Our lab is interested in the mechanisms of membrane trafficking in eukaryotic cells. Using a combination of biochemistry, in vitro reconstitution, and structural biology, we seek to understand how protein complexes assemble to bend and perturb membranes during vesicle budding (endocytosis) and vesicle fusion (exocytosis). Our group also specializes in cryo-electron microscopy (cryo-EM) and we use semi-native substrates (nanodiscs, liposomes) to visualize complexes engaged with the membrane.
Our lab is interested in the molecular mechanisms of adaptive stress responses. These responses to environmental or metabolic stress are essential for survival but frequently dysregulated in disease. We use an integrated approach combining biophysical, structural, and biochemical methods to investigate the roles of intrinsically disordered proteins and dynamic enzymes that orchestrate these critical stress responses, with the ultimate goal of developing new approaches for modulating the functions of dynamic molecules.
Microbiology & Immunology
Our long-term goal is to define the molecular mechanisms of two-component regulatory systems, which are utilized for signal transduction by bacteria, archaea, eukaryotic microorganisms, and plants. Our current focus is to identify and understand the features that control the rates of several different types of protein phosphorylation and dephosphorylation reactions. The kinetics of phosphotransfer reactions can vary dramatically between different pathways and reflect the need to synchronize biological responses (e.g. behavior, development, physiology, virulence) to environmental stimuli. Member of the Molecular & Cellular Biophysics Training Program.
We are interested in the mechanism by which eukaryotic cells are polarized and the role of vesicle transport plays in the determination and regulation of cell polarity and tumorigenesis.
Our research group uses several biochemical and structural techniques (e.g. enzyme assays, X-ray crystallography, and cryo-EM) to understand how molecular machines drive the cell cycle. Dysregulation of these enzymes results in numerous cancer types.
A growing body of work in the biomedical sciences generates and analyzes omics data; our lab’s work contributes to these efforts by focusing on the integration of different omics data types to bring mechanistic insights to the multi-scale nature of cellular processes. The focus of our research is on developing systems genomics approaches to study the impact of genomic variation on genome function. We have used this focus to study genetic and molecular variation in both natural and engineered cellular systems and approach these topics through the lens of computational biology, machine learning and advanced omics data integration. More specifically, we create methods to reveal functional relationships across genomics, transcriptomics, ribosome profiling, proteomics, structural genomics, metabolomics and phenotype variability data. Our integrative omics methods improve understanding of how cells achieve regulation at multiple scales of complexity and link to genetic and molecular variants that influence these processes. Ultimately, the goal of our research is advancing the analysis of high-throughput omics technologies to empower patient care and clinical trial selections. To this end, we are developing integrative methods to improve mutation panels by selecting more informative genetic and molecular biomarkers that match disease relevance.
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.
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.
Cross-talk between insulin like growth factor -1 and cell adhesion receptors in the regulation of cardiovascular diseases and complications associated with diabetes.
The Drewry lab is focused on designing, synthesizing, evaluating, and sharing small molecule chemical probes for protein kinases. These tools are used to build a deeper understanding of disease pathways and facilitate identification of important targets for drug discovery. Through wide ranging partnerships with academic and industrial groups, the Drewry lab is building a Kinase Chemogenomic Set (KCGS) that is available to the community for screening.
The research in my lab is divided into two main areas – 1) Atomic force microscopy and fluorescence studies of protein-protein and protein-nucleic acid interactions, and 2) Mechanistic studies of transcription elongation. My research spans the biochemical, biophysical, and analytical regimes.
We are interested in basic DNA-protein interactions as related to – DNA replication, DNA repair and telomere function. We utilize a combination of state of the art molecular and biochemical methods together with high resolution electron microscopes.
Cell Biology & Physiology
The human placenta is the first organ to develop after fertilization and is the least studied! We hope to change this by using a multidisciplinary approach. From iPSC-derived trophoblasts in culture to mouse models and human placenta tissue, the Placental Cell Biology Group at NIEHS answers fundamental questions about placenta cell and developmental biology. Our lab uses a range of microscopy (cryo-EM, fluorescence), recombinant protein production, and -omics techniques. The goal of our research is to understand how autophagy controls placenta development, differentiation, and function.
The Jarstfer lab uses an interdisciplinary approach to solve biological problems that are germane to human health. Currently we are investigating the structure of the enzyme telomerase, we are developing small-molecules that target the telomere for drug discovery and chemical biology purposes, and we are investigating the signals that communicate the telomere state to the cell in order to control cellular immortality. We are also engaged in a drug/chemical tool discovery project to identify small molecules that control complex social behavior in mammals. Techniques include standard molecular biology and biochemistry of DNA, RNA, and proteins, occasional organic synthesis, and high throughput screening.
We take inspiration from Nature to build new proteins that guide our understanding of how natural proteins function: we can distill complex natural proteins into simple model proteins where we have exact control over the physicochemical properties of the entire system. Our group combines protein design strategies with biochemistry, biophysics, and structural biology to 1) test mechanistic hypotheses of membrane protein structure and function, and 2) define novel protein-protein interactions in immunology for engineering protein-based therapeutics.
Dr. Krupenko’s research is focused on the role of folate metabolism in cellular homeostasis and cancer disease. He is especially interested in the function of a major folate enzyme and a putative tumor suppressor ALDH1L1 as metabolic regulator and a guardian of non-malignant phenotype. At present he studies function of this enzyme and related proteins using mouse knockout models. Recently his research team has also demonstrated that dietary folate regulates cancer metastasis. He now pursues studies of specific signaling pathways involved in metastatic response to dietary folate status.
We focus on a variety of design goals including the creation of novel protein-protein interactions, protein structures, vaccine antigens and light activatable protein switches. Central to all of our projects is the Rosetta program for protein modeling. In collaboration with developers from a variety of universities, we are continually adding new features to Rosetta as well as testing it on new problems.
Dr. Edward (Ed) LeCluyse is currently a Senior Research Investigator in the Institute for Chemical Safety Sciences at The Hamner Institutes of Health Sciences. Dr. LeCluyse leads a program initiative to identify and develop novel in vitro hepatic model systems to examine cellular responses to drugs and environmental chemicals that target known toxicity pathways. The focus of his research efforts has been to create more organotypic, physiologically-relevant in vitro models that integrate the architectural, cellular and hemodynamic complexities of the liver in vivo.
We study protein structure and dynamics as they relate to protein function and energetics. We are currently using NMR spectroscopy (e.g. spin relaxation), computation, and a variety of other biophysical techniques to gain a deeper understanding of proteins at atomic level resolution. Of specific interest is the general phenomenon of long-range communication within protein structures, such as observed in allostery and conformational change. A. Lee is a member of the Molecular & Cellular Biophysics Training Program.
The overall goal of our research is to develop an enzyme-based approach to synthesize heparin- and heparan sulfate-like therapeutics. The lab is currently focusing on improving the anticoagulant efficacy of heparin drug as well as synthesizing heparin-like compounds that inhibit herpes simplex virus infections. We are also interested in using protein and metabolic engineering approaches for preparing polysaccharides with unique biological functions.
Research in the Lockett group focuses on the development of analytical model systems to: i) chemically modify the surface of thin films, and study chemical and biochemical reactions occurring on those surfaces; ii) study drug metabolism in an environment that closely mimics the human liver; iii) measure tumor invasion in an environment that closely mimics human tissue. / / While these problems require techniques found in analytical chemistry, biochemistry, molecular biology, bioengineering, and surface science we are particularly interested in the technologies that allow us to quantitatively measure reactions and analytes.
The McGinty lab uses structural biology, protein chemistry, biochemistry, and proteomics to study epigenetic signaling through chromatin in health and disease. Chromatin displays an extraordinary diversity of chemical modifications that choreograph gene expression, DNA replication, and DNA repair – misregeulation of which leads to human diseases, especially cancer. We prepare designer chromatin containing specific combinations of histone post-translational modifications. When paired with X-ray crystallography and cryo-electron microscopy, this allows us to interrogate mechanisms underlying epigenetic signaling at atomic resolution.
Our lab seeks to better understand the maturation and regulation of a group of human lipases. We aim to uncover how these lipases properly fold and exit the ER, and how their activity is subsequently regulated. We study the membrane-bound and secreted proteins that play a role in lipase regulation. Our research can potentially impact human health as biochemical deficiencies in lipase activity can cause hypertriglyceridemia and associated disorders, such as diabetes and atherosclerosis. We are an interdisciplinary lab and aim to address these questions using a variety of techniques, including membrane protein biochemistry, enzymology, and structural and molecular biology.
My graduate students and I use the formalism of equilibrium thermodynamics and the tools of molecular biology and biophysics to understand how nature designs proteins.
Biochemistry & Biophysics, Bioinformatics & Computational Biology, Chemistry, Microbiology & Immunology, Oral & Craniofacial Biomedicine, Pathobiology & Translational Science, Pharmaceutical Sciences, Pharmacology
Bacteriology, Biochemistry, Bioinformatics, Biophysics, Cancer Biology, Chemical Biology, Computational Biology, Drug Delivery, Drug Discovery, Metabolism, Microbiology, Molecular Biology, Molecular Medicine, Pharmacology, Plant Biology, Structural Biology, Systems Biology, Toxicology
We are interested in unraveling the molecular basis for human disease and discover new treatments focused on human and microbial targets. Our work extends from atomic-level studies using structural biology, through chemical biology efforts to identify new drugs, and into cellular, animal and clinical investigations. While we are currently focused on the gut microbiome, past work has examined how drugs are detected and degraded in humans, proteins designed to protect soldiers from chemical weapons, how antibiotic resistance spreads, and novel approaches to treat bacterial infections. The Redinbo Laboratory actively works to increase equity and inclusion in our lab, in science, and in the world. Our lab is centered around collaboration, open communication, and trust. We welcome and support anyone regardless of race, disability, gender identification, sexual orientation, age, financial background, or religion. We aim to: 1) Provide an inclusive, equitable, and encouraging work environment 2) Actively broaden representation in STEM to correct historical opportunity imbalances 3) Respect and support each individual’s needs, decisions, and career goals 4) Celebrate our differences and use them to discover new ways of thinking and to better our science and our community
Dr. Shih is the Director of Small Animal Magnetic Resonance Imaging (MRI) at the Biomedical Research Imaging Center. His lab has implemented multi-model MRI techniques at high magnetic field to measure cerebral blood oxygenation, blood flow, blood volume, and oxygen metabolism changes in preclinical animal models. Dr. Shih’s lab is also developing simultaneous functional MRI (fMRI) and electrophysiology recording techniques at high spatial resolution to elucidate the pathophysiological mechanisms of neurovascular diseases. They will apply these techniques to (i) explore/validate functional connectivity network and neurovascular coupling in the rodent brain, (ii) study tissue characteristics after stroke, and (iii) investigate deep brain electrical stimulation, optogenetic stimulation, and pharmacogenetic stimulation in normal and Parkinsonian animal models.
Our lab examines cytoskeletal dynamics, the molecules that regulate it and the biological processes it is involved in using live cell imaging, in vitro reconstitution and x-ray crystallography. Of particular interest are the microtubule +TIP proteins that dynamically localize to microtubule plus ends, communicate with the actin network, regulate microtubule dynamics, capture kinetochores and engage the cell cortex under polarity-based cues.
Bioinformatics & Computational Biology
My primary research area is computational geometry, in which one studies the design and analysis of algorithms for geometric computation. Computational geometry finds application in problems from solid modeling, CAD/CAM, computer graphics, molecular biology, data structuring, and robotics, as well as problems from discrete geometry and topology. Most of my work involves identifying, representing, and exploiting geometric and topological information that permit efficient computation. My current focus is on applications of computational geometry in Molecular Biology and Geographic Information Systems (GIS). Examples of the former include docking and folding problems, and scoring protein structures using Delaunay tetrahedralization.
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.
Our lab is interested in understanding the structural basis for activation of cell surface receptors. Using a combination of biochemistry, structural biology and cell biology, we seek to understand how the membrane environment and receptor:ligand interactions are modulated to generate the wide diversity of signaling regulated by these receptors, and how these interactions are modified in disease.
Bioinformatics & Computational Biology, Neuroscience, Pharmaceutical Sciences, Toxicology
The major area of our research is Biomolecular Informatics, which implies understanding relationships between molecular structures (organic or macromolecular) and their properties (activity or function). We are interested in building validated and predictive quantitative models that relate molecular structure and its biological function using statistical and machine learning approaches. We exploit these models to make verifiable predictions about putative function of untested molecules.
One of the most amazing discoveries of recent years has been the profound role of RNA in regulating all areas of biology. Further, the functions of many RNA molecules require that an RNA fold back on itself to create intricately and complexly folded structures. Until recently, however, we had little idea of the broad contributions of RNA structure and function because there simply did not exist rigorous methods for understanding RNA molecules in cells and viruses. The vision of our laboratory is therefore, first, to invent novel chemical microscopes that reveal quantitative structure and function interrelationships for RNA and, second, to apply these RNA technologies to broadly important problems in biology. Mentoring and research in the lab are highly interdisciplinary. Students learn to integrate ideas and concepts spanning chemical and computational biology, and technology development, and extending to practical applications in virology, understanding biological processes in cells, and discovery of small molecule ligands targeted against medically important RNAs. Each student has a distinct project which they drive to an impactful conclusion, but do so as part of the lab team which, collectively, has shown an amazing ability to solve big problems in RNA biology. The overarching goal of mentoring in the lab is to prepare students for long-term leadership roles in science.
Pathobiology & Translational Science
The overall objective of our research is to understand the connection between structure of protein-DNA complexes, protein dynamics and function. We currently focus on the methyl-cytosine binding domain (MBD) family of DNA binding proteins. The MBD proteins selectively recognize methylated CpG dinucleotides and regulate gene expression critical for both normal development and carcinogenesis. We use a combination of NMR spectroscopy and biophysical analyses to study protein-DNA and protein-protein complexes involving the MBD proteins. Building on these studies, we are developing inhibitors of complex formation as potential molecular therapeutics for b-hemoglobinopathies and cancer.