This is a summary list of all laboratories at Harvard University . The list includes links to more detailed information, which may also be found using the eagle-i search app.
In the first few years of life, humans tremendously expand their behavioral repertoire and gain the ability to engage in complex, learned, and reward-driven actions. Similarly, within a few weeks after birth mice can perform sophisticated spatial navigation, forage independently for food, and engage in reward reinforcement learning. Our laboratory seeks to uncover the mechanisms of synapse and circuit plasticity that permit new behaviors to be learned and refined. We are interested in the developmental changes that occur after birth that make learning possible as well as in the circuit changes that are triggered by the process of learning. Lastly, we examine how perturbations of these processes contribute to human neuropsychiatric disorders such as Tuberous Sclerosis Complex and Parkinson’s Disease. Take a video tour of the lab and building (actually a music video produced for Chairlift filmed, in part, in our lab)
Dr. David Breault's research has exploited the fact the mouse telomerase (mTert) is a biomarker for embryonic and tissue stem cells. He has developed a streamlined technique for isolating and characterizing adult stem cells from a variety of tissues using genetically engineered reporter mice.
The Bulyk Lab investigates transcriptional regulation. We are particularly interested in transcriptional enhancers and the interactions between sequence-specific transcription factors and their DNA binding sites. For these studies, we develop genomic, proteomic, and computational technologies and approaches and apply them to a wide variety of biological organisms including the yeast S. cerevisiae, the fruit fly D. melanogaster, mouse and human.
The Carpenter Lab is based at the Broad Institute of MIT and Harvard in Cambridge, Massachusetts, USA. Our research group develops advanced methods and software tools to quantify and mine the rich information present in cellular images to yield biological discoveries. Our laboratory is best known for our open source software packages CellProfiler and CellProfiler Analyst.
We study the molecular biology and genetics of circadian clocks, endogenous oscillators that drive daily rhythms in behavior and physiology. Under natural conditions, circadian clocks become precisely synchronized, or entrained, to the 24-hour light-dark cycle by the action of light on circadian photoreceptors. Together the intrinsic rhythms of the circadian clock and its entrainment to light-dark cycles control the temporal organization of complex behavioral and metabolic programs. In flies and mammals, the master circadian clock regulating behavioral activity is located within specific clock cells in the brain. Of late it has become clear that multiple peripheral tissues in mammals contain circadian clocks, but the roles of peripheral clocks and their relationship to the central clock are not yet understood.
Neurotransmitters, hormones, and pharmacologic agents act by binding specific receptors or ion channels on the cell surface. We are interested in the structure and function of ion channels, their physiological function, and the signal transduction pathways with which they interact.
Our laboratory takes molecular approaches to gene regulation and protein function during herpesvirus replication and latency. We conduct these studies to provide excellent models for biological processes in eukaryotic cells and, because herpesviruses are important pathogens, to exploit differences between herpesvirus and cellular processes for safe and effective antiviral therapy.
Areas of research include:
Novel post-transcriptional regulatory mechanisms. Projects include exploring microRNAs, regulated polyadenylation, ribosomal frameshifting, internal ribosome entry sites (IRES's), and translational regulation during herpes simplex virus (HSV) infection.
Herpesvirus DNA replication proteins. antiviral drug targets and prototypes for human replication proteins. Projects include determining the 3-D structures of these proteins (with the Hogle lab) and exploring their interactions with each other and nucleic acids via biochemical, mutational, and biophysical approaches, including (with the Golan and van Oijen labs) single molecule methods. These studies should permit detailed understanding of these complicated proteins and rational drug design.
Drug targets and development of new therapies. Aside from studies of herpesvirus DNA replication proteins, projects include exploiting for drug discovery the human cytomegalovirus protein kinase that phosphorylates the nucleoside analog ganciclovir and the important cellular proteins Rb and lamin A/C investigating how it promotes replication of the virus, and finding new drug targets by a combination of "chemical genetic" and molecular genetic approaches.
HSV latency/pathogenesis. HSV forms latent infections that persist for the life of the host. How this occurs is biologically fascinating and clinically important. Projects entail mutant construction, and PCR-based and microarray methods to explore viral gene regulation (e.g. how microRNAs repress viral gene expression, thereby maintaining latency), and neuronal genes whose expression is altered during viral latency.
Current translational research projects in the lab focus on brown and white adipose tissue function, energy balance, clinical physiology, and imaging in collaboration with teams from Beth Israel Deaconess Medical Center, Massachusetts General Hospital, Boston Children’s Hospital, and the Harvard School of Public Health.
1. Integrative physiology: we are conducting studies in both rodents and humans to understand BAT and WAT function and teleology from the molecular and cellular through the epidemiological levels.
2. Noninvasive imaging: new technologies are being developed, including PET/CT, MRI, infrared, and ultrasound, to quantify BAT mass and activity as a way of understanding its structure and function.
3. Therapeutics: physiological and hormonal interventions are being evaluated to identify which ones increase BAT energy expenditure and have the potential for use as treatments for obesity and diabetes.
Our laboratory is a multinational group located at Children's Hospital Boston. We study development, cellular reprogramming, disease processes, and the improvement of therapeutics with an emphasis on leukemia and genetic blood disorders. These projects build upon basic studies of pluripotent stem cells, the development of blood-forming or hematopoietic tissue, epigenetic regulation, and mechanisms of cancer initiation, progression, and therapy resistance.
In my laboratory, we pursue two interlocking areas of investigation: the basic biology of stem cell programming and reprogramming, as well as the application of the resulting technologies to studies of the neuromuscular system and the diseases that affect it.
Coming to a fundememtal understanding of how a cell's identity is determined during differentiation and how it can in turn be manipulated experimentally, is a central goal of developmental biology, one with susbstantial ramifications for biomedicine. We study both the differentiation of embryonic stem cells into the neural lineage and the reprogramming of commonly available differentiated cell types, such as fibroblasts, into either pluripotent stem cells or cells of therapeutic interest such as spinal motor neurons. To study differentiation and dedifferentiation, we employ a variety of approaches including stem cell differentiation, nuclear transfer and defined reprogramming strategies using known transcriptional regulators and novel small molecule compounds.
A number of devestating diseases, including ALS and SMA specificaly affect the neuromuscular system. Little is known concerning the molecular pathology underlying these conditions at least in part because it has been impossible to access significant quantities of the disease affected cell type, the spinal motor neuron. With recent advances in stem cell and reprogramming biology we can now produce billions of spinal motor neurons with control and diseased genotypes. We use this new resource to design in vitro disease models for both mechanistic studies and for the discovery of novel small molecule therapeutics.
Research in our laboratory is committed to expanding our molecular understanding of the formation and regeneration of tendons and ligaments. Injuries to tendons and ligaments result in a slow and imperfect regenerative response. In most cases, the original biomechanical properties of the tissue are never restored, resulting in scarring and limited mobility. We use a multidisciplinary approach, combining genetic and chemical screening with different model systems such as zebrafish and stem cells, to identify essential regulators of tendon and ligament biology.
One major area of research in the laboratory aims to identify the cues that direct progenitor cells to become mature tendons and ligaments. During embryogenesis, progenitor cell populations will form the tendon or cartilage tissues in our limbs, head and spine. We are interested in elucidating the pathways that regulate this fate decision, expand tendon and ligament populations, and promote more faithful differentiation into these lineages.
We are also focused on understanding the critical factors that coordinate the attachments between muscle, tendon, and bone. By combining live-imaging and high-throughput screening approaches, our goal is to identify the molecules and cellular behaviors governing these processes. In the long term, my laboratory aims to transform these discoveries into regenerative biology solutions to better heal and repair tendon and ligament injuries.
Hanna Gazda's research focuses on identifying the genetic causes and molecular pathogenesis of Diamond-Blackfan Anemia (DBA), a bone marrow failure characterized by anemia, bone marrow erythroblastopenia and congenital abnormalities. The first DBA gene, ribosomal protein S19, was found to be mutated in ~25% of DBA patients. Gazda and colleagues recently identified four other genes, RPS24, RPL5, RPL11, and RPS7, mutated in ~15% of DBA patients, and confirmed that DBA is a first human disease caused by mutations in ribosomal proteins. They also discovered the first known correlation between mutations in certain genes and particular clinical findings. In particular, mutations in RPL5 are associated with multiple physical abnormalities including cleft lip/cleft palate, thumbs and heart anomalies, while isolated thumb malformations are predominantly present in patients carrying mutations in RPL11. The laboratory’s current goal is to identify other genes involved in DBA, to uncover the pathogenesis of the disease and to generate an animal model for DBA.
Raif Geha's lab pursues the molecular basis of inherited immune deficiencies. The Geha lab has established a mouse model of Atopic Dermatitis and is studying the mechanisms of allergic sensitization through the skin and of recruitment of T cells & eosinophils to the skin. The researchers are pursuing several investigational avenues. One seeks to identify the molecular process by which a B cell switches from producing one class of antibody to another. A second explores inherited immune deficiency disorders, with special emphasis on Wiscott-Aldrich Syndrome. A third investigates the molecular basis of atopic dermatitis (AD) a common, an allergic inflammation of the skin that is common, but poorly understood. The lab has created an animal model of AD that may ultimately be used to develop potential drugs.
Isotype switching is the mechanism by which a B cell goes from producing one type of antibody to another while maintaining antigenic specificity. This phenomenon allows the immune system to produce various antibody types against the same antigen, but having different effector functions. Isotype switching is a highly orchestrated process with several cytokines and T and B cell surface molecules participating. The Geha laboratory has shown that B cell surface molecules CD40, BAFF and APRIL are important for the switching process, and that defects in these molecules, or in the signaling cascade emanating from them, could potentially lead to immunodeficiency. Geha and colleagues have also shown that C4BP, a complement regulatory protein, binds to CD40 and induces isotype switching. At present, they are studying the role of BAFF and APRIL in isotype switching and antibody affinity maturation.
Wiskott-Aldrich syndrome (WAS) is a primary immunodeficiency caused by mutation in the gene encoding for the WAS protein (WASP). The Geha group identified a novel cellular negative regulator of WASP they have named WIP. WASP and WIP together regulate most cell functions that require the remodeling of the actin-based cytoskeleton--the structural framework of the cell. The Geha lab is now studying the role of WASP and WIP in immune cell functions that require active cytoskeletal remodeling such as migrating in response to chemical signals and homing. They are also mapping the domains of WASP and WIP that are involved in discrete functions of these molecules.
We are interested in developing and applying new technologies in the fields of mass spectrometry and proteomics. The impressive amount of data generated by the genomics revolution is being organized and made accessible in a variety of databases and libraries. These include genomic and expressed sequence tag databases, transcriptome maps, and protein databases that describe the identity of some of the proteins expressed by a tissue or cell, as well as other relevant properties including their structure, function and macromolecular interactions. Many of these databases describe the situation encountered at the time of the measurements in a static manner. However, many biological processes are dynamic responses to extraneous perturbations, be they environmental, pharmacological, pathological, genetic or otherwise. The ability to detect accurately and to quantify all of the changes included by a specific perturbation is therefore an essential part of the study of dynamic biological processes. At the heart of all aspects of our lab is protein sequencing by mass spectrometry. Simplified greatly, a tandem mass spectrometer can "sequence" a peptide ion by first measuring the mass of the peptide and then selectively isolating and gently fragmenting that peptide at peptide bonds followed by mass measurement of the fragment ions. The resulting tandem mass spectrum contains the sequence information for a single peptide. The astounding power of the technique can be understood when one compares traditional peptide sequencing by Edman degradation with peptide sequencing by mass spectrometry. A decapeptide can be sequenced by Edman degradation in about 12 hours. That same peptide can be sequence by a tandem mass spectrometer in about 1 second at 10 to 100 times the sensitivity.
The broad interest of my lab is to characterize the biology of stem cells in the normal lung and in lung cancer using a combination of mouse genetics, cell biology and genomics approaches. Our lung stem cell studies are focused on a population of adult stem cells in murine lung, bronchioalveolar stem cells (BASCs), which we hypothesize are crucial for lung injury repair in adults. We initially showed that BASCs have the potential to differentiate into bronchiolar and alveolar lineages in two-dimensional cultures. We recently created unique three-dimensional systems that demonstrate the ability of BASCs to produce bronchiolar and alveolar structures in culture and in vivo after subcutaneous injection. We have also used genetic lineage tracing studies to demonstrate the potential of BASCs to mediate alveolar cell repair in vivo. We have developed transplant assays to deliver lung stem cells and several new mouse strains, which now allow us to track the fate of BASCs after injury or in lung disease contexts. Our new assays for studying the self-renewal and differentiation potential of lung stem cells are making it possible to address critical areas in lung biology.
Our work has identified novel molecular regulators of lung stem cells. We demonstrated that the Polycomb protein Bmi1 is required for self-renewal of BASCs, repair of lung injury, and lung tumorigenesis (Dovey et al, PNAS). This work uncovered a much broader role for Bmi1 in adult stem cell function and tumorigenesis than was previously appreciated. More recently, we determined that p57 and a large subset of imprinted genes are Bmi1 target genes. We found that these imprinted loci are key regulators of lung stem cell self-renewal, uncovering a whole new set of stem cell regulatory genes that are likely needed in diverse adult tissue-specific stem cells (Zacharek et al, Cell Stem Cell).
My lab has also made key advances in elucidating the biology of stem cells in lung cancer. We discovered an important link between the genetic status of lung tumors and the phenotype of the tumor-propagating cells (TPCs), the cells that have the capacity to recapitulate the tumor by transplantation (often referred to as cancer stem cells). Using an orthotopic transplantation assay for TPCs that my lab created, we showed that lung cancers of different genotype have TPCs with distinct markers (Curtis et al, Cell Stem Cell). This work identified the first bona fide lung TPC population, opening up many new opportunities to study the most crucial lung cancer cells to target for lung cancer therapy. More recently we have used our TPC assay to prospectively isolate metastatic lung cancer cells. We are currently identifying the molecular pathways crucial for metastatic TPCs.
Our current and future work will build on these discoveries to lead the field towards a better understanding of stem cell biology in the lung, development of innovative approaches for examining the cellular and molecular basis of lung disease and cancer, and identification of new avenues of therapy for pulmonary diseases.
The study of the relative contribution of genes and environment to the risk of common diseases presents a number of statistical challenges, from study design to analysis. My research focus is statistical methodology in genetic epidemiology, including family-based and population-based case-control studies.
My current projects include methods to measure association between haplotypes of multiple tightly-linked markers and disease in matched case-control studies and to detect gene x gene and gene x environment interactions. I am also interested in using joint variation in DNA sequence and gene expression to better understand disease etiology.
I collaborate with colleagues in the Department of Epidemiology and the Channing Laboratory on a number of large-scale cohort studies, such as the Nurses' Health Study, as well as the international Cohort Consortium for Breast and Prostate Cancer.
Abnormal regulation/degeneration of midbrain dopamine neuron is associated with major neurological and psychiatric disorders such as Parkinson’s disease, schizophrenia, and substance abuse. We are interested in understanding the molecular mechanisms underlying the development and maintenance of dopamine neurons in healthy and diseased brains. This is accomplished through detailed mechanistic studies of the relationship between critical extrinsic signals and intrinsic transcription factors, leading to important genetic networks and their functional roles in orchestrating the development and maintenance of dopamine neurons. Based on this molecular information, we seek to translate our results to preclinical and clinical application for neurodegenerative disorders such as Parkinson’s disease. In particular, we identified several key transcription factors that are crucial for early development and long-term maintenance and protection of midbrain dopamine neurons, leading us to identify them as potential drug targets for neurodegenerative disorders. We established efficient in vitro and in vivo assay systems and are currently investigating the development of novel therapeutics that may have neuroprotective and disease-modifying effects on neurodegenerative disorders.
Another area of research interest is the study of stem cells. In particular, we have recently focused on the development of clinically feasible and safe induced pluripotent stem (iPS) cell technology, which has great potential to study and treat human diseases. At present, the majority of iPS cells are derived through the use of viral vectors, resulting in clinically unsafe stem cells. We are interested in developing clinically and biomedically ideal iPS cells by safe techniques such as protein-based reprogramming with the long-term goal of advancing future personalized regenerative medicine. Once this technology is fully optimized, it will open an era of ‘cellular alchemy’ and provide potential platforms for human disease mechanism studies and novel therapeutic developments.
We are interested broadly in the use of genetic approaches to understand human disease. One major interest is the tumor suppressor gene syndrome tuberous sclerosis. We pursue studies on the human molecular genetics of this disease, develop mouse models using null and conditional alleles of TSC1 and TSC2, explore biochemical and signaling pathways, and explore therapeutic approaches. There is a particular interest in the generation of brain models of this disorder. A second major interest is lung cancer genetics. We are developing assays for the detection of clinically relevant mutations in lung cancer specimens, and are exploring the role of the TSC genes in lung cancer development.
Research approaches in common use in my lab include DNA variation detection, automated sequencing, generation of conventional and conditional mouse knock-outs, primary cell culture, protein analysis and immunoblotting, signaling pathway analysis, and high throughput genotyping. I am Director of the Brigham and Women's Hospital DNA Sequencing Core Facility, and Director of the Harvard Partners Center for Genetics and Genomics Genotyping Facility
Research in my laboratory focuses on developmental oncobiology of epithelial cancer. We are particularly interested in understanding how cancer stem cells evolve from normal target cells of cancer through accumulation of mutations and through interaction with microenvironments, as avenues for identifying pathways unique to them. We study this mainly through developing and analyzing novel mouse models of human cancer based on genetic events occurring in patients. Currently, we focus on modeling recurrent chromosomal abnormalities recently identified in increasing numbers of epithelial cancers (e.g., breast cancer, prostate cancer). The in vivo studies are complemented by cell culture based studies to decipher molecular mechanisms underlying tumor initiation and progression.
Xihong Lin is Professor of Biostatistics and Co-ordinating Director of Program in Quantitative Genomics of Harvard School of Public Health. My group's major research interests lie in development and application of statistical and computational methods for analysis of high-dimensional genomic and 'omics data in population and clinical sciences, and for analysis of correlatd data, such as longitudinal, clustered and spatial data.
We are interested in statistical genetics and genomics, genetic and epigenetic epidemiology, genes and environment and medical genomics. Current research projects include genome-wide association studies, next generation sequencing studies, gene-environment interactions, and genome-wide DNA methylation studies, pathway analysis and network analysis, proteomics.
* Statistical missing data problems, imputation methodology.
* Gibbs sampling and other MCMC methods, rate of convergence.
* Markov structure, graphical models (software BUGS), and genetics.
* Image reconstructions: PET, SPECT, etc.
* Bayesian methodology; Even Bill Gates talks about Bayesian ideas!!
* Nonparametric hierarchical models, model selections and testings.
* Large-scale computation and optimization, e.g., VLSI design; Dynamic systems; Computer vision.
* Monte Carlo filters, Sequential importance sampling and resampling.
We utilize genetic engineering techniques in mice, in conjunction with electrophysiology, optogenetics, pharmacogenetics and rabies mapping, to elucidate central neurocircuits controlling feeding behavior, body weight homeostasis, and fuel metabolism. Specifically, transgenic, knockout, knockin, and cre-dependent AAV viral approaches (for delivery of optogenetic, DREADD and monosynaptic rabies reagents) are used to manipulate and map neuronal circuits. The goal of these studies is to link neurobiologic processes within defined sets of neurons with specific behaviors and physiologic responses. The ultimate goal is to mechanistically understand the “neurocircuit basis” for regulation of food intake, energy expenditure and glucose homeostasis. Given our expertise in gene knockout and transgenic technology, we can efficiently and rapidly create numerous lines of genetically engineered mice, important examples being neuron-specific ires-Cre knockin mice, which enable cre-dependent AAV technology. This allows us to bring novel, powerful approaches to bear on the neural circuits underlying behavior and metabolism. Our combined use of mouse genetic engineering, brain slice electrophysiology, and whole animal physiology is ideally suited to studying these problems.
Specific areas of interest include:
Neurobiological and neurocircuit basis for leptin action and melanocortin-4 receptor action, role of synaptic transmission and NMDAR-mediated synaptic plasticity within feeding circuits, afferent inputs regulating AgRP and POMC neurons, efferent circuits responsible for effects of AgRP and POMC neurons on feeding behavior, dissection of neural pathways regulating sympathetic outflow and energy expenditure, and finally neural mechanisms by which the brain controls glucose homeostasis.
The ultimate goals of Joseph Majzoub's work are to understand how various stresses affect health.
The specific aims of the Majzoub laboratory's studies are to determine the impact of corticotropin releasing hormone (CRH) and vasopressin excess and deficiency on regulation of the neuroendocrine and behavioral responses to stress. The researchers seek to identify other neuropeptides related to CRH which may have similar functions. Because abnormal regulation of such neuropeptides likely contributes to disease, the molecules and their receptors are attractive targets for the development of new drugs.
Majzoub's work is also directed at determining how DNA variants in the gene for corticotropin releasing hormone affect stress and other behaviors, including appetite. He and his colleagues are currently working to define how transcriptional silencers interact with transciptional activators to regulate CRH gene expression
About Joseph Majzoub
Joseph Majzoub received his MD from Stanford University School of Medicine. He completed an internship and residency in Internal Medicine at Brigham and Women's Hospital and a fellowship in Adult Endocrinology at Massachusetts General Hospital.
He is the recipient of several teaching awards, including the A. Clifford Barger Award for Excellence in Mentoring from Harvard Medical School and the 2002 Irving M. London Teaching Award from Harvard Medical School-Massachusetts Institute of Technology Health Sciences Technology (HST) Program.
The Megason lab is interested in how the program contained in the genome is executed during development to turn an egg into an embryo. To this end we have initiated the Digital Fish project. In the Digital Fish project, we are using several technologies we developed including in toto imaging, GoFigure, and FlipTraps to "watch" the execution of circuits in living zebrafish embryos during development in a systematic fashion.
We study the developmental biology of the pancreas with a view to finding new treatments for diabetes. Our aim is to understand how the pancreas develops and use that information to grow and develop new pancreatic cells (Islets of Langerhans). This project is an example of the larger question of how vertebrates make an organ from undifferentiated embryonic cells.
Our experimental approaches use the tools of molecular, cellular and chemical biology to investigate how precursor or stem cells give rise to the pancreas and how pancreatic tissue is maintained in adults. This includes identifying cells and gene products that specify developmental fates and physiological functions during organogenesis, regeneration, and following autoimmune attack. We use a variety of techniques including functional genomics, chemical screening, tissue explants and grafting. While we use several vertebrate organisms, including frogs, chickens, and axolotls, the main thrust of our work is done with human stem cells, both embryonic and iPS cells, as well as their mouse counterparts.
Directing cells to form new pancreatic tissue has a practical significance: if our studies are successful, it should be possible to apply our conclusions to human cells and provide a source of insulin-producing beta-cells for diabetics.
Probing skeletal diseases. Human beings are 60% water; so what keeps us from slipping off our bones and into a puddle on the floor? The short answer is collagen, a chainlike molecule that helps prevent joints from pulling apart and teeth from getting loose. Breakdowns in the formation and organization of collagen cause a number of diseases, including osteoarthritis. The Olsen lab is trying to identify and sequence the genes that help to create different types of collagen. Mice that are missing the gene for one type, collagen IX, seem predisposed to suffer from a disease much like human osteoarthritis. This exciting indication of a genetic cause of arthritis, which the lab is investigating further, creates an even stronger motivation to learn the genetic basis for diseases involving other types of collagen and other proteins in the extracellular matrix that surrounds and connects cells. In addition, the lab is identifying gene mutations that are responsible for defects in skeletal patterns in developing limbs and growth of bones during development. In a recent discovery the inherited disorder synpolydactyly, a condition characterized by extra fingers and variable fusion of fingers, was found to be caused by mutations in a gene, HOXD13, that controls the activity of many other genes which are important for cell growth and differentiation during limb development. Cleidocranial dysplasia, a condition characterized by delayed suture ossification in the skull, supernumerary teeth and missing clavicles, was found to be caused by mutations in the gene CBFA1, a transcription factor needed for cells to become bone cells.
Probing vascular disorders. Blood vessels are tubes of endothelial cells surrounded by layers of smooth muscle cells and connective tissue proteins. During development this complex structure forms as a result of biochemical signals between endothelial cells and smooth muscle cells. Sometimes this biochemical communication fails and abnormal blood vessels form. By analyzing gene mutations causing such vascular abnormalities, much can be learned about the signals that are necessary for normal blood vessel development. In addition, identification of genes responsible for inherited vascular malformations provides a basis for development of rational therapies in the clinical treatment of vascular disorders. One by one, the Olsen lab is trying to identify the genes that cause several forms of venous malformations and determine the precise mutations in these genes.
The goal of the Orkin laboratory is to understand how commitment to specific blood lineages is programmed and how cell-specific patterns of gene expression are established. Since gene expression is controlled by nuclear regulatory factors (transcription factors), efforts have centered on identifying those crucial for development of stem cells or individual lineages. Research encompasses conventional molecular biology and contemporary mouse genetics.
Our research focuses on the development of statistical methods for uncovering the genetic basis of human disease, and on the population genetics underlying these methods.
The Reich laboratory studies Population Genetics & Medical Genetics.
Neutrophils and Pulmonary Infection
The Remold-O’Donnell Laboratory studies the role of SerpinB1 in protecting the host defenses of the lung against microbial infection. SerpinB1 (also called MNEI) is an ancestral and highly conserved serine protease inhibitor and a highly efficient inhibitor of neutrophil proteases. Our studies include work with patient specimens (cystic fibrosis, chronic lung disease of infancy) as well as microbial infection of animal models. We have shown that SerpinB1-/- mice are susceptible to bacterial lung infection with Pseudomonas aeruginosa. On infection with sublethal dose, SerpinB1-/- mice fail to clear infection. This defect is accompanied by an increased inflammatory response and by destruction of innate immune defense molecules in the lung including surfactant protein-D (SP-D). The recruited neutrophils also have a survival defect, accumulating as late apoptotic/necrotic cells and releasing proteases. Current studies are addressing the role of SerpinB1 and neutrophil proteases in lung infection with influenza virus, a highly important pathogen. The contribution of protective molecules such as SP-D that are targeted by neutrophil proteases are being examined through the use of transgenic mice. The role of SerpinB1 in neutrophil generation and neutrophil survival in steady state and in models of lung inflammation is being examined.
Platelet and T cell Defects in Wiskott-Aldrich syndrome
Our lab performs platelet studies based on the hypothesis that platelets from patients with Wiskott-Aldrich syndrome (WAS) are specifically defective in activation processes that depend on integrin “outside in” signaling. On treatment with agonists, the major platelet integrin αIIbβ3 is conformationally activated allowing binding to extracellular matrix. Bound ligand transduces signals across the membrane (integrin “outside-in” signaling) that activate the WAS protein (WASP), localized in platelets in the membrane skeleton. Active WASP generates new actin filaments responsible for altering platelet morphology as occurs when platelets spread on matrices or bind and aggregate at the blood vessel wall. The role of WASP in integrin outside-in alteration of cell morphology is thought to be important in stabilizing platelet aggregates and regulating platelet conversion to the procoagulant phenotype.
The lab performs research in the areas of Bone Marrow Transplantation, Leukemia, Tumor Antigens, and Immunotherapy.
Our laboratory focuses on two major areas: 1) understanding the molecular mechanism of insulin and IGF-1 action and their alterations in pathologic states; and 2) the developmental heterogeneity of adipose tissue and its role in diabetes, metabolic syndrome and longevity. To achieve these goals, we use a wide variety of methods ranging from basic cell biology to creation and analysis of tissue-specific knockouts mice, and analysis of human cells and tissues.
The insulin and IGF-1 receptor tyrosine kinases are major regulators of metabolism and growth, and sites of both physiological and disease regulation. Following stimulation, the insulin receptor phosphorylates as many as 10 different intracellular substrate proteins, each of which dock to a number of other intracellular proteins through SH2 and non-SH2 mediated interactions. This results in stimulation of both the PI 3-kinase pathway and the Ras-MAP kinase pathway, as well as activation of many serine and threonine kinases involved in control of metabolism and glucose uptake. To understand the complementarity and redundancy between these various complex pathways, we have utilized cellular transfection models, mouse knockout models and cells derived from knockout mice. We have used this approach to define the differential role of both receptors, their substrates (the IRS proteins) and various components of PI 3-kinase and its downstream target. These studies indicate that the insulin signaling network is a finely tuned network with critical nodes of signal divergence and regulation. Through the use of tissue-specific knockouts created using Cre-lox recombination, the role of each of these pathways in specific insulin actions in specific tissues has been determined. This includes the actions of insulin in both classical targets, like liver, muscle and fat, and non-classical targets, like the brain. We have shown how these genetic modifications are further modulated by acquired alterations and by genetic background in the mouse. We are also studying how these pathways affect longevity and how they are altered in type 2 diabetes, obesity and metabolic syndrome.
The second major focus of the laboratory is defining the developmental origins and heterogeneity of white and brown fat. This is based on the important difference in fat in various depots on development of insulin resistance and energy balance. We have shown that fundamental developmental genes play a role in this process, and that fat cells in different depots have cell autonomous differences in function which affect whole body metabolism. The difference between energy burning brown fat and energy storing white fat also affects metabolism. The role of this heterogeneity and insulin action on mitochondrial function is also being explored at a cellular and molecular level, since mitochondrial function is altered in diabetes and may play an important role in longevity.
The unique ability of stem cells to perpetuate themselves through self-renewal, and to give rise to mature effector cell types in a sustained fashion has positioned stem cell biology at the forefront of regenerative medicine -- the goal of which is to develop strategies capable of harnessing the clinical potential of stem cells to treat both heritable and acquired degenerative conditions. Hematopoietic stem cells (HSCs) are the only cells within the bone marrow that possess the ability to both differentiate to all blood lineages, and to self-renew for life. These properties, along with the remarkable ability of HSCs to engraft conditioned recipients upon intravenous transplantation, have established the clinical paradigm for stem cell use in regenerative medicine. Despite the enormous clinical potential of HSCs, surprisingly little is known about the mechanisms that regulate their fundamental properties of self-renewal and multi-potency. Our lab has a profound interest in understanding the mechanisms enabling self-renewal and multi-potency in HSCs, which we study using cellular, molecular, genetic and epigenetic approaches.
Another focus of the lab is in understanding the extent to which the aging of hematopoietic stem and progenitor cells contributes to the pathophysiological conditions arising in the aged hematopoietic system, which include; declining immuno-competence, diminished stress response, anemia, and cancer. To address this we are evaluating hematopoietic stem and progenitor cells in the context of aging in order to determine the cellular and molecular mechanisms underlying the aging of the hematopoietic system. In particular we are exploring the contribution of epigenetic regulatory mechanisms to hematopoietic stem cell biology and aging. We are also studying the mechanisms through which stem cells maintain genomic integrity, and examining how age-dependent DNA damage accrual impacts stem cell functional capacity to contribute to hematopoietic pathophysiology.
Numerous studies have shown that it is possible to experimentally reprogram the cellular identity of one cell type to another. One approach to effect cellular reprogramming involves enforcing expression of defined transcriptional regulators important for specifying one cell type in a different cell type in order to convert its fate. This methodology is perhaps best exemplified by the generation of induced pluripotent stem (iPS) cells from a variety of differentiated cell types by the ectopic expression of a small number of defined factors. This approach is also proving to be a viable method to reprogram a variety of cell types to alternative fates. Our lab is pursuing several lines of investigation aimed at reprogramming the cellular identity of a number of cell types into clinically useful cell types through various approaches including the use of novel technologies.
My lab is investigating the normal cellular functions of signaling pathways implicated in neurological disease, with an emphasis on axon growth and guidance. Our research centers upon the proteins affected in tuberous sclerosis complex (TSC) and spinal muscular atrophy (SMA) -- two neurological disorders whose genetic basis is well understood but whose cell biology remains unknown. As a clinical neurologist, I also treat patients with neurological disease. One of the ultimate goals of our research is to guide the development of therapeutics for disorders of neural connectivity. My team is currently conducting clinical trials investigating new treatments for TSC.
Tuberous sclerosis complex
TSC is a multi-system autosomal dominant disease caused by loss-of-function mutations in the TSC1 or TSC2 gene. This disease is characterized by the formation of benign tumors (hamartomas) in several organs. The brain is almost invariably affected, and patients often present with epilepsy, autism and mental retardation. We hypothesize that a miswiring of neuronal connections may underlie these neurological symptoms.
We have recently found that the Tsc1 and Tsc2 proteins restrict axon formation and growth. In mouse models of TSC, we observe ectopic axons and abnormal axon path-finding in the brain. The axonal functions of the Tsc proteins may be important in understanding the neurological features of the disease--and, more generally, in understanding the pathology of the autism spectrum disorders that affect patients both with and without TSC.
Click to see how TSC proteins control axon development.
We are further exploring the molecular network in which the Tsc proteins function, and have found that modulation of the growth-promoting mTOR pathway, which is regulated by Tsc proteins, can promote axon regeneration in the adult central nervous system. We are also interested in other neuronal functions of the Tsc signaling network, such as the control of neuron size, myelination, survival and stress responses. For instance, my lab, in collaboration with others, has shown that in a mouse model of TSC, neurons are sized abnormally, are not sufficiently myelinated and are prone to cell death. In other studies, we have found that Tsc activity mediates mTOR's response to neuronal stress. In particular, neurons lacking a functional Tsc protein complex are more vulnerable to endoplasmic reticulum stress-induced cell death.
Click to see a schematic of the mTOR signaling pathway.
Spinal muscular atrophy
Our second major line of research aims to understand axonal pathology in SMA, an autosomal recessive neuromuscular disease. SMA is characterized by hypotonia and muscle weakness, as spinal motor neurons are lost, and is caused by mutations in the SMN gene.
It is known that the SMN protein controls RNA processing and is important for axon development, but the details remain enigmatic. We hypothesize that axonal RNA transport and/or translation are not properly regulated in the disease. To investigate this, we are characterizing the role of the SMN protein in axon growth and guidance in vivo, as well as identifying proteins and mRNA targets that interact with SMN in neurons. We hope that our work will provide new insight into the signaling mechanisms responsible for establishing brain circuitry, and ultimately suggest therapeutic interventions for disorders in which these signaling mechanisms are perturbed.
Since my years as a Harvard faculty member, I have focused a sustained effort toward cancer biology, and my initial most significant contribution was the first to discover that pro-survival pathway activation is directly associated with p53-dependent genotoxic responses in cancer cells, and have provided a unique and significant contribution in this area. As an Assistant and then as an Associate Professor at the BIDMC and the MGH/Harvard Medical School, I pursued my major interest in how tumor suppressor p53-mediated transcriptional regulation influences cell fate decisions: live or die. Based on my contribution concerning the dark side of p53 in cancer therapeutics that wt-p53 can function as a guardian of cancer genome for their survival against therapeutic stress, I have established close collaborations with the Broad Institute utilizing their technological, computational and chemical biological tools under their Chemical Genetics Platform. Together with Broad scientists, I have identified several promising small molecules with anti-cancer activity through the activation of tumor suppressor p53 apoptotic pathway. Specifically, we have identified a small molecule to induce apoptosis selectively in cells having a cancer genotype by targeting a non-oncogene co-dependency acquired by the expression of the cancer genotype in response to transformation-induced oxidative stress. This highlights a novel strategy for cancer therapy that preferentially eradicates cancer cells by targeting the ROS stress-response pathway. My experience in this area has played a major role in the development of a Chemical Genetics Core facility at CBRC in collaboration with the Broad Institute. My group now possesses considerable experience in systematic small molecule technologies. I will continue to assist with the design, validation, execution and interpretation of investigator initiated chemical genetic screens.
The molecular mechanisms of transcriptional regulation are highly conserved among eukaryotes. Transcriptional regulation in response to environmental and developmental cues is mediated by the combinatorial and synergistic action of specific DNA-binding activators and repressors on components of the general transcription machinery and chromatin modifying activities. Much of the work in this laboratory combines genetic, molecular, and genomic approaches available in yeast to address fundamental questions about transcriptional regulatory mechanisms in living cells. In addition, we are defining physiological targets of human transcriptional regulatory proteins and chromatin modifications on a whole-genome basis using a novel microarray approach.
We are interested in structural and evolutionary analysis of genome variation and divergence. We apply bioinformatic approaches to problems of evolutionary genetics and human population genetics.
Additionally we develop novel computational techniques for proteomics and for comparative analysis of protein sequences and structures.
The laboratory studies the genetic basis by which form and structure are regulated during vertebrate development. We combine classical methods of experimental embryology with modern molecular and genetic techniques for regulating gene expression during embryogenesis.
One of the classic systems for the study of embryonic development is the chick embryo, where grafting experiments have given profound insight into such questions as the patterning of developing limb axes, and the control of organogenesis. These classical experiments provide a context for interpreting modern molecular studies and the methods they employed also give us an additional set of tools for manipulating the embryo. For example, we can use retroviral vectors to alter gene expression in the context of specific transplantations or extirpations. Important complementary information is gained from studies taking advantage of the powerful techniques for regulated misexpression and gene deletion in the mouse.
The lab has major efforts underway exploiting these approaches to understand limb development, from the establishment of the initial axes, to understanding the difference in genetic controls between an arm and a leg, through later specific events such as differential bone growth and specific muscle patterning; and to understand the establishment of left-right asymmetry (e.g.. why your heart is on the left and not the right) from the initiation of the left-right difference, through signaling cascades, to left- or right-specific morphogenesis. We also currently have projects looking at patterning of the gut, the differentiation of the somites and morphogenesis of the heart, as well as biochemical analysis of the hedgehog signal transduction system, a key signaling pathway during development.
Obesity is an epidemic health problem worldwide, and is a significant risk factor for many human diseases, including diabetes, dyslipidemias, non-alcoholic fatty liver, gallstones, cardiovascular disease, Alzheimer’s disease and even some cancers. Obesity develops when energy intake exceed energy expenditure. Despite this simple nature, the maintenance of energy balance is complex. The long-term research interest in Dr. Tseng’s lab is to understand the regulation of energy homeostasis and use it to develop potential therapeutic approaches for obesity and related diseases. The current research projects in Dr. Tseng’s lab are focused around the following specific areas:
Role of developmental signals in the determination of brown versus white adipose cell fate
Excess adipose tissue is the characteristics of obesity. Two functionally different types of adipose tissues are present in mammals: white adipose tissue, which is the primary site of energy storage, and brown adipose tissue, which is specific to thermogenic energy expenditure. Given its specialized function to dissipate chemical energy, brown adipose tissue provides a natural defense against cold and obesity. Several developmental signaling molecules have been shown to impact development of different adipose depots. These include members of the transforming growth factor β (TGF)-β and bone morphogenetic protein (BMPs) family, the fibroblast growth factor (FGF) family, the wingless (Wnt) family, the hedgehog family and others. Combining cellular, molecular and physiological approaches, Dr. Tseng and her colleagues have discovered that BMP7 specifically promotes brown adipocyte differentiation and function. Treatment of mice with BMP7 results in an increase in brown fat mass and reduced weight gain. Current ongoing studies in Dr. Tseng’s lab are to further determine the role of BMPs in the control of brown versus white adipogenesis and whole body energy metabolism using a variety of in vitro and in vivo approaches. In addition to BMPs, Dr. Tseng and her colleagues continue to identify additional factors that differentially regulate the development and function of brown versus white adipose tissue using genomics, proteomics, and small molecule screenings.
Identification and characterization of progenitor/stem cells that give rise to different adipose depots
The adipose tissue arises from the multipotent stem cells of mesodermal origin. When triggered by appropriate developmental cues, these cells become committed to the adipocytes lineage. It has been suggested that different fat depots located in different anatomical locations of the body may derive from distinct developmental origins. Recently, we have identified and isolated a subpopulation of adipogenic progenitors (Sca-1+/CD45-/Mac1-; referred to as Sca-1+ progenitor cells, ScaPCs) residing in murine brown fat, white fat, and skeletal muscle. ScaPCs derived from different tissues possess unique molecular expression signatures and adipogenic capacities. Importantly, while the ScaPCs from interscapular BAT are constitutively committed brown fat progenitors, Sca-1+ cells from skeletal muscle and subcutaneous white fat are highly inducible to differentiate into brown-like adipocytes upon stimulation with BMP7. ScaPCs from obesity-resistant mice exhibit markedly higher thermogenic capacity compared to cells isolated from obesity-prone mice. Currently, ongoing studies in Dr. Tseng’s lab are to further define these progenitors by single cell analysis, microRNA profiling and in vivo fate mapping.
Integration of central and peripheral controls on whole body energy homeostasis
The maintenance of energy balance involves coordinated changes in energy intake and expenditure, and these two limbs of energy balance are physiologically linked. The central nervous system receives diverse inputs to coordinate appetite and energy expenditure, and is therefore the key control center for body weight. Despite recent advances in defining the neuronal circuits for appetite regulation, factors that regulate feeding via these pathways have not yet been fully elucidated. TGF-β/ BMP are known to regulate neuronal development. Recently, this signaling system has been demonstrated to be involved in the regulation of food intake and energy homeostasis in lower organisms, such as C. elegans and Drosophila. However, whether a similar pathway in the regulation of energy balance exists in mammals is currently unknown. Recently, Dr. Tseng and her colleagues have discovered that in addition to its role in brown adipocyte development, central BMP7 signaling appears to play a critical role in regulation of food intake. Studies in Dr. Tseng’s lab are currently dissecting the molecular and neuronal mechanisms that underlie the anorectic effect of BMP7. Ultimately, we hope this combined knowledge will allow us to integrate central and peripheral controls of energy homeostasis and aid in identifying specific targets for therapy of obesity and diabetes.
Our laboratory focuses on the study of subpopulations of human and murine CD4+ (helper) T cells, which play a central role in the regulation of the immune system. CD4+ T cells have multiple functions, but little is known about mechanisms that selectively activate one function over another. Since the coordinated expression of restricted profiles of lymphokines appears to be the major mechanism for the regulation of these diverse functions, we are examining the cellular, molecular and genetic mechanisms that regulate lymphokine synthesis in CD4+ T cells.
Our research is concerned with structural aspects of protein function. We are interested in how proteins interact with other macromolecules or small-molecule ligands, and how these interactions relate to biological function. In this context, we are interested in identifying small-molecule inhibitors of functionally important protein interactions. To pursue these goals we use NMR spectroscopy, computational methods and chemical biology approaches.
The primary focus of our research is on how protein interactions control gene expression. On the one hand, we want to understand how eukaryotic translation initiation factors regulates the fate of cells. In particular, we are interested in the interaction of the cap-binding protein eIF4E with the mRNA cap, the scaffold protein eIF4G, and the regulatory 4E-BPs, and how these interactions are related to cell transformation and apoptosis. To address this, we have identified small-molecule inhibitors of the eIF4E/eIF4G interaction and found that these may have anti-tumor activity. We are also working on other factors involved in eukaryotic translation initiation, such as eIF2, eIF2B, eIF5B, eIF5 and eIF4A. In a related effort we are interested in the regulation of transcriptional activation. We are studying the interaction of transactivation domains of transcriptional activators with components of co-activator complexes, such as the human ARC or the mediator of yeast.
We also seek to understand mechanisms of T-cell function from structural studies of T-cell protein complexes involving CD2, the αβTCR, CD3, proteins that bind cytoplasmic tails of T-cell receptor proteins, or protein involved in signaling pathways, such as calcineurin and NFAT. In addition, we are interested in protein-protein interactions in apoptosis and inhibitors of pro-survival proteins. This includes studies of several anti- and pro-apoptotic proteins located in the cytoplasm or the mitochondrial membrane.
Furthermore, we are interested in developing improved experimental and computational methods for studying structures of large proteins and protein complexes.
Recently, we have engaged in a project to develop methods for characterizing the health conditions of human individuals from the composition and concentrations of metabolites. Our goal is to develop NMR and mass spectroscopy methods that will allow us to identify individuals with chronic myologenic leukemia (CML) from healthy persons. The methodology being developed has the potential of rapidly monitoring, in a non-invasive way, the status of patients undergoing drug treatment. If successful this approach can be applied for diagnosis and monitoring numerous other diseases.
We are devoted to the study of theoretical population genetics. The goal of population genetics is to identify and to understand the forces that produce and maintain genetic variation in natural populations. These forces include mutation (also recombination and gene conversion), natural selection, various kinds of population structure (e.g. subdivision with migration), and the random fluctuations of gene frequencies through time known as genetic drift. We study these forces mathematically, using both analysis and computation. For more information about specific areas of research, follow the leads to lab members.
Dr. Woolf’s laboratory is currently devoted to investigating how the functional, chemical and structural plasticity of neurons contributes to adaptive and maladaptive functions of the mammalian nervous system. The group’s major efforts are devoted to the study of pain, the formation of neural circuits during development, and the failure of regeneration in the adult CNS. Most of this work is focused on primary sensory and spinal cord neurons, which are studied using a multidisciplinary approach that spans mouse and human genetics, molecular and cell biology, bioinformatics, synaptic electrophysiology, neuroanatomy, integrative systems biology and behavior. The group works closely with a wide number of academic groups and the pharmaceutical and biotechnology industry to identify and validate molecular targets for novel analgesics and axonal growth determinants. The lab represents a complex mixture of basic and translational neuroscience.
The research in our laboratories are focused on the following three areas:
1. Bioinformatics: The development of high throughput genomic technologies has created many exciting opportunities as well as analysis challenges. Our group has developed some of the most widely used and cited bioinformatics methods to analyze high throughput data. Our transcription factor motif finding tools have been cited over 1500 times and our ChIP-chip/seq peak callers have over 6,000 registered users. We will continue to develop novel computational algorithms to analyze new high throughput data, such as ChIP-seq (MACS, CEAS), RIP-seq, DNase-seq, MNase-seq (NPS), DNA-seq, and RNA-seq (Gfold). We will also build integrative analysis pipelines (Cistrome) to better help experimental biologists, and conduct efficient data integration to better mine the hidden biological insights from publicly available high throughput data and refine hypotheses. Finally, we will integrate good genomics experimental design and bioinformatics analyses to best utilize the newest technologies in gene regulation studies.
2. Epigenetics: Epigenetics play an important role in gene regulation, and include diverse topics such as DNA methylation, nucleosome positioning, histone marks, epigenetic enzymes, and higher order chromatin interactions. We and colleagues generated the first high throughput nucleosome map in the human genome, identified monovalent genes in early embryonic development, and found the relationship between H3K36me3 exon enrichment and co-transcriptional splicing. We will focus on two major areas of epigenetic research. The first is use the dynamics of histone mark ChIP-seq and DNase-seq to infer in vivo transcription factor binding and understand transcription regulatory networks. The second is to use genome-wide approaches to understand the specificity and mechanism of epigenetic enzymes and lncRNAs (with epigenetic function). Despite intensive research efforts, our knowledge about these areas is still limited, so there will be exciting opportunities in the future.
3. Cancer: As one in three people in the developed countries will get cancer, research on the mechanisms and treatments of cancer will become increasingly important. We and colleagues identified the function of estrogen receptor, androgen receptor, and FoxA1 in breast and prostate cancers, TET1 in leukemia, DREAM complex in cell cycle control, and found metabolic and autoimmune genes as signatures associated with cancer initiation. Cancer is a genetic disease amenable for research using genomic approaches. First, we will integrate publicly available high throughput data to better understand cancer pathways. Recently many cancer studies have found mutations or misregulations in epigenetic enzymes. Many pharmaceutical and biotech companies as well as academic scientists are actively developing cancer drugs targeting epigenetic enzymes. We will study the genome-wide function and response of cancer cells to epigenetic drugs, and identify cancer patients that might respond better to certain cancer drugs based on the genetic, epigenetic, and gene expression status of their tumor.
The Young-Pearse lab focuses on the identification of the mechanistic causes of neurodegenerative and developmental disorders of the nervous system, with the ultimate goal of identifying novel targets for therapeutic interventions for these diseases.
We are interested in how kinases in general, and phosphatidylinositol 3-kinases (PI3K) in particular, control malignant transformation. The work of our laboratory integrates molecular biology, tissue engineering and novel mouse models of human cancer to study oncogenic alterations in kinases that are involved in tumor formation and metastasis. In addition to our unique genetically engineered mouse models, we have developed a number of additional experimental systems, including, synthetic human tumors, and kinome-wide libraries of activated kinases to elucidate the mechanisms by which kinases function in cancer.
The PI3K pathway is a key signal transduction system that links oncogenes and multiple receptors to many essential cellular functions, which is tightly regulated by PI3Ks and the tumor suppressor PTEN. This pathway is perhaps the most commonly activated signaling pathway in human cancer, therefore presenting both an opportunity and a challenge for cancer therapy. Studies in our group using genetic engineered mouse models of tissue-specific ablation of PIK3CA or PIK3CB begin to reveal distinct roles of these two isoforms in cellular signaling, metabolism, development and tumorigenesis. For example, PIK3CA plays essential roles in cellular signaling in response to various growth factors, while PIK3CB is important in mediating GPCR signaling. PIK3CA is critical in regulating hepatic and hypothalamic insulin action, glucose homeostasis and energy expenditure. We also made the surprising and important discovery that it is PIK3CB, not PIK3CA, that drives tumor formation in PTEN null prostate tumors. This work provided the foundation for a new field of targeting PI3K isoforms in cancer.
In parallel, we take kinome-wide approaches to the systematic study kinase signaling in oncogenic transformation. We constructed the first kinome-wide libraries of “gain of function” human kinases and used this system in a number of functional genetic screens leading to the identification of novel oncogenes. We also take kinome-wide “loss of function” approaches to decipher the process of transformation. For example, we identified SIK1 as a novel kinase that regulates p53 in response to loss of adhesion. We demonstrated that SIK1 couples LKB1 to p53-dependent anoikis and suppression of metastasis, thus establishing the LKB1-SIK1-p53 axis as a potentially important pathway in metastatic disease.
In summary, our research interests and unique integrated approaches allow us to continue to work at the forefront of cancer biology and foster innovative and productive science.
The laboratory focuses on the developmental biology of hematopoiesis and cancer. We have collected over 30 mutants affecting the hematopoietic system. Some of the mutants represent excellent animal models of human disease. For instance, the isolation of the ferroportin iron transporter was based on a mutant zebrafish and subsequently was shown to be mutated in patients with iron overload disorders. The mutants also represent interesting key regulatory steps in the development of stem cells. We also have undertaken chemical genetic approach to blood development and have found that prostaglandins upregulates blood stem cells. We recently developed suppressor screening genetics and found that transcriptional elongation regulates blood cell fate.
The laboratory has also developed zebrafish models of cancer. A screen for cell cycle mutants found 19 mutants. Some of these mutants get cancer at a very high rate as heterozygotes based on a carcinogenesis assay. We have used small molecules in a chemical suppressor gene to find chemicals that bypass cancer genes. We also have generated a melanoma model in the zebrafish system using transgenics. Transgenic fish get nevi, and in a combination with a p53 mutant fish develop melanomas. We also recently have generated a model of muscle tumors in the zebrafish. This faithfully recapitulates the human muscle tumors and the tumors arise at 10 days of life, making this an ideal system for looking for enhancers and suppressors of cancer.
We study the genetic basis of complex traits and common diseases in humans. Our group is in the Department of Medical Genetics and of Epidemiology of University Medical Center Utrecht, and the Division of Genetics of the Brigham and Women's Hospital and Harvard Medical School. We are also affiliated with the Program in Medical and Population Genetics at the Broad Institute of Harvard and MIT.
A central goal of our lab is to develop computational tools and statistical approaches to analyze patterns of genetic variation in human populations, and to apply these methods to identify genetic determinants of disease susceptibility, disease progression, and drug response.
We pursue these activities in the context of immune-related disorders including HIV/AIDS and autoimmune disease, as well as cerebrovascular and cardiovascular traits, involving many collaborators in Boston and elsewhere.
Found 54 laboratories .