Our Faculty

Bio

David A. Bernlohr, PhD, is the Distinguished McKnight Professor and Head of the Department of Biochemistry, Molecular Biology and Biophysics and the Cargill Chair in Systems Biology of Human Metabolism. His lab focuses on the metabolic relationships between obesity and insulin action. The lab specifically examines cytoplasmic fatty acid binding proteins and their role(s) in mediating fatty acid metabolism in adipocytes and macrophages, particularly leukotriene synthesis.

Research Summary

Age is associated with increased inflammation, visceral adiposity and metabolic disease. Tissue resident immune cells are required for dampening inflammation and maintaining tissue homeostasis. There are changes in resident immune cells that drive the increased inflammation and metabolic impairments that are seen with increased age. We are studying the cellular and molecular changes within tissue resident immune cells that drive metabolic impairments in tissues. In particular, we are focused on lipolysis, a metabolic process that is required for release of energetic substrates from stored triglycerides in adipocytes. Lipolysis is impaired in aged individuals and this impairment may contributes to a worsened ability of elderly to maintain a healthy body-weight, stay warm or exercise. Our work has previously shown that adipose tissue immune cells reside in microenvironment niches and are able to inhibit lipolysis in the aged adipose tissue. There are two broad projects within the lab: Adipose tissue macrophage-specific regulatory effects on lipolysis and inflammation during aging Fat-associated lymphoid cluster (FALC) and lymphocyte regulation of metabolism Our lab focuses on mouse models of aging and uses a wide variety of techniques to investigate the changes occurring with age. We combine this in vivo approach with a complementary in vitro cell culture system to better understand a direct mechanism. Ultimately, our goal is to generate candidates that could be targets for therapeutically treating to improve health span and restore metabolism in the elderly.

Research Summary

My long-term goal is to discover and characterize novel posttranslational modification (PTM) pathways that are involved in protein homeostasis, cellular signaling and epigenetic regulation. To achieve this goal, I develop and apply mass spectrometry-based quantitative and chemical proteomics technology as well as bioinformatic analysis tools for system-wide characterization of protein modification networks. My work employs both cellular and animal-based models that involve diverse biological applications including cancer, metabolic diseases, nutrition and aging.

Research Summary

We collect multiplatform (including genomic, transcriptomic, proteomic, metabolomic) data from human breast cancer cell lines, animal models and patients. Analyze these data using machine learning and artificial intelligence based algorithms to build predictive models of drug resistance. Finally, we validate model predictions mechanistically in experimental in vitro and in vivo models.

Dr. Clarke’s research is involved in mechanistic translational and transdisciplinary studies in breast cancer, with an emphasis on endocrine responsiveness and drug resistance. Focusing initially on the interactions of hormones and cytotoxic drugs in breast cancer cells, research expanded into studies of the cellular and molecular mechanisms of how breast cancers become resistant to endocrine and cytotoxic therapies. Dr. Clarke’s laboratory takes a systems biology approach, applying state-of-the-art ‘omics’ (genomic, transcriptomic, proteomic, metabolomic), bioinformatic, cellular and molecular biologic technologies to cell cultures, animal models, and human specimens from clinical studies. A long time collaboration with computer scientists and engineers has enabled much of this work.

Bio

Administrator Info

Vice Dean of Research Role 

Name: Christina Clarkson

Division of Molecular Medicine Role 

Name: Kelly LaPara
Email: schot014@umn.edu
Mail: 420 Washington Ave SE, MMC 194, Minneapolis, MN 55455

Summary
Obesity and cardiovascular disease are among the leading causes of morbidity and mortality worldwide. Our research focuses on the interplay between intermediary metabolism and these disease processes. Derangements in the processing of carbohydrates, fats, and amino acids are central drivers of disease pathogenesis, but the roles of another metabolic fuel class, ketone bodies, are less well understood. We use novel genetic mouse models with engineered deficiencies in ketone body metabolism to study the metabolic shifts that occur in response to obesity, cardiovascular disease, and dynamic environmental challenges. From these models, we have developed new perspectives of how metabolism adapts in obesity, diabetes, nonalcoholic fatty liver disease (NAFLD/NASH), and cardiomyopathy; how these adaptations ultimately prove deleterious, and how innovative and personalized nutritional and pharmacological therapies may mitigate these adverse responses.

We leverage recent advances in stable isotope tracer based NMR and mass spectrometry-based untargeted metabolomics technologies to study metabolism on a systems level, and we also employ established techniques in molecular cell biology and biochemistry to reveal phenotypic shifts at the cellular level. Complex in vivo phenotyping methodologies are strategically aligned with these sophisticated chemical profiling platforms to generate high resolution phenotypic pictures. In addition to our mouse studies, we perform studies in humans to learn how alterations of ketone metabolism and related pathways may serve as diagnostic biomarkers and therapeutic targets for obesity, diabetes, NAFLD/NASH, heart failure/CHF, and metabolic maladaptations that can occur in any disease state.

Teaching Summary

Metabolic Biochemistry

Clinical Summary

Heart Failure

Research Summary

Agrobacterium tumefaciens incites crown gall tumor disease on plants. The bacterium transfers a segment of its plasmid-borne DNA to plant cells using a type IV secretion apparatus assembled at a cell pole. My research focuses on the mechanism of polar assembly of the secretion apparatus and that of substrate translocation.

Research Summary

The Elias Lab investigates the mechanisms by which biological molecules evolve, the molecular basis of their functions, and develop methods for their engineering, with the aim of developing efficient, soft solutions to current or emerging society issues.

Research Summary

My laboratory primarily studies the structure and cellular function of the dystrophin-glycoprotein complex, which spans the muscle cell plasma membrane (or sarcolemma) and links the cortical actin cytoskeleton with the extracellular matrix. Greater understanding of the physiologic role of the dystrophin-glycoprotein complex is necessary to understand how its absence or abnormality leads to Duchenne muscular dystrophy and forms of human dilated cardiomyopathy. The lab has defined the complete actin-binding region of 400 kDa dystrophin and shown that its homologue utrophin binds actin filaments through a distinct molecular mechanism. Novel methods to visualize the sarcolemmal cytoskeleton without interference from internal structures provided the first evidence that dystrophin functions in vivo to mechanically stabilize ?-actin filaments in costameres. Studies of dystrophin-deficient mice and new animal models generated by the lab have provided insight into the function of costameres in striated muscle and suggest novel links between dystrophin deficiency and alterations in cell signaling, or gene expression manifest by dystrophic muscle. My lab's unique capability to express biochemical amounts of full-length dystrophin and utrophin has made possible new studies to i) characterize the effects of dystrophy-causing point mutations on dystrophin structure/function, ii) to identify novel associated proteins and iii) to develop new protein-based therapies for dystrophinopathies. In a completely new line of investigation, my group is working to determine the potentially unique roles of non-muscle actin isoforms in the establishment/maintenance of cell polarity in a variety of tissues. The ?- and ?-isoforms of actin distribute to distinct locations within a variety of polarized cell types, including neurons, epithelial cells, and hair cells of the inner ear yet ?- and ?-actin differ from each other by only 4 amino acids. Using new isoform-specific reagents and conditional knock-out mouse lines developed during the course of our muscular dystrophy studies, the lab is now working to identify non-overlapping functions of these two highly conserved and widely expressed proteins.

Research Summary

My research interests involve engaging students in structural biology/biophysics collaborations in the Medical School and College of Biological Science. Primary methodologies include macromolecular x-ray diffractometry (x-ray crystallography), computer modelling and analysis, instrument design, and computer programming for XRC process pipeline automation.

Research Summary

My lab is interested in how small molecules known as natural products are made in the environment. We are especially interested in natural products produced by uncultivated microbial ‘dark matter’ and those produced by unconventional bacterial and fungal sources. For more information, please visit our lab website.

Research Summary

The Goldstrohm Lab seeks to discover the mechanisms that control translation, stability, and localization of mRNAs and to identify the networks of genes that are coordinately regulated by RNA-binding proteins and ribonucleases. Our discoveries are broadly relevant, with particular importance to stem cell and developmental biology. The results of our work will promote development of therapeutic approaches to correct deleterious gene expression in cancer and neurological diseases.

Research Summary

The Gordon Lab is interested in how cell surface receptors convert signals from extracellular stimuli like mechanical force into a biological response, as dysregulation in a cell's force-sensing ability can lead to disease. We use X-ray crystallography and other biophysical methods to ask what "mechanosensors" look like in order to understand the range of structures nature uses to sense forces of different magnitudes and in different contexts, and hopefully identify potentially novel therapeutic targets. We also use and develop single molecule and cell-based assays based on magnetic tweezers to apply forces to mechanosensors to probe how mechanosensors are converted from an "off" to "on" state. We measure both magnitudes of forces to effect a biological response and are developing methods to probe the corresponding structural changes that occur. Finally, we are developing general signaling assays to help us map mechanosensor domains, understand differences between on and off states, and search for new potential mechanosensors.

Research Summary

Work in my group focuses on the development and application of mass spectrometry-based tools to study proteins and proteomes. The goal of this work is to provide the necessary tools to enable the system-wide characterization of proteins expressed within a cell, tissue, biological fluid or organism, in order to better understand basic mechanisms of biological function and disease. My group also works on the Galaxy for proteomics, or Galaxy-P project, which focuses on "multi-omic" analysis integrating genomic, proteomic and metabolomic data to gain new insights into biological systems. Our work is highly interdisciplinary and collaborative, working across the fields of analytical chemistry, computer science and biochemistry. We work with numerous researchers to apply our tools and technologies to problems of biological and biomedical importance.

Research Summary

Enzymes function in the natural world to digest nutrients, build structures as plants ans animal grow and construct complex molecules. Protein engineering can adapt these natural enzymes to industrial, medical and agricultural applications to make them more efficient and sustainable. My group engineers enzymes to catalyze new reactions to expand the range of molecules that they can make, to act faster on plastics to break them down for recycling and to help animals digest feed more efficiently.

Bio

The Kim Lab is interested in understanding the molecular networks that coordinate nutrient metabolism and cell growth. How cells assess nutrient- or energy states and relay this information into appropriate decisions on growth is poorly understood. Coordinate regulation of nutrient metabolism and cell growth is of fundamental importance, and many human diseases, such as cancer, diabetes, and developmental disorders, are affected by alterations in this process.

Research Summary

mTOR signaling network

Our research is focused on the mTOR signaling network that plays a crucial role in controlling cell growth in response to nutrient levels and growth factors. mTOR binds several proteins to form two distinct protein complexes. mTORC1 (mTOR complex 1) contains raptor (KOG1 ortholog), Gbl/mLst8, PRAS40 and DEPTOR, whereas mTORC2 (mTOR complex 2) conatins rapamycin insensitive companion of mTOR (rictor) (Avo3 ortholog), GbL/mLst8, Sin1 (Avo1 ortholog), PRR5/protor and DEPTOR. In spite of considerable efforts, it has not been possible to obtain a clear understanding of the molecular mechanisms by which the mTOR network is regulates by nutrient- and growth factor-signals. Utilizing novel molecular biology and biochemical tool as well as a variety of structural approaches, we identify novel components and connectivity in the network and determine biological functions and signaling specificity thereof. Our recent studies have led us to identify PRAS40 and PRR5 as key components of mTORC1 and mTORC2. We investigate the functions of these newly-identified components in the regulation of cell growth and metabolism with links to human diseases such as cancer and diabetes. We anticipate this study will advance our understanding of the molecular bases underlying the coordinate regulation between metabolism and growth during animal development and the pathogenesis of metabolic diseases such as cancer and diabetes.

Autophagy pathway

As a crucial pathway downstream of mTOR, autophagy (cellular self-eating) plays an important role for metabolic homeostasis and cellular survival. Autophagy is an evolutionarily-conserved process through which cytoplasm, organelles, or long-lived proteins or protein aggregates are sequested in a double-membrane structures and subsequently degraded in lysosomes. Through destruction of cellular organelles and proteins, autophagy provides energy for starved cells or allows for balanced regulation between biogenesis and degradation of cellular structures, thereby playing important roles in growth, survival, differentiation, and development. Dys-regulation of autophagy is associated with many human diseases including cancer, myopathies, innate immunity, and neurodegenerative diseases such as Parkinson's and Huntington's diseases. Autophagy is induced when cells are starved of nutrients or mTOR is inhibited. Our recent study revealed that ULK1 and ULK1 protein kinases play key roles in autophagy induction in mammalian cells. We determined that mTORC1 phosphorylates ULK1 and ULK2 to inhibit the kinase functions. Later, studies from other groups identified that AMPK phosphorylates and positively regulates ULK1. We investigate how mTORC1 and AMPK regulate ULK functions with focus on its phosphorylation and its interaction with Atg13 and FIP200. We also study the shared and distinct functions of ULK1 and ULK2 in autophagy and non-autophagy processes.

mTORC1-regulated immunoproteasome assembly pathway

Protein stress, such as misfolded protein aggregates and oxidized proteins, occurs in many human diseases, including cancer, diabetes, neurodegeneration, and age-related pathol- ogies. One major source of protein stress originates when the ribosomal protein synthesis is upregulated with a consequential reduction of translational fidelity, producing defective ribosomal products. Prevalent in many cell growth disorders, such cancer and tuberous sclerosis complex (TSC), mutations of PTEN (phosphatase and tensin homolog), RAS, TSC1 (tuberous sclerosis complex 1), or TSC2 commonly enhance the activity of mTORC1 (mechanistic target of rapamycin complex 1). Hyper-activation of mTORC1, the central regulator of the ribosomal protein synthesis, can reduce translational fidelity as a result of increased rates of ribosomal elongation. The resulting aberrant proteins, if not properly removed, can cause cell death or contribute to human diseases.Our recent study showed that mTORC1 promotes the formation of immunoproteasomes for efficient turnover of defective proteins and cell survival. mTORC1 sequesters precursors of immunoproteasome beta subunits via PRAS40. When activated, mTORC1 phosphorylates PRAS40 to enhance protein synthesis and simultaneously to facilitate the assembly of the beta subunits for forming immunoproteasomes. Consequently, the PRAS40 phosphorylations play crucial roles in clearing aberrant proteins that accumulate due to mTORC1 activation. Mutations of RAS, PTEN, and TSC1, which cause mTORC1 hyperactivation, enhance immunoproteasome formation in cells and tissues. Those mutations increase cellular dependence on immunoproteasomes for stress response and survival. The results have defined a mechanism by which mTORC1 couples elevated protein synthesis with immunoproteasome biogenesis to protect cells against protein stress. The novel pathway (mTORC1-immunoproteasome) may regulate many other cellular and physiological processes, and its disturbance may lead to human diseases associated with cancer, neurodegenerative diseases, and autoimmune diseases.

Bio

Doug Mashek, PhD, is currently a professor with a primary appointment in the Department of Biochemistry, Molecular Biology and Biophysics (BMBB) and a secondary appointment in the Department of Medicine, Division of Diabetes, Endocrinology and Metabolism. Dr. Mashek earned his B.S. from Iowa State University, M.S. from Michigan State University and Ph.D. from the University of Wisconsin. Doug did his postdoctoral training in Nutritional Biochemistry at the University of North Carolina-Chapel Hill.

Research Summary

Research in the Mashek Lab focuses on the relationship between lipid metabolism and the development of metabolic and aging-related diseases. A primary emphasis is on studies involving lipid droplet biology in the context of non-alcoholic fatty liver disease, Type 2 Diabetes, cancer and aging. A major focus is on understanding how lipid droplets are catabolized and how they communicate within cells to influence cell function. We also conduct pre-clinical and clinical studies to determine how alterations in diet and dietary patterns (fasting, time-restricted feeding, etc.) and exercise alter metabolism to improve health.

Research Summary

My research in structural biology is aimed at understanding cell adhesion at the molecular level where protein-protein and protein-carbohydrate interactions are critical. Biomolecular conformations and interactions are analyzed primarily by using high resolution NMR spectroscopy, circular dichrosim spectropolarimetry and computer modeling. As models for these interactions, for example, we are studying the solution conformations of platelet factor-4 cytokine family proteins and haparin-derived short-chain glycosaminoglycans. We also are interested in studying protein/peptide dynamics and intra- and intermolecular forces which stabilize native structure. In collaboration with Drs. Jim McCarthy and Leo Furcht, we are identifying cell adhesion - promoting peptides derived, for example, from fibronectin, laminin and type IV collagen. Computer models of these structures then allow us to design constrained peptides which have the same conformation and similar biologic activity. Ultimately, my work will aid in the rational design of pharmaceutical drugs which help to control the spread of cancer, to combat stroke and heart disease, or to reduce viral infection.

Research Summary

The Mendonça Lab uses integrative imaging approaches (cryoEM/ET, cryoFIB/SEM, CLEM) to investigate cellular pathways exploited by RNA viruses and identify novel molecular targets for therapeutic interventions. Our research has the potential to reveal molecular weak links to be exploited to fight viral diseases such as AIDS and COVID-19.

Bio

Sharon Murphy, PhD, is a professor in the Department of Biochemistry, Molecular Biology and Biophysics and the Director of Graduate Studies. Dr. Murphy received her Doctorate from the University of Colorado. Her research interest include nicotine metabolism in smokers and are on-going to investigate the influence of individual differences in nicotine metabolism on smoking behavior and nicotine dependence. Her studies in the laboratory have characterized P450 2A6 and P450 2A13-catalyzed metabolism of both nicotine and cotinine. P450 2A6, which is present in human liver is 94% identical to the extrahepatic enzyme, P450 2A13 found in the lung. Recently her laboratory determined that both enzymes are inactivated during nicotine metabolism, and are investigating the mechanism of this inactivation. P450 2A6 and P450 2A13 are also catalysts of the metabolic activation of the tobacco specific carcinogens NNN and NNK. However, despite the similarity of these two enzymes, they catalyze NNK metabolism with strikingly different efficiencies. Metabolism by site directed mutagens of these two enzymes are being studied to investigate these structure activity relationship. Polymorphisms of both P450 2A6 and P450 2A13 exist and her laboratory and others are studying the influence of enzyme variants on nicotine and nitrosamine metabolism.

Research Summary

My laboratory studies the activation and detoxification pathways of nicotine and carcinogens; investigating the role of these pathways in tobacco carcinogenesis. We use LC-MS/MS based methods to quantify nicotine and carcinogen exposure and metabolism in people. In collaborations with geneticists and epidemiologists, we study the contribution of enzyme variants and individual differences in metabolism to lung cancer risk.

Bio

Laura Niedernhofer, MD, PhD, joined the University of Minnesota in July 2018 to direct the new Institute on the Biology of Aging & Metabolism (iBAM) and Medical Discovery Team on the Biology of Aging. She is a professor in the Department of Biochemistry, Molecular Biology and Biophysics. Dr. Niedernhofer’s expertise is in DNA damage and repair, genome instability disorders, cellular senescence and aging. Her research program is centered on studying fundamental mechanisms of aging and developing therapeutics to target them. Her research program implements a murine model of a human progeroid syndrome caused by a defect in DNA repair. She contributed to the discovery of a new class of drugs called senolytics. Dr. Niedernhofer has served on study section for NCI, NIEHS and NIA. She has been awarded for research in aging, cancer and environmental health science. 

Research Summary

Dr. Niedernhofer's research career has been dedicated to investigating the impact of DNA damage on the structure of DNA, cell function and organism health. The DNA in each of our cells is damaged thousands of times per day by exposure to environmental factors, dietary components, chemotherapeutic agents and even endogenous by-products of normal metabolism. Studying patients with rare diseases caused by inherited defects in DNA repair provides important insight into the consequences of DNA damage. These patients have a dramatically increased risk of cancer and age prematurely. The Niedernhofer Lab has engineered mouse models of these genome instability syndromes as a sensitive tool to test hypotheses about how DNA damage promotes cancer and aging.

Research Summary

My lab is interested in the structural foundations for biological function. Just as a picture is worth a thousand words, we believe a structure is worth a thousand pictures.

Research Summary

The Parker lab focuses on assay development for post-translational modifications, with an emphasis on protein phosphorylation by tyrosine kinases. Our team uses chemical biology and proteomics to develop tests to quickly screen for better inhibitor drugs, and/or determine effectiveness of inhibitors to improve patient outcomes during cancer treatment.

Research Summary

Research in the Rivera-Mulia Lab is focused on understanding the mechanisms that control the genome organization and function during development, as well as their alterations in human diseases. We are exploiting differentiation protocols of induced pluripotent stem cells (iPSCs) derived from patients to model disease progression and genomic technologies to characterize nuclear organization.

Bio

Dr. Paul Robbins is a Professor of Biochemistry, Molecular Biology and Biophysics and the Associate Director of the Institute on the Biology of Aging and Metabolism (iBAM) and the Medical Discovery Team on the Biology of Aging at the University of Minnesota.

He was one of the first to identify enhancer elements that regulate transcription at a distance, the first to show that the retinoblastoma tumor suppressor regulates transcription and the first to develop gene therapies for autoimmune disease including an ongoing clinical trial for osteoarthritis. More recently, he was part of a collaborative team that was the first to identify senotherapeutic compounds, able to reduce the senescent cell burden and extend healthspan and lifespan in mouse models, that are in more than 15 clinical trials for age related diseases and conditions.

Research Summary

The pathways important for driving autoimmune and inflammatory diseases as well as age related degeneration are surprisingly similar. For example, inhibition of the transcription factor NF-?B is therapeutic in mouse models of autoimmunity and inflammation as well as Duchenne muscular dystrophy and aging. Similarly, inhibition of IL-1ß signaling by gene transfer of the IL-1 receptor antagonist protein is therapeutic in multiple models of diseases. The Robbins Lab is developing novel approaches to treat autoimmune (type 1 diabetes, rheumatoid arthritis), inflammatory (inflammatory bowel disease, delayed type hypersensitivity) and age-related degenerative diseases using biologics and small molecules. The therapeutic approaches being developed include: 1) AAV mediated gene transfer of anti-inflammatory or immunosuppressive agents; 2) Peptide and small molecule inhibitors of the transcription factor of NF-?B; 3) Novel osteogenic peptides; 4) Adult stem cells; 5) Microvesicles (exosomes) derived from immunoregulatory or stem cells able to block inflammation or promote regeneration; and 6) Identification of drugs able to reverse cellular senescence for improving healthy aging. Although the majority of the studies are being performed in mouse models of disease, approaches to treat osteoarthritis by intra-articular AAV-mediated gene transfer and Duchenne muscular dystrophy by systemic treatment with a NF-?B inhibitory peptide will soon be entering the clinic.

Research Summary

Most eucaryotic genes are controlled by developmental, hormonal, tissue-specific, and/or nutritional cues. Insight into these complex regulatory events is fundamental to our understanding of the processes controlling cellular proliferation and oncogenesis, differentiation, and development. The long-term goal of the research in my laboratory focuses on investigating how estrogen and testosterone regulate gene expression, both physiologically and pathologically. To address this, we are investigating the structure and function of the estrogen- and testosterone-responsive ZEB-1 (delta EF1) transcription factor.

Bio

Dr. Claudia Schmidt-Dannert is a Distinguished McKnight Professor and Kirkwood Chair of Biochemistry in the Department of Biochemistry, Molecular Biology and Biophysics. She is also the Director of the BioTechnology Institute at the University of Minnesota.

She completed her BS and MS in Biochemistry and Genetics at the TU Braunschweig and performed her PhD research at the National Research Center for Biotechnology (GBF, now Helmholtz Centre for Infection Research) in Braunschweig. She then moved to the University of Stuttgart, and after a brief postdoctoral time, led he Molecular Biotechnology Group in the Institute of Technical Biochemistry as “Habilitant”. In 1998, she received a habilitation-fellowship from the German Science Foundation for her research proposal on in vitro pathway evolution and with this project, joined 2018 Chemistry Nobel Laureate Prof. Frances Arnold’s group at the California Institute of Technology to carry out her research on “molecular breeding of pathways” using carotenoid biosynthesis as a model system. In 2000, she joined the faculty at the University of Minnesota.

Research Summary

One area of current research focuses on the design self-organizing systems from genetically encoded protein building blocks for applications in biocatalysis, biosynthesis and as functional materials. We are also engineering microbial cells to produce living materials and biocomposites as well synthetic biofilms with tailored functions. Another long-standing interest in our lab is the discovery and design of biosynthetic pathways (for example from mushrooms) for the production of pharmaceutically relevant compounds.

Research Summary

Microbial-based Cancer Therapies; Regulation of Gene Expression; Stress ResponsesOne of my primary research interests is the development of microbial-based therapies for cancer. An attenuated strain of Salmonella enterica Typhimurium is currently used in these studies. This organism is a gram-negative facultative bacterium that can invade and divide with macrophages and other cell types and thrives in hypoxic areas of tumors. Previous reports have indicated that administration of this organism significantly reduced tumor size and number in mouse models of metastatic osteosarcoma, primary neuroblastoma and liver adenocarcinoma. Current work is focused on optimizing the cancer suppressing activity of this bacterium by expressing various genes that modulate the immune system and determining the most effective protocol for administration of this organism to the mice with potential future applications to humans. Another research interest focuses on the regulation of gene expression in cells in response to stresses such as desiccation, nutrient deprivation, culture density, osmotic stress, heat shock, and mechanical stress. Our approaches include studying the regulation of transcription, mRNA degradation and protein synthesis in cells grown under a variety of culture conditions.

Research Summary

The Seelig Lab implements Darwinian molecular evolution in a test tube to generate novel proteins for synthetic biology and biomedical applications, to study the origin and evolution of functional proteins, and to investigate the history of the genetic code. We generate de novo proteins with custom-made properties through in vitro and in vivo selection and evolution. We study our new proteins in detail to help elucidate fundamental principles of protein biochemistry and the origin of protein-based life.

Research Summary

Virtually all genes in higher organisms are interrupted by regions of noncoding DNA called introns. These introns must be removed from messenger RNA precursors to allow proper gene expression. The process of pre-mRNA splicing is responsible for accurately identifying introns and catalyzing their excision. A fundamental challenge in modern molecular biology is to understand how the splicing apparatus specifically recognizes and removes introns. Because the splicing machinery is highly conserved throughout evolution, my laboratory approaches this question using the genetic and biochemical tools available uniquely in the yeast Saccharomyces cerevisiae.

Research Summary

The Smanski Lab leverages the latest tools in DNA synthesis, assembly, and genome modification to engineer biotechnologies that address global problems in health, agriculture, and the environment.

Bio

The Thomas Lab studies fundamental molecular motions and interactions that are responsible for cellular movement, to determine the molecular bases of muscle disorders, and to devise novel therapies based on these discoveries.

Research Summary

Our goal is to understand the fundamental molecular motions and interactions that are responsible for cellular movement, to determine the molecular bases of muscle disorders, and to devise novel therapies based on these discoveries. We approach this multidisciplinary problem with a wide range of techniques -- physiology, enzyme kinetics, molecular genetics, peptide synthesis, computer simulation -- but our forte is site-directed spectroscopic probes. After attaching probes (spin labels, fluorescent dyes, phosphorescent dyes, or isotopes) to selected muscle proteins in solution or in cells, we perform magnetic resonance or optical spectroscopy to directly detect the motions of the force-generating proteins, actin and myosin, or the membrane ion pumps and channels responsible for muscle excitation and relaxation. These same tools are then used to test the efficacy of gene or drug therapies designed to treat heart failure or muscular dystrophy. Our research involves several types of muscle, but the laboratory focuses increasingly on the heart. Indeed, our newest and most exciting direction is to use the principles of structural biophysics to design new molecular therapies for heart failure. This is an extremely ambitious and high-risk goal, but we are in a unique position to achieve it, due to an unparalleled combination of technologies, insights, and expert collaborators. As a result of these advances, we have started a company, Photonic Pharma LLC, with the goal of commercializing our discoveries in the field of drug discovery.

Research Summary

The Truong Lab is focused in the areas of cancer stem cells (CSCs), therapy resistance, steroid receptors (SRs), and cancer metabolism. Our research aims to define the molecular links between oncogenic signaling and altered metabolic events in breast cancer progression and metastasis that contribute to endocrine and chemotherapy resistance.

Research Summary

The Veglia Lab focuses on two critical aspects of cell regulation: cAMP-mediated cell signaling and calcium transport. These events are orchestrated by soluble and membrane-bound protein complexes. To characterize their structure, dynamics, and interactions, we utilize a multidisciplinary approach combining solution and solid-state NMR spectroscopy with other biophysical methods. Our goal is to understand how these protein complexes mediate allosteric signal transduction in cells and how pathological mutations of these proteins are linked to diseases.

Research Summary

The Wackett Lab investigates enzyme transformations for biotechnological applications. The applications focus on biodegradation for environmental purposes and biocatalysis for producing specialty chemicals or detection kits. The biodegradation research is now directed toward the treatment of waters generated during the process of hydraulic fracturing to obtain oil and gas from shale resources. We also study the biodegradation ofs-triazine compounds such as the herbicide atrazine and pool water chemical cyanuric acid. The biocatalysis research is heavily focused on better understanding the enzymatic basis of bacterial hydrocarbon biosynthesis. Renewable hydrocarbons are currently of interest as fuels or feedstocks. The Wackett Lab also studies enzymes that degrade food adulterants to use them for developing detection systems. For example, we had previously worked with Bioo Scientific to help develop the MaxSignal Melamine kit for detection melamine in milk and other food products.

The Wackett Lab studies microbial enzymes and pathways for biocatalysis and biodegradation and helped build theBiocatalysis/Bioegradation Database.Cyanuric acid hydrolase X-ray structure showing bound inhibitor in center. The Wackett Lab investigates microbial biodegradative metabolism and enzymes. In one example, bacteria initiate metabolism of atrazine via the enzyme atrazine chlorohydrolase for which we first reported the structure (Seffernick, et al, 2010). In collaboration with Hideki Aihara’s group, we have defined the novel cyanuric acid hydrolase protein family (Seffernick, et al, 2012) and more recently, the X-ray structure.

The Wackett Lab is also studying the biodegradation of acrylamide and polycyclic aromatic hydrocarbons.BioremediationOur studies on biodegradation provide opportunities for bioremediation of chemical contaminants in water. The chemicals treated are atrazine, cyanuric acid, acrylamide, polycyclic aromatic hydrocarbons, benzene and substituted aromatic compounds. Biodegrading microbes are being deployed in silica microspheres. The silica encapsulation stabilizes thein vivoenzyme activities and makes a formulation that can be stored and used as needed. We are developing specialized silica gels that enhance biotransformation rates and thus have important industrial applications. We have helped found the bioremediation company, Minnepura Technologies Inc. Bacterial hydrocarbon biosynthesisIndustry is interested in renewable hydrocarbons as specialty chemical products. Our research investigates the fundamental mechanistic and structural issues underlying biological hydrocarbon synthesis. Studies are focused on the biosynthesis of long-chain olefins and diesel-length alkanes.

The Wackett Lab is involved in a multi-investigator project to design the RAPID algorithm. RAPID is defined as reactive activity product identification and is a bioinformatics project designed to help predict the reactions catalyzed by broad-specificity enzymes that have significance in biosynthesis and biodegradation.

Research Summary

I determine at the atomic level how enzyme cofactors are synthesized and used. I use X-ray crystallography, spectroscopy, mass spectrometry and freeze-trapping to define these processes both in solution and in crystals of the enzymes.

Research Summary

My research focuses on the reprogramming of gene expression during human pathogenic processes using biochemistry, and molecular and cellular biological approaches. We also integrate numerous Omics (Genomics, Transcriptomics, Proteomics and Metabolomics) approaches into our research to understand pathogenic processes at a global scale. Our current projects are mTOR-regulated transcriptome changes and their functional relevance in the control of alternative splicing and polyadenylation of mRNA, regulation of energy homeostasis, and the reprogramming of chromatin modifications.

Research Summary

Aging is a universal trait that is characterized by a progressive loss of physiological integrity, leading to declined function in tissues and increased vulnerability to disease and death. It has been long hypothesized that the functional decline in aging is caused by genome instability. The general interest of the Zhang Lab focuses on the somatic genome and epigenome instability in aging and longevity. More specifically we study somatic DNA mutations and epi-mutations and their effects on cellular functional decline in normal aging process or age-related diseases. We have been developing experimental approaches of single-cell multi-omics and applying them to discover interactions of genome, transcriptome and epigenome in individual cells from different tissues of humans during aging or species with different maximum life spans.