This multidisciplinary laboratory has 6 interests: 1) Defining regionally specific adaptations responsible for functions altered by chronic ethanol; 2) Characterizing regional CNS biochemical changes induced by stress and CRF after chronic ethanol; 3) Defining the role of central cytokines in behaviors induced by stress; 4) Exploring how a benzodiazepine (BZD) agonist shares actions with a BZD antagonist; 5) Defining TRH receptor subtype(s) responsible for its anti-anxiety and analeptic actions; and 6) Defining the action of galanin on ethanol withdrawal-induced anxiety. To undertake our interests, behavioral, anatomical, pharmacological, electrophysiological, biochemical, and molecular biological approaches are used.
Cell adhesion, both to other cells and to ECM, signaling, the cytoskeleton and cell migration. The Rho family of GTPases, their regulation by guanine nucleotide exchange factors and GAPs. Inflammation and leukocyte transendothelial migration.
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.
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.
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 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?
The work in our laboratory is focused on understanding the molecular pathogenesis of Kaposi’s sarcoma-associated herpesvirus (KSHV), an oncogenic human virus. KSHV is associated with several types of cancer in the human population. We study the effect of KSHV viral proteins on cell proliferation, transformation, apoptosis, angiogenesis and cell signal transduction pathways. We also study viral transcription factors, viral replication, and the interactions of KSHV with the human innate immune system. Additionally, we are developing drug therapies that curb viral replication and target tumor cells.
Cellular and molecular basis of the mucociliary clearance system in the airways of the lung. Our focus is on the regulation of mucin secretion and ciliary activity at the cell and molecular levels.
Our research centers on understanding the
molecular basis of human carcinogenesis. In particular, a major focus of our studies is the Ras oncogene and Ras-mediated signal transduction. The goals of our studies include the delineation of the complex components of Ras signaling and the development of anti-Ras inhibitors for cancer treatment. Another major focus of our studies involves our validation of the involvement of Ras-related small GTPases (e.g., Ral, Rho) in cancer. We utilize a broad spectrum of technical approaches that include cell culture and mouse models, C. elegans, protein crystallography, microarray gene expression or proteomics analyses, and clinical trial analyses.
We study how mammalian cells activate the programmed cell death pathway and die by apoptosis. We have focused our work on identifying unique mechanisms by which this pathway is regulated in postmitotic cells such as neurons, cardiomyocytes, and myotubes, as well as cancer, senescent, and stem cells. Excessive cell death is seen in many pathological conditions such as after stroke, neurodegeneration or cardiovascular diseases. In contrast, reduced cell death is a hallmark of cancers. Therefore, discovering the mechanism by which mammalian cells regulate cell death has significant therapeutic implications.
We use an integrated approach (genomics, proteomics, computational biology) to study the molecular mechanisms of hormone and drug desensitization. Our current focus is on RGS proteins (regulators of G protein signaling) and post-translational modifications including ubiquitination and phosphorylation.
We are characterizing the structural signals that are responsible for moving proteases normally stored intracellularly in lysosomes into the extracellular environment, where they may participate in tumor cell metastasis. One putative mediator of this altered protease targeting is an endosomal integral membrane protein that behaves like a cellular "dirty bomb", undergoing proteolysis which releases fragments that target to various cellular sites where they serve distinct functions. The multiple proteolytic cleavages ultimately release the cytoplasmic tail from the membrane. This tail, which possesses a putative signal for import into the nucleus, can modify other proteins with ubiquitin, which causes them to be degraded rapidly. Proteolysis of the putative receptor is mediated by the same enzymes that cleave the Alzheimer's precursor protein into fragments that can aggregate to form plaques in the brain. When neurite outgrowth is stimulated, expression of this protein is upregulated, suggesting that it also plays a role in development. We are using biochemical characterization of the protein's domain structure to relate its proteolysis, cellular targeting, and signaling to the nucleus to altered targeting of lysosomal enzymes.
We are using C. elegans embryos to address fundamental issues such as how cells move to specific positions during embryonic morphogenesis, how the orientation of cell division is determined, how the mitotic spindle is positioned in cells and how cells respond to cell signaling. We use diverse methods, including methods of cell biology, developmental biology, forward and reverse genetics including RNA interference, biochemistry, molecular biology and live microscopy of cells and the cytoskeleton. We are also developing water bears as a
new model system to study the evolution of development.
Our primary research is in the area of computational systems biology, with particular interest in the study of biological signaling networks; trying to understand their structure, evolution and dynamics. In collaboration with wet lab experimentalists, we develop and apply computational models, including probabilistic graphical and multivariate methods along with more traditional engineering approaches such as system identification and control theory, to current challenges in molecular biology and medicine. Examples of recent research projects include: prediction of protein interaction networks, multivariate modeling of signal transduction networks, and development of methods for integrating large-scale genomic data sets.
We are interested in how complex signaling systems interact to preserve homeostasis, while also optimizing the response of the organism to environmental changes. Two different projects are ongoing in the laboratory: Project 1: Matching renal salt excretion with dietary salt intake is vital for survival. We are integrating whole animal physiological studies and innovative molecular techniques to investigate the role of a new intestinal hormone, uroguanylin, in this process. Project 2: How do target organs communicate with neural circuits? We are investigating feedback regulation of a simple neural circuit that uses a novel form of muscle-to-nerve communication to control the contractions of the heart musculature.
Dynamic control of signaling networks in living cells; Rho family and MAPK networks in motility and network plasticity; new tools to study protein activity in living cells (i.e., biosensors, protein photomanipulation, microscopy). Member of the Molecular & Cellular Biophysics Training Program and the Medicinal Chemistry Program.
We focus on mechanistic/structural aspects of regulatory proteins (heterotrimeric and Ras family GTPases, RGS proteins, and PLC isozymes) involved in inositol lipid signaling, and on G protein-coupled receptors for extracellular nucleotides.
This laboratory focuses on the identification of signaling pathways regulating host/bacteria interaction and the pathological consequences of a dysregulated response. Using germ free mice and gnotobiotic approaches, we investigate the functional impact of toll-like receptor (TLR) and nucleotide oligomerization domain (Nod) signaling on bacteria-mediated intestinal inflammation, colitis-associated colon cancer and intestinal response to injury (ischemia-reperfusion, radiation).
Hormones influence virtually every aspect of plant growth and development. My lab is examining the molecular mechanisms
controlling the biosynthesis and signal transduction of the
phytohormones cytokinin and ethylene, and the roles that these hormones play in various aspects of development. We employ genetic, molecular, biochemical, and genomic approaches using the model species Arabidopsis to elucidate these pathways.
The regulatory role of platelet membrane phosphatidylserine in blood coagulation; mechanism of protein-mediated membrane fusion in secretory processes and virus infection. Director of the Molecular & Cellular Biophysics Training Program.
Specialized cell types allow plants to shed their structures-such as leaves, flowers and fruit-through the carefully orchestrated process of cell separation. The research focus of the Liljegren lab is to investigate the molecular mechanisms that control cell separation using the Arabidopsis flower as a model system. As in many other higher plants, Arabidopsis flowers contain pattern elements which allow distinct separation events such as floral organ shedding, fruit opening, pollen dehiscence, and seed dispersal to take place during their life cycle. Currently, we are characterizing the functions of key regulators of floral organ separation, including NEVERSHED, LOVES-ME-NOT and STAMENSTAY. We have discovered that NEVERSHED regulates vesicle trafficking during flower development and are using sensitized genetic screens to identify additional components of a signaling pathway, such as the receptor-like kinase EVERSHED, that likely control the movement and secretion of specific molecules during the shedding process.
My research goals are to identify the mechanisms by which environmental factors regulate smooth muscle cell phenotype and to define the transcriptional pathways that regulate SMC-specific gene expression.
My laboratory has two main interests: 1) P2Y receptor trafficking in epithelial cells. Our laboratory investigates the cellular and molecular mechanisms by which P2Y receptors are differentially targeted to distinct membrane surfaces of
polarized epithelial cells and the role of lipid rafts and caveolae in P2Y receptor function. 2) Antibiotic resistance mechanisms. We are interested in the mechanisms of antibiotic resistance in the pathogenic bacterium, Neisseria gonorrhoeae. Our laboratory investigates how acquisition of mutant alleles of existing genes confers resistance to penicillin and cephalosporin. We also study the biosynthesis of the gonococcal Type IV pilus and its contribution to antibiotic resistance.
Cell adhesion, signal transduction, and cytoskeletal regulation during embryogenesis and in cancer. We focus on the regulation of cadherin-based cell-cell adhesion, and on Wnt signaling and its regulation by the tumor suppressor APC.
The main focus of our research is to examine the molecular and cellular mechanisms that are involved in conferring neural identity to stem cells during embryogenesis and the adult.
The focus of my research group is the tumorigenesis of renal cell carcinoma. Our approach utilizes genetically engineered cells expressing clinically important point mutations in genes identified from renal cancers. Using cellular and animal models we are able to investigate processes integral to tumorigenesis including angiogenesis, hypoxic response signaling, extracellular matrix remodeling, and cell cycle signaling. Using data from the experimental models, I oversee a clinical research program that offers biologically active protocols to patients with renal cell carcinoma and examines correlative radiographic and serum or tumor biomarkers of tumor response to treatment.
Regulation of plant development: We use techniques of genetics, molecular biology, microscopy, physiology, and biochemistry to study how endogenous developmental programs and exogenous signals cooperate to determine plant form. The model plant Arabidopsis thaliana has numerous technical advantages that allow rapid experimental progress. We focus on how the plant hormone auxin acts in several different developmental contexts. Among questions of current interest are i) how auxin regulates patterning in embryos and ovules, ii) how light modifies auxin response, iii) how feedback loops affect kinetics or patterning of auxin response, iv) how flower opening and pollination are regulated, and v) whether natural variation in flower development affects rates of self-pollination vs. outcrossing.
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The research in our lab is centered on understanding the mechanisms and principles of movement at the cellular level. Cytoskeletal filaments - composed of actin and microtubules - serve as a structural scaffolding that gives cells the ability to divide, crawl, and change their shape. Our lab uses a combination of cell biological, biochemical, functional genomic, and high resolution imaging techniques to study cytoskeletal dynamics and how they contribute to cellular motion.
Ion channels and ionotropic receptors. Molecular mechanisms of ligand binding, channel activation, ion selectivity, and allosteric modulation. Techniques used: Molecular modeling, site directed mutagenesis, heterologous expression in Xenopus oocytes and other cells, chemical modification, and voltage clamp electrophysiology.
Regulator of G-protein signaling (RGS) proteins accelerate the GTPase activity of G-alpha subunits and thereby act as critical negative regulators of hormone and neurotransmitter signaling via G protein-coupled receptors. Our lab first recognized the existence of these critical signaling regulators in 1996. We continue to study their structural and functional diversity, as well as their roles in physiological and disease processes, including immunity, oncogenic transformation, and pain processing.
Our laboratory studies signal transduction systems controlled by heterotrimeric G proteins as well as Ras-related GTPases using a variety of biophysical, biochemical and cellular techniques. Member of the Molecular & Cellular Biophysics Training Program.
The goal of our research is to identify signaling mechanisms that contribute to normal and pathophysiological cell growth in the cardiovascular system. We study cardiac and vascular development as well as heart failure and atherosclerosis.
Projects involve the study of cellular and molecular events involved in autoimmunity, and development and application of genetic vaccines to prevent and treat autoimmunity and cancer.
Blood Flow and Endothelial Cell Function. We are interested in how vascular endothelial cells signal and respond to blood flow in the context of cardiovascular disease and tumor progression.
We are interested in understanding how autoreactive B cells become re-activated to secrete autoantibodies that lead to autoimmune disease. Our research is focused on understanding how signal transduction through the B cell antigen receptor (BCR) and Toll Like Receptors (TLR) lead to secretion of autoantibodies in Systemic Lupus Erythematosus (SLE).
My laboratory is interested in characterizing the role of cytoplasmic signal transduction pathways in regulation of androgen receptor activity and progression of prostate cancer. Our studies have focused on HER-2 receptor tyrosine kinase and we have demonstrated that HER-2 activation stimulates androgen receptor activity and HER-2 inhibition inhibits androgen receptor transcriptional function at the level of recruitment to the androgen responsive enhancers. These findings have led to the design and initiation of the protocol involving lapatinib, a clinical HER-2 inhibitor, in treatment of patients with prostate cancer. More recently, we have demonstrated that activated Cdc42-associated kinase Ack1 promotes progression of prostate cancer via tyrosine phosphorylation of androgen receptor at Tyr-267 and Tyr-363
residues. We are interested in further characterizing the role of tyrosine phosphorylation of androgen receptor in prostate cancer and development of Ack1 targeted therapy for clinical use.
Our research focuses on the mechanisms used by the bacterium Pseudomonas aeruginosa to cause disease. We are interested in identifying signal transduction pathways that regulate the expression of virulence genes in response to the host environment.
