cells in the adult could constitute a stem cell niche available for repair of damaged kidney. The laboratory is focused on the identification of intrarenal stem/precursor cells that may participate in repair. Genetic lineage approaches are in place and have provided a great deal of insight into the source of the cells. 3) Biomarkers: The insensitivity of commonly used biomarkers of renal dysfunction not only prevents timely diagnosis and estimation of injury severity, but also delays administration of putative therapeutic agents. Dr. Bonventre cloned and characterized Kidney Injury Molecule-1 (KIM-1) as a very sensitive and specific biomarker of proximal tubular injury. The laboratory is exploring the role of KIM-1 in the injured kidney using genetic and cell biological approaches and the role of this biomarker in a large number of kidney diseases in rodents and man is being evaluated. The laboratory has established a Biomarker Core facility to evaluate of urinary proteins that have the potential to serve as sensitive and specific biomarkers for kidney injury.

David M. Briscoe, MD, Director, Pediatric Nephrology Training Program, Associate Professor of Pediatrics, Harvard Medical School

Research interests: Vascular Biology, Vascular Immunology, Endothelial cell Biology, Angiogenesis. Cell signaling, mechanisms of allorecognition, chronic allgraft rejection.

Summary: Dr. Briscoe's research focuses on 3 broad areas of leukocyte-endothelial cell biology. These include 1) Immune Mechanisms of Angiogenesis: Lymphocytes and monocytes initiate angiogenesis in the process of their recruitment into allografts. Initial studies identified that cell surface molecule(s) expressed on T cells may stimulate the production of Vascular Endothelial Cell Growth Factor (VEGF, an established potent angiogenesis factor). Dr. Briscoe further identified that cell surface interactions among CD40L (known to be expressed on activated platelets and T cells) and its receptor CD40 (expressed on endothelial cells and monocytes) mediate the transcription of VEGF. A focus of ongoing studies is to determine the signaling pathways in CD40- dependent activation of VEGF. 2) Vascular Endothelial Growth Factor (VEGF) in Allograft Rejection: VEGF, an established angiogenesis factor, is chemoattractant for monocytes via interactions with its receptor Flt-1 (VEGFR1). In addition, VEGF is functional in endothelial cells to promote leukocyte-endothelial cell interactions via its ability to induce endothelial cell adhesion molecule expression as well as the expression of the chemokine MCP-1. These observations imply mechanisms by which VEGF may be involved functionally in delayed type hypersensitivity responses and chronic inflammation. Ongoing studies in the laboratory have determined that VEGF has major proinflammatory properties in the development of chronic rejection and a focus of ongoing studies is to determine if VEGF functions as a proinflammatory cytokine independently of its effect on angiogenesis. 3) Post Transplant Monitoring of Humans Following Transplantation: The laboratory has had a long-standing interest in the evaluation and monitoring of endothelial cell activation responses in allografts post transplantation. Several longitudinal analyses of consecutive allografts identified a pattern to the expression of adhesion and activation molecules in the rejection process. These findings may have clinical implications for 1) the monitoring of patients for early predictors of rejection, 2) assessment of the efficacy of immunosuppression post transplantation; and 3) for the identification of patients at high risk for the development of chronic rejection.

Markus Frank, MD, Assistant Professor of Medicine, Harvard Medical School

Research Interests: stem cell therapeutics, cancer stem cell multidrug resistance, P-glycoprotein family of ATP-binding cassette (ABC) transporters.

Summary: Dr. Frank's laboratory research focuses on the physiological and pathological roles of the human P-glycoprotein family of ATP-binding cassette (ABC) transporters. His laboratory has cloned and characterized a novel human ATP-binding cassette (ABC) transporter, ABCB5, which marks mesenchymal stem cell (MSC) subpopulations in human and murine skin. Dr. Frank's work has demonstrated a unique regulatory role of ABCB5 in the newly recognized phenomenon of stem cell fusion, and in cell fusion-dependent growth and differentiation. Current and future research efforts of Dr. Frank's laboratory are geared towards using adult skin-derived ABCB5+ stem cells as a transplantable cell source for novel therapeutic applications in tissue engineering and regeneration, and for stem cell-based modulation of transplant allograft rejection and autoimmune disorders. Dr. Frank's laboratory has also shown that ABCB5 serves as a multidrug resistance transporter in human malignant melanoma, confering resistance to chemotherapy in vitro. Subsequent work has shown that ABCB5 expression marks melanoma cells of stem cell phenotype and function; and correlates with tumorigenic growth of melanoma cells in vivo (Nature, 2008 Jan 17; 451(7176):345-9). To further establish ABCB5 as an identifier of melanoma stem cells and to characterize the functional roles of ABCB5 in physiological and cancer stem cells, Dr. Frank's laboratory is also exploring the clinical relevance of ABCB5 as a biomarker of melanoma progression, prognosis, and outcome, and he plans to investigate the therapeutic efficacy of ABCB5 targeting in preclinical animal models of human malignant melanoma.

John Iacomini, PhD, Associate Professor of Medicine, Harvard Medical School

Research Interests: Tolerance, transplantation immunology, B cell development, T cell activation, Gene Therapy, Autoimmunity, Type 1 diabetes.

Summary: Dr. Iacomini directs a large immunology research effort in four major areas: alloreactivity; immunological tolerance; development of B cells producing anti-carbohydrate antibodies; and type 1 diabetes. He is well recognized as a mentor/trainer, and he is the Principal Investigator Harvard Longwood Medical Area T32 Training Grant in Transplantation. He directs a course in transplantation immunology at Harvard Medical School, and he is a recipient of an American Society of Transplantation Basic Science Award. Dr. Iacominis research interest relates to the fundamental requirements for alloreactive T cell activation, and his studies are focused on T cell-derived signals that are necessary to drive antigen presenting cells to become fully activated in response to alloantigens, as well as molecular pathways leading to T cell activation. He is also developing approaches to induce immunological tolerance by modifying the recipient's immune system through genetic modification of autologous bone marrow cells using gene therapy. The laboratory is developing methods to improve genetic modification of bone marrow stem cells using viruses as gene delivery tools, developing methods to allow for long-term stable gene expression in genetically modified cells and their progeny, and determining the mechanism by which genetic engineering of bone marrow leads to the induction of T and B cell tolerance. Dr. Iacomini is also actively engaged in analyzing development of B cells producing anti-carbohydrate antibodies because of the importance of such antibodies in host immunity and transplant rejection. Specific studies are focused on determining how the production of anti-carbohydrate antibodies is regulated using a mouse molecular genetics approach. Lastly, he is studying the mechanisms that lead to type 1 diabetes, evaluating the role of MHC class II in type I diabetes, and attempting to develop methods to overcome autoimmunity in diabetics.

Raghu Kalluri, PhD Professor of Medicine, Harvard Medical School

Research Interests: mechanism of chronic renal disease, tumor biology, extra cellular matrix (ECM), basement membranes, epithelial to mesenchymal transition, angiogenesis, stem cells.

Summary: Dr. Kalluri's research interest is the study of cellular microenvironment as determined by extra cellular matrix (ECM) and basement membranes (BM). This fundamental interest in matrix biology has been translated into five major focus areas in the laboratory. 1) Vascular Biology and Angiogenesis: Relative levels of pro- and anti-angiogenic factors likely govern tumor progression: the "angiogenic balance". Conversion of dormant in situ carcinomas into an invasive malignant phenotype is considered to involve a shift in favor of enhanced angiogenesis potential. Genetic control of the physiological levels of endogenous inhibitors of angiogenesis might constitute a critical last line of defense against conversion of neoplastic events into a malignant phenotype of cancer. We are currently testing this hypothesis. This approach in the laboratory has led to the discovery of anti-angiogenic protein fragments which are providing new insights into the progression of cancer. 2) Tumor Microenvironment: Studies are focused on determining the role of fibrobasts, pericytes, immune cells and specific ECM composition in cancer progression and metastasis. 3) Genetic and Acquired Kidney Diseases: Most kidney diseases are associated with proteinuria and thus an alteration within glomerular filtration apparatus. We are employing and genetic, biochemical and cell biological approaches to study the glomerular filtration apparatus in the health and disease. 4) Organ Fibrosis: In many organs, including the kidney and liver, fibrosis (excessive deposition of matrix molecules in association with activated fibroblasts) is the hallmark feature associated with the failure of organ function. Organ fibrosis represents a common final pathway leading to destruction of tissue architecture and function. Our laboratory examines the contribution of epithelial to mesenchymal transition (EMT) involving resident epithelial cells in the accumulation of scar-forming activated fibroblasts during organ fibrosis. 5) Basement Membrane Assembly, Tissue Engineering and Stem Cells: Basement membranes are composed of large glycoproteins such as type IV collagen, laminin, heparin sulfate proteoglycan and nidogen/entactin. In recent years, tissue specific variants/isoforms of type IV collagen and laminin have been identified, leading to the proposal of a new concept that 'not all basement membranes are created equal'. In the laboratory we have isolated several tissue specific basement membranes and performed in vitro self-assembly studies to analyze their effects on the propagation of stem cell cultures. Recent studies in the laboratory suggest that stem-cell therapy can be successfully used to repair matrix defects in the kidney and elsewhere.

Jordan Kreidberg, MD, PhD, Director, Office of Fellowship Training, Boston Children's Hospital, Associate Professor of Pediatrics, Harvard Medical School

Research Interests: inductive mechanisms of early organ development, regulatory interactions for normal glomerular function, stem cells and the developing kidney.

Summary: Dr. Kreidberg's research focuses on how stem cell and progenitor populations in developing organs are regulated by signaling networks. Important areas of study include how integrin cell adhesion receptors and receptor tyrosine kinases integrate signals that control the gene expression of signaling molecules that regulate stem cell populations and that also regulate morphogenetic events during organogenesis. His laboratory is also studying how transcription factors and chromatin modification proteins are involved in organ development. Recently, Dr. Kreidberg's laboratory determined that angioblasts, the precursors of endothelial cells in the vascular system, are involved in the early inductive events of the kidney. They are presently attempting to identify angioblast-derived signals mediating these events, and whether signals derived derived from angioblasts are targeted to stem cell populations. It is also being determined whether stem-cell associated genes, such as Nanog and members of the Polycomb Group, whose expression we have defined in the developing kidney, are targets of the angioblast signals, or other signals known to be important in the induction of the kidney. Another project in the laboratory involves the Wilms' tumor-1 tumor suppressor gene, that encodes a zinc finger transcription factor. Knockout of this gene completely blocks kidney and gonad development. Dr. Kreidberg's laboratory is using approaches that include in vitro and in vivo RNAi, conditional gene knockout, and microarrays to identify Wt1 target genes within the stem cell population of the kidney. The Wilms' Tumor gene is also expressed in podocytes, a key cell type in the kidney, that is damaged in several types of kidney disease including chronic renal failure. The laboratory is attempting to understand how this gene is involved in kidney disease. Finally, Dr. Kreidberg has an interest in Polycystic Kidney Disease (PKD), as a Project Head within a NIH Center of Excellence grant in PKD awarded to the Brigham and Women's Hospital, (Dr. Jing Zhou, Principal Investigator). Dr. Kreidberg's laboratory has demonstrated that coordinate signaling between integrins and receptor tyrosine kinases is disrupted in PKD, and they are presently testing a novel treatment for PKD based on this research in mice.

Dr. Kreidberg has significant experience in mentorship/training. He is Program Director of a Child Health Research Program K12 grant and a Pediatric Scientist Training Program T32 grant from the NIH to the Department of Medicine at Boston Children's Hospital. In addition, he founded and directs the Office of Fellowship Training at Boston Children's Hospital.

David M. Mount, MD, Assistant Professor of Medicine, Harvard Medical School

Research Interests: renal physiology, molecular and cellular physiology of salt and solute transport, molecular physiolology of transporters function, cloning of novel transporters.

Summary: Dr. Mount is the Director of the Laboratory of Molecular Transport Physiology. He has exploited genomic and cDNA databases to identify novel members of four transporter gene families and 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 also characterized five new members of the SLC26 gene family; these include SLC26A6, a multifunctional transporter that is the primary candidate for both the apical chloride-formate/oxalate exchanger in the renal proximal tubule and the CFTR-dependent chloride-bicarbonate exchanger in the pancreas, and SLC26A9, a lung-specific Cl-base exchanger. 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. Other gene families of interest include the sodium-solute (SLC5) and organic anion (SLC22) transporters, particularly novel family members with a potential or proven role in renal urate absorption. Basolateral and apical oxalate exchange in the proximal tubule, mediated by SLC26A1 AND SLC26A6, respectively, may also play a significant role in renal oxalate secretion. The transport function of cloned transporters is primarily studied by isotopic flux measurements, using heterologous expression in Xenopus laevis oocytes. In addition, the electrogenic properties of at least some of the SLC26 exchangers and other transporters leave them amenable to electrophysiological analysis. Isoform-specific functional properties provide a starting point for structure-function analysis, using chimeric and mutant cDNAs. Immunolocalization of transporter transcripts and proteins also provide important information on physiological roles in the kidney and brain, which have guided the laboratory on the physiological characterization of relevant knockout mice. Finally, Dr. Mount has developed collaborative investigations to address the role of multiple human transporters in both monogenic and polygenic renal disease(s). In particular, he is a project leader in an NIDDK program project grant on the pathobiology of nephrolithiasis, assessing the contribution of several solute transporters to the genetics and pathophysiology of kidney stones.

Martin Pollak, MD, Associate Professor of Medicine, Harvard Medical School

Research interests: genetics of FSGS, candidate genes in human kidney disease, mouse models of glomerular disease, cell signaling at the glomerular slit-diaphragm.

Summary: Dr. Pollack's laboratory is working to identify genes involved in the development of focal segmental glomerulosclerosis (FSGS). FSGS is a common form of renal disease, seen both as an isolated entity and as a consequence of HIV infection, diabetes, obesity, and hypertension. Towards this goal, blood for DNA extraction and clinical analyses have been performed on members of approximately 90 families with an inherited form of this condition. The laboratory identified the first FSGS locus on chromosome 19q13. This locus was subsequently refined and demonstrated genetic heterogeneity of FSGS. Using careful analyses of genomic sequence databases, it was possible to identify a number of candidate genes. We identified the first of these genes, FSGS-1, or ACTN4 (alpha-actinin-4), a gene which encodes a protein which seems to be important in the structure in the cytoskeleton of certain kidney cells. When ACTN4 is mutated, it causes an autosomal dominant form of proteinuria, kidney failure, and FSGS. Dr. Pollak's laboratory developed ACTN4 mutant (knockin) and knockout mice to help us understand the underlying disease mechanisms; and ongoing studies are exploring the role of mutations in the alpha-actinin-4 protein in altering the biomechanical properties of the actin cytoskeleton. In addition, the laboratory is studying the human genetics and biology of other inherited forms of FSGS, and is working to identify other FSGS genes. Dr. Pollak has a large collection of human DNA samples from subjects with kidney disease which forms the basis of many of these studies.

Mohamed H. Sayegh, MD, Research Director, Division of Nephrology, Professor of Medicine, Harvard Medical School, Director, Transplantation Research Center, Brigham and Women's Hospital and Boston Children's Hospital, Boston, MA, Associate Chief, Division of Nephrology, Brigham and Women's Hospital and Boston Children's Hospital, Boston, MA

Research Interests: Mechanisms of allograft rejection and tolerance. Mechanisms of autoimmune diabetes and islet allograft destruction.

Summary: Dr. Sayegh's major research interests include the role and mechanisms of allorecognition in rejection and tolerance. Dr. Sayegh has studied the role of effector and regulatory cells activated by the so-called "direct" pathway, where T cells recognize intact allo-MHC molecules on the surface of donor cells. Peptides, derived from endogenous proteins including MHC molecules, bound into the groove of the MHC appear to play an important role in this mode of allorecognition. In the so-called "indirect" pathway T cells recognize processed alloantigen presented as allopeptides by self antigen-presenting cells (APCs). These allopeptides are derived from allo-MHC molecules or from minor histocompatibility or tissue specific antigens. Dr. Sayegh has demonstrated that the indirect pathway occurs during allograft and xenograft rejection and plays an important role in the rejection process, especially in chronic rejection. His laboratory is currently focusing on studying the contribution of indirect allorecognition to the rejection process including establishing a TCR transgenic animal which is specific to class II MHC allopeptides. In addition, human studies in his laboratory are focusing on developing novel assays to predict transplant outcome. Another major interest of Dr. Sayegh's laboratory is investigating the role and mechanisms of T cell costimulation in transplantation and autoimmune diseases. Dr. Sayegh's research studies focus on the role of costimulatory molecules CD28-B7 and ICOS-ICOSL as well as coinhibitory molecules such as PD-1-PDL-1 families of in allograft rejection and autoimmune diseases, including diabetes. In addition, his studies focus on dissecting the mechanisms by which blockade of these pathways may prevent acute rejection and induce long term allograft survival and tolerance, and prevent and/or cure autoimmune diseases. Dr. Sayegh has an outstanding record of mentoring of trainees, several of his trainees have become NIH funded investigators and are leaders in the filed of transplantation immunology. He syupervises many post doctoral trainees within our program. He is the recipient of the 2008 Mentoring Award of the American Society of Transplanation.

Terry B. Strom, MD, Professor of Medicine and Surgery, Harvard Medical School

Research interests: Immunology with an emphasis upon T cell immunobiology and immune tolerance.

Summary: Dr. Strom is the Director of the Transplant Research Center and the Division of Transplant Immunology at the Beth Israel Deaconess Medical Center in Boston, MA. He has a long-standing interest in mechanisms of allograft rejection, the regulation of cytokine gene expression and in tolerance induction. His laboratory has focused efforts on the understanding of the molecular aspects of T cell biology, transplantation rejection and tolerance. The ultimate goal of his research is to use molecular technology to 1) understand the mechanism of graft rejection, and, create tolerance, and 2) to develop new therapeutics and molecular diagnostic techniques to support the goal of creating immune tolerance. Ongoing studies in the laboratory involve an analysis of the fundamental basis of T cell tolerance; and the laboratory is significantly involved in the design of agents and the development of regimens that create T cell tolerance in vivo. In addition, the laboratory uses expression profiling and molecular diagnostic strategies to help achieve tolerance through analysis of the host and the allograft at the time of implantation and serially thereafter. Beginning with basic studies of lymphocyte growth and development, Dr. Strom has identified and characterized several T-cell growth factors involved in T cell activation responses, and he has studied them in vitro and evaluated them in experimental small animal models, in primates, and in clinical trials. Various forms of IL-2, CTLA4, CD2 and IL-15 fusion proteins have been developed in the laboratory for use as specific immunosuppressive agents. His most recent work has focused on the influence of inflammation on the texture of transplant rejection and autoimmunity and on investigation of a family of T-cell proteins known as TIM (T-cell Immunoglobulin Mucin domain), which serve as "checkpoints" for the survival or activation of T-cell subsets. To date, these findings have been published in the journals Nature, Nature Immunology and the Journal of Experimental Medicine. Other work has given insight into the effect of certain therapies on the inhibition or promotion of activation-induced T cell death, an event that is crucial for tolerance induction. Finally, studies have been performed on the basic biology governing the commitment of na?ve or activated to distinctive T cell subset phenotypes, with new insights concerning the commitment to tissue protective Foxp3+ regulatory cells. The Strom laboratory places strong emphasis on the development of innovative biotherapeutics and some recent agents that have been developed and tested within the lab have shown great promise in the murine model of type1 diabetes and mouse and non-human primate models of islet and cardiac transplantation.

Jing Zhou M.D., PhD, Associate Professor of Pediatrics, Harvard Medical School

Research Interests: Genetics of human disease, Polycystic kidney disease, Pathophysiology of polycystins, Glomerular disease, Epithelial cell biology, Cell signaling and organ development.

Summary: Dr. Zhou is the Director of the Harvard Center for Polycystic Kidney Disease Research. Her laboratory has three major areas of study: 1) Molecular mechanisms underlying polycystic kidney disease. Polycystic kidney disease (PKD), characterized by the growth of numerous, large epithelial-lined cysts from kidney tubules, is the most common lethal monogenic disease. Autosomal dominant polycystic kidney disease is the most common form of the disease and is caused by mutations in either of two genes, PKD1 and PKD2. Dr. Zhou's laboratory has created four lines of mouse models for both dominant and recessive forms of PKD by gene targeting of Pkd1. The laboratory has shown that mice homozygous for a Pkd1 mutation develop severe embryonic PKD, cystic pancreas, polyhydramnios, hydrops fetalis, and defective skeletal development. These animals provide an entry point for research into pathways that lead to aberrant epithelial and chondrocyte development. More recently, Dr. Zhou has also demonstrated that full-length polycystin-1 acts as a G-protein coupled receptor and polycystin-2 suppresses its G-protein activation. 2) Molecular physiology and pathophysiology of polycystins. In addition to polycystins-1 and -2, the laboratory has identified four novel members of the polycystin family and have shown that two polycystins, polycystin-2 and -L, are Ca2+-permeable cation channels. Expression patterns of these polycystins indicate that they have a role in heart, brain function and in the male reproductive system. Dr. Zhou has developed polycystin-L and -2L2 knockout mice, and their phenotype is being characterized. 3) Molecular basis of glomerular disease: Dr. Zhou's laboratory also studies Alport syndrome, which is a progressive hereditary nephropathy associated with deafness and ocular abnormalities. Over 90% of Alport syndrome cases are X-linked and affect the COL4A5 gene that encodes the alpha-5 chain of type IV collagen. The laboratory has demonstrated that deletions of the 5' ends of COL4A5 and COL4A6 genes are associated with Alport syndrome. Dr. Zhou is interested in evaluating additional molecular components of the glomerular basement membrane and how they has found that they differ from those of the Bowman's capsule and tubular basement membrane.

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