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Harvard Medical School offers an extraordinarily rich environment for research in genetics, including both laboratory and clinical research. Although trainees are not necessarily restricted to working with these investigators, the following is a list of researchers in genetics who are closely affiliated with the training program. The researchers are listed by their last name: (please press Ctrl F to search for a particular subject)
Dr. Alt's laboratory is studying the molecular mechanisms involved with the differentiation of lymphocytes. A particular focus is the mechanism and control of the genomic rearrangement processes involved with antigen receptor variable region gene assembly and immunoglobulin heavy chain class-switching. They have recently identified gene products that function both in the context of double strand DNA break repair and antigen receptor variable region gene assembly. For their studies, they use a combination of molecular and cellular methods in combination with transgenic and chimeric animal approaches. During the past years they have created numerous lines of mutant and transgenic mice including immunodeficient mice that cannot assemble antigen receptor genes and mice deficient in expression of various transcription factors, nuclear oncogenes and signaling molecules. Their most recent studies have shown the role of non-homologous end-joining pathway of DNA repair in the maintenance of genomic stability and have exploited mice mutantin this pathway to generate new models for the study of the role of genomic instability in that generation of various types of cancer.
Dr. Beggs uses molecular genetic methods to understand the genetic basis for, and pathophysiology of, neuromuscular diseases, particularly congenital myopathies. The laboratory takes three primary approaches: the first involves identifying and characterizing genes for new skeletal muscle-specific proteins. The second involves testing these and other candidate genes for linkage and mutations in patients and families with neuromuscular disease. Finally, high throughput genomic and proteomic methodologies, such as micrarray-based studies of gene expression, are employed to better understand the molecular pathophysiology of these diseases.
The major focus of Dr. Beier's research is the utilization of genetic analysis of the mouse, and especially of murine mutations, as a means to study fundamental problems in mammalian biology. Most recently, we have been pursuing a screen for recessive ENU-induced mutations of late embryonic development to identify models of human malformation syndromes which affect organogenesis. In our present study we have identified mutations affecting the development of the neural tube and brain, the heart, the liver, the skeletal system, the craniofacial system, and the kidneys. As part of this project, we are adapting a strategy of haplotype analysis that allows us to rapidly map new mutations using small numbers of affected progeny. With the rapid progress in the sequence analysis of mammalian genomes, which will facilitate the molecular characteristics of these novel mutants, we anticipate that this will be a valuable resource for understanding organ development.
Dr. Bieber's interests include embryofetal pathology, cytogenetic epidemiology and forensic science and medicine. His work has focused on study of lethal malformations and their molecular and cytogenetic correlates, and the diagnostic utility of various cytogenetic approaches to the study of malformations and untoward pregnancy outcomes. His work also deals with population genetic and statistical approaches to the interpretation of forensic evidence and the public policy aspects of DNA forensics.
Dr. Bruns's research is focused on genes and chromosomal regions associated with human developmental anomaly disorders. The region of chromosome 11 deleted in the WAGR syndrome (Wilms tumor, aniridia, genitourinary anomalies and mental retardation) encodes a number of loci important for normal development of the eye, brain, kidney and genitourinary system as well as one of the genes for Wilms tumor. A novel gene with predominant expression in developing forebrain has recently been isolated in the laboratory from a deletion subregion implicated in at least part of the mental retardation component of the syndrome. This gene is the index member of a new family of neural loci with extensive conservation in the C. elegans genome. Additionally, maps are being developed of the chromosomal locations of human homologs of genes that play key roles in developmental processes in C. elegans, Drosophila, zebrafish, and Mus musculus.
Dr. Cepko and associates are interested in the mechanisms that direct development of the central nervous system (CNS) of vertebrates. They have been focusing their efforts on the development of the neural retina, an excellent model system for the CNS. They have found that lineage alone does not appear to direct choice of cell fate of retinal cells, but that environmental signals are probably of importance as well. The laboratory has made a major effort to understand the role of the environment, and the environmental signals that direct retinal cell fate decisions. In vitro culture systems have developed that allow study of the mitotic cycle, which is most likely intimately involved with cell fate decisions, as well as commitment and differentiation of retinal cells. These culture systems are being used to identify the relevant molecules through biochemical and genetic approaches. As a parallel approach, the laboratory has been using genomics methods to characterize the gene expression patterns within progenitor cells and their progeny. They have used serial analysis of gene expression, SAGE, and microarrays to find the genes that are expressed in temporally distinctive manners suggestive of a role in cell fate decisions or early steps in differentiation. In addition, they have defined all, or nearly all, of the genes expressed in photoreceptor cells. Of these genes, 264 were newly characterized and found to be enriched or specific to photoreceptor cells. Many of them were found to be candidate genes for human diseases that lead to blindness. Follow up of these genes, and those believed to be involved in the definition of distinct types of progenitors and their cell fate decisions, are being followed up using genetic approaches in mice, e.g. knock-outs and transgenics, and in chickens, using replication-competent retroviral vectors.
By obtaining from complete genome sequences complete list of parts for microbial cells, Dr. Church and his laboratory expect to facilitate experiments to uncover connections among the parts: homologies, substrates, tertiary and quaternary interactions. Toward these goals he has developed new methods including "Multiplexing" and an automated DNA sequence film reading program called REPLICA. Dr. Church has also been searching for abundant proteins which have eluded previous biochemical and genetic studies of E. coli, by systematically correlating N-terminal protein sequence data from 2D gel spots with the growing E. coli DNA sequence and 2D gel databases. Finally, he is investigating DNA transport across membranes using single pore conductance measurements. Initially he is looking at phage lambda ds-DNA injection and conjugative plasmid pilus injection of ss-DNA. These are tested for the effects of DNA transport on ion flux by patch-clamp current measurements. Ultimately such processes might be capable of delivering DNA sequence information.
Zinc finger transcription factor genes represent a substantial portion of the genes in the human genome. Some Cys2His2 type zinc fingers have conserved motifs that help to define these regulators. Dr. Collins' group named a novel domain of this type, the SCAN box, which is a highly conserved 84 residue module that functions as an oligomerization domain, mediating self-association or selective association with other proteins bearing SCAN domains. The SCAN box is a highly conserved vertebrate-specific protein domain found in approximately 60 genes in the human genome. Only a handful of these gene products have been characterized thus far, and they appear to control a wide range of biological processes, including development, cell differentiation, and lipid metabolism. Dr. Collins' group is attempting to define the structure of the SCAN domain, characterize the mechanisms involved in selective dimerization and determine the functions of this large family of transcription factors.
The laboratory is investigating the molecular basis of inherited congenital eye movement disorders in order to learn about human ocular motoneuron development and to understand how these neurons differ from anterior horn cells in the spinal cord. Specifically, we study individuals born with restrictive ophthalmoplegia and/or ptosis. Although historically these disorders, referred to as the "congenital fibrosis syndromes", were believed to result from primary extraocular muscle fibrosis, our work is based on the belief that they result from aberrant development and/or axonal targeting of specific motor nuclei/subnuclei in the midbrain and pons. Neuropathologic examinations by our lab and others support this hypothesis. The focus of the lab has been to define inherited congenital fibrosis syndromes (CFEOM1, CFEOM2, CFEOM3, Duane syndrome, and congenital ptosis), employ linkage analysis to determine their genetic loci (FEOM1, FEOM2, FEOM3, PTOS1, DURS3), and use positional cloning approaches to identify the mutated disease genes. We have identified ARIX, a transcription factor essential to oculomotor and trochlear nuclear development, as the gene mutated in CFEOM2. In addition to identifying new syndromes and searching for the mutated genes underlying this series of disorders, we are now initiating functional studies of ARIX and exploring the differentially expressed genes in these cranial nuclei. Her lab website can be found at http://www.childrenshospital.org/research/engle.
Dr. Fletcher's laboratory evaluates oncogenic mechanisms in solid tumors and hematological neoplasia. Major areas of focus include: 1) an FGFR1 fusion oncoprotein in leukemia and lymphoma; 2) KIT oncoproteins in several types of solid tumor; and 3) receptor tyrosine kinase oncoproteins in mesenchymal neoplasia. Our major interest is in characterizing oncogenic signal transduction pathways, and, in so doing, identifying novel therapeutic targets.
Dr. Geha has five ongoing studies of interest. These include projects on the regulation of IgE synthesis, signal transduction via MHC class II molecules, signal transduction via Fc RI, generation of CD40 knockout mice, and activation of HIV.
The laboratory's long term goal is to optimize muscle cell therapy for clinical use in treating patients with muscular dystrophy. We are now pursuing this goal by optimizing human mucle stem cell isolation and characterization, as well as creating new animal models for preclinical testing of this, and other possible therapies. We intend to thoroughly characterize human muscle stem cells by investigating patterns of specific genes they express using microarray technology. These studies will hopefully lead to the identification of specific markers that will allow us to more easily purify human muscle stem cells and study their biological origin. Cell injections into recipient animals will be optimized to assess the efficacy of human cells to repair damaged muscle.
Dr. Gusella directs the MGH Molecular Neurogenetics Unit, a collection of laboratories dedicated to a common theme, the investigation of human neurogenetic disorders using a four-step strategy: 1) genetic mapping of the defect/modifier; 2) positional cloning; 3) characterization of the gene in biochemical, culture, animal and/or lower organism models and 4) exploration of potential therapeutic approaches based on knowledge of the genetic mechanism of pathogenesis. His own laboratory is currently focused on projects at each of the four stages of the above strategy, with a primary continuing interest in Huntington's disease (He also directs the HD Center Without Walls, a long-standing multidisciplinary program aimed at understanding the pathogenesis of HD). Projects in the Gusella laboratory include genetic modifier studies in HD, genetic linkage mapping in Parkinson disease and several rare neurological disorders, positional cloning of the defect in biotin-responsive basal ganglia disease, cellular and biochemical studies in neurofibromatosis 1, neurofibromatosis 2 and HD, developing Drosophilia models in HD, dystonia and FD, and identification of potential therapeutics for HD and FD. The Gusella group also collaborates with a number of local investigators interested in exploring the genetic aspects of reproductive deficiencies, attention defecit disorder, schizophrenia, stroke and migraine headache. With investigators at the BWH and Children's Hospitals, Dr. Gusella is also pursuing the use of translocations to identify genes of developmental interest, a program that dubbed the Developmental Genome Anatomy Project (DGAP).
Dr. Holmes is based in the Genetics and Teratology Unit in the Pediatric Service at the Massachusetts General Hospital (MGH). The research activities are carried out at MGH and through offices at MGH-East and at Brigham and Women's Hospital. One major theme of these research studies is the search for genetic differences that are the basis for the teratogenesis of anticonvulsant drugs in one study and the fetal alcohol syndrome (with Dr. Joan Stoler) in another study. The comparison is made between the phenotypic features of the exposed individuals and the polymorphisms (SNPs) in several candidate genes in a TDT analysis including the genotypes of both parents. Another study focuses on the correlation between cognitive dysfunction in anticonvulsant-exposed individuals and their associated midface hypoplasia. A second major theme is the epidemiology of congential malformations in fetuses and infants born at Brigham and Women's Hospital, a project underway since 1972. One current project with pediatric surgeons (PK Donahue - PI) at Massachusetts General Hospital is the search for genes associated with the occurrence of congenital diaphragmatic hernia, a common and often lethal malformation.
Dr. Korf's research interest is neurogenetics, particularly neurofibromatosis. He is principal investigator for a multicenter clinical trial involving the use of volumetric MRI as a means of measurement of the growth of plexiform neurofibromas in NF1. The goals of the study are to validate the use of this approach and to develop normative data on the growth rate of these tumors as a prelude to clinical trials. He has also set up the infrastructure to support multicenter clinical trials as new medications that target the NF1 cellular pathway become available. Dr. Korf is already involved in trials including a farnesyl transferase inhibitor and inhibitors of angiogenesis. In addition, he is working on genotype-phenotype correlations in NF1, examining the role of allelic heterogeneity and modifying genes in determining the NF1 phenotype. Dr. Korf is also active in the area of medical genetics education. As medical director of the Harvard-Partners Center for Genetics and Genomics, he has been working with his group to develop new educations programs for health professionals in genetics. In addition, he is developing new tools to help clinicians use genetics in their daily practice, such as point-of-care sources of information and computer-based approaches to collecting family history information and supporting clinicians in the use of this information for medical decision-making.
Dr. Kunkel and his associates are continuing their study of dystrophin and dystrophin related proteins. Dystrophin is the protein disrupted by mutation to yield Duchenne/Becker muscular dystrophy, and these other proteins are likely candidates to be involved in the generation of other neuromuscular genetic diseases. The related proteins are also potential proteins to replace dystrophin's function in diseased muscle and represent an avenue for therapeutic intervention. The overall aim is to design means of treating boys with muscular dystrophy.
We Dr. Kwiatkowski has a general interest in using genetics/genomics to understand human disease. One major interest is the human autosomal dominant tumor supressor gene syndrome tuberous sclerosis in which brain hamartomas (tubers) cause significant nerologic morbidity. We identified the TSC1 gene by a positioning cloning strategy, and have developed technologies for robust mutation detection in TSC1 and TSC2, to enable genotype-phenotype studies, and analysis for mosaicism and modifier alleles. We have generated knock out and conditional alleles of murine TSC1 and TSC2, which are being studied in vivo and in cultured cells to understand the function of these genes. A second major interest is a set of genes that participate in modulating the actin filament architecture of cells to produce cell motility: gelsolin, profilin, capG, rac, and filamin-1. We are developing KO and CO alleles for these genes and are studying the physiology of the resulting mice and their cultured cell lines. We are also interested in the role of these genes in invasion and metastasis. A third major developing interest is that of using the rapidly growing resource of single nucleotide polymorphisms (SNPs) to analyze the large epidemiologic cohorts (500,000 individuals) in the Channing Laboratory to identify alleles predisposing to human disease. Dr. Kwiatkowski is the director of the Brigham & Women's DNA sequencing and genotyping facility, and we are developing technologies for high thoroughput SNP genotyping. Initial diseases to be studied are those affecting the respiratory system, including asthma, chronic obstructive pulmonary disease, and lung cancer.
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