It has been postulated for some time that cellular transplantation to the liver might allow for the reversal of hepatic based genetic defects or augmentation of hepatocellular function. However, the identification of the proper cell type and transplant conditions to produce liver engraftment and normal hepatocyte function has remained elusive. We have developed an alternative strategy using embryonic stem (ES) cells differentiated /in vitro/ and transplanted into hepatic parenchyma as “gene vectors” in order to restore wild type hepatocellular function.
Current research projects in the Campbell laboratory include structural, biophysical and biochemical studies of wild type and variant Ras and Rho family GTPase proteins, as well as the identification, characterization and structural elucidation of factors that act on these GTPases. Ras and Rho proteins are members of a large superfamily of related guanine nucleotide binding proteins. They are key regulators of signal transduction pathways that control cell growth. Rho GTPases regulate signaling pathways that also modulate cell morphology and actin cytoskeletal organization. Mutated Ras proteins are found in 30% of human cancers and promote uncontrolled cell growth, invasion, and metastasis. Another focus of the lab is in biochemical and biophysical characterization of the cell adhesion proteins, focal adhesion kinase, vinculin, paxillin and palladin. These proteins are involved in actin cytoskeletal rearrangements and cell motility, amongst other functions. Most of our studies are conducted in collaboration with laboratories that focus on molecular and cellular biological aspects of these problems. This allows us to direct cell-based signaling, motility and transformation analyses. Member of the Molecular & Cellular Biophysics Training Program.
The Cancer Biology Group at NIEHS focuses on early events in skin tumor development using a transgenic mouse model (TgAC). This model possesses a v-Ha-ras transgene under the regulation of a fetal globin promotor integrated at an ectopic site which confers a unique phenotype of inducible skin papillomas with a high rate of progression to invasive squamous and spindle cell neoplasms. The goals of our studies are to identify and characterize: 1) The cellular origin of the tumors and 2) critical genes which are involved in ras-mediated tumor induction and progression. Conventional cancer therapies have until recently depended on treatment late stages of tumor growth and involved non-specific mechanisms of cellular injury. By focusing on understanding early events in tumor induction we hope to gain insights into targets for intervention that can more specifically inhibit cancer cell growth.
Research in the Carelli laboratory is in the area of behavioral neuroscience. Our studies focus on the neurobiological basis of motivated behaviors, including drug addiction. Electrophysiology and electrochemistry procedures are used during behavior to examine the role of the brain 'reward' circuit in natural (e.g., food) versus drug (e.g., cocaine) reward. Studies incorporate classical and operant conditioning procedures to study the role of the nucleus accumbens (and dopamine) and associated brain regions in learning and memory, as they relate to motivated behaviors.
Gene targeting and state-of-the-art phenotyping methods are used to elucidate the reproductive and cardiovascular roles of the adrenomedullin system and to characterize the novel GPCR-signaling mechanism of Adm’s receptor and RAMP’s.
This laboratory has worked for over 25 years investigating both fundamental and clinically relevant aspects of ciliary and flagellar motility in eukaryotic cells. Our primary focus has been the elucidation of the processes surrounding differentiation, function, and injury of mammalian airway ciliated epithelial cells and how these cells respond to challenge by infectious agents, environmental irritants including tobacco smoke, and pharmacologic agents. Our laboratory is also part of a large national center for diagnosis, research, and treatment of Primary Ciliary Dyskinesia, a genetic disease affecting mucociliary clearance of the airways. This laboratory is designed around facilitating light and electron microscopic
analyses but collaborates closely with other laboratories and colleagues working on cell and molecular biology topics in airway epithelial cell biology.
Molecular evolution and mechanistic enzymology find powerful synergy in our study of aminoacyl-tRNA synthetases, which translate the genetic code. Class I Tryptophanyl-tRNA Synthetase stores free energy as conformational strain imposed by long-range, interactions on the minimal catalytic domain (MCD) when it binds ATP. We study how this allostery works using X-ray crystallography, bioinformatics, molecular dynamics, enzyme kinetics, and thermodynamics. As coding sequences for class I and II MCDs have significant complementarity, we also pursuing their sense/antisense ancestry. Member of the Molecular & Cellular Biophysics Training Program.
Developing and applying novel mass spectrometry (MS)-based proteomics methodologies for high throughput identification, quantification, and characterization of the pathologically relevant changes in protein expression, post-translational modifications (PTMs), and protein-protein interactions. Focuses in the lab include: 1) technology development for comprehensive and quantitative proteomic analysis, 2) investigation of systems regulation in toll-like receptor-mediated pathogenesis and 3) proteomic-based mechanistic investigation of stress-induced cellular responses/effects in cancer pathogenesis.
Our research centers on the cell biology and biochemistry of motor proteins and the cytoskeleton and their roles in processes such as cell crawling, phagocytosis, organelle transport.
Our research is concerned with proteases and their inhibitors in various disease processes (thrombosis and cancer); our science tools are structure-activity, cell biology and signaling, pathobiology, immunohistochemistry, and in vivo models.
Steroid hormones regulate tissue-specific gene expression in animals via receptor dependent intracellular signal transduction pathways. We are particularly interested in glucocorticoid receptors and their actions on the immune system because they reflect the primary response to environmental stress. Current research projects are examining the following aspects of glucocorticoid hormone action. A second major interest of the laboratory focuses on evaluating the mechanisms involved in the regulation of apoptosis in normal and neoplastic cells. Research is aimed at the identification and cloning of genes that are responsible for both the initiation and execution of apoptosis.
The major interest of this laboratory is the differentiation and regulation of autoreactive B cells in health and disease. Our long-range goal is to identify and understand the mechanisms that regulate autoreactive B cells and how they fail in disease. Such information is key to devise rational new therapeutic strategies for the treatment of autoimmune diseases such as systemic lupus erythematosus (SLE). The lab currently has three main research focuses: 1) regulation of B cells specific for the ribonucleoprotein antigen Sm, a target of the immune system in SLE, 2) analysis of how Epstein Barr virus (EBV) contributes to SLE and 3) investigation of activation of anti-Sm B cells in blood of human SLE patients.
Cross-talk between insulin like growth factor -1 and cell adhesion receptors in the regulation of cardiovascular diseases and complications associated with diabetes
The research in our laboratory involves several major projects related to the molecular pathogenesis of human cancer and investigations related to the biology of liver stem-like progenitor cells, including (i) characterization of human liver tumor suppressor genes, (ii) analysis of genetic determinants of breast cancer, (iii) investigation of mechanisms governing aberrant DNA methylation in breast cancer, (iv) liver progenitor cell responses after toxic liver injury, and (v) transplantation of liver stem-like progenitor cells for correction of genetic liver disease.
Diabetes and insulin resistance: lipid and carbohydrate metabolism; obesity: partition of energy between triacylglycerol storage and fatty acid oxidation; regulation of triacylglycerol synthesis; hepatic steatosis
We study how Cytotoxic T Lymphocytes (CTL) are activated during infection and cancer. Our long-term goal is to increase immunity in the case of infection or cancer and to decrease immunity in the case of autoimmunity. The approaches that we use include x-ray crystallography and other biophysical techniques such as SPR and ITC, and immunological assays. We are currently working on three systems. 1) basic immunology to understand how cytotoxic T cells are signaled to kill infected or cancer cells. 2) immunotherapy of melanoma using modified T cell receptors. 3) Determining why specific T cells populate pancreatic islets of Langerhans in Type I diabetes. Students working on these projects could work on immunological or biophysical aspects (or both) depending on their interests. Member of the Molecular & Cellular Biophysics Training Program.
Our lab is studying the molecular mechanisms which are involved in the induction and proliferation and patterning of cardiac progenitor cell populations. To identify the molecular pathways involved in these processes, we have used Xenopus and mouse as model systems with particular focus on the endogenous role of genes implicated in the early steps of cardiogenesis and human congenital heart disease. Present projects in the lab involve embryological manipulations, tissue explant cultures, molecular screens as well as protein-DNA interaction experiments, biochemistry and promoter analysis.
We study cell cycle control of DNA replication licensing, the process that renders replication origins competent to initiate DNA synthesis. We investigate how the replication process is linked to cell cycle progression and the signaling pathways that gather and transmit information about the cellular environment. Our experimental approach is to manipulate human cells in culture (both cancer cell lines and normal cells) through a variety of molecular and genetic strategies; some projects utilize budding yeast as a model system due to the sophisticated genetic tools available in that organism. We measure protein abundance and stability, chromatin localization and modifications, cell cycle progression, protein-protein interactions, and checkpoint functions. Our long-term goals are to understand the molecular events that ensure genome stability and how those events are disrupted in cancer cells.
The primary research area my lab is the regulation of meiotic recombination at the genomic level in higher eukaryotes. Genomic instability and disease states, including cancer, can occur if the cell fails to properly regulate recombination. We have created novel tools that give our lab an unparalleled ability to find mutants in genes that control recombination. We use a combination of genetics, bioinformatics, computational biology, cell biology and genomics in our investigations. A second research area in the lab is the role of centromere DNA in chromosome biology. We welcome undergraduates, graduate students, postdoctoral fellows and visiting scientists to join our team.
Mechanisms of DNA replication, DNA repair, and cell cycle checkpoints are studied in cultured human cells and using biochemical assays in vitro. It includes translesion synthesis by DNA polymerase eta and its role in suppressing mutagenesis by solar radiation. Inherited and acquired defects in the network of protection of genetic stability are associated with increased risk for mutations underlying cancer pathogenesis. Current goals are to identify key molecular events in melanoma development associated with sun exposure. Other collaborative studies aim at localization of functional origins and characterization of DNA replication dynamics.
Dr Costa's primary research interests focus on the potential for air pollutants to adversely affect human health. By using animal models representing healthy and susceptible human populations (chronic heart and lung diseases), he has made major in-roads into understanding how contaminants in the air can cause illness and even death. He uses methods in cardiopulmonary and neuro-physiology coupled with modern cell-molecular biology to develop these models and to ascertain how health impairments influence responsiveness to pollutant stresses.
The main research project is to determine the role of intercellular junctions in normal development, cell aging and cataract formation in human and animal lenses.
Our lab is interested in molecular mechanisms of oncogenesis, specifically as regulated by Ras and Rho family small GTPases. We are particularly interested in understanding how membrane targeting sequences of these proteins mediate both their subcellular localization and their interactions with regulators and effectors. Both Ras and Rho proteins are targeted to membranes by characteristic combinations of basic residues and lipids that may include the fatty acid palmitate as well as farnesyl and geranylgeranyl isoprenoids. The latter are targets for anticancer drugs; we are also investigating their unexpectedly complex mechanism of action. Finally, we are also studying how these small GTPases mediate cellular responses to ionizing radiation - how do cells choose whether to arrest, die or proliferate?
Research in the lab is focused on four major areas - (1) Genetic, cellular, and genomic analyses of Drosophila CNS development, (2) Brain development and behavior, (3) Molecular genetics of gene regulatory pathways, and (4) Control of cell migration and fusion events.
Our laboratory has research interests that include developmental neurotoxicity, with an emphasis on the use of mode-of-action models to study the impact of endocrine disruptors and the cumulative risk of thyroid disruptors and pesticides.
The Cyr laboratory studies cellular mechanisms for cystic fibrosis and prion disease. We seek to determine how protein misfolding leads to the lung pathology associated with Cystic Fibrosis and the neurodegeneration associated with prion disease.
