The work in this laboratory is focused on mechanisms underlying motor coordination in mammalian systems. These mechanisms are to be found in the structure and dynamic properties of the musculoskeletal system as well as in the organization of neuronal circuits in the central nervous system. Our work concerns the interactions between the musculoskeletal system and spinal cord that give rise to normal and abnormal movement and posture, and in the manner in which central pattern-generating networks are modified for specific motor tasks. Our studies have applications in several movement disorders, including spinal cord injury. The experimental approaches span a number of levels, from mechanical studies of isolated muscle cells to kinematic measurements of natural behavior in quadrupeds.
My laboratory studies a category of lipids, termed sphingolipids, that are important in cell structure, cell-cell communication and signal transduction. This research concerns both complex sphingolipids (sphingomyelins and glycosphingolipids) and the lipid backbones (ceramide, sphingosine, sphingosine 1-phosphate and others) that regulate diverse cell behaviors, including growth, differentiation, autophagy and programmed cell death. The major tool that we use to identify and quantify these compounds is tandem mass spectrometry, which we employ in combination with liquid chromatography for "lipidomic" analysis and in other mass spectrometry platforms (e.g., MALDI) for "tissue imaging" mass spectrometry. To assist interpretation of the mass spectrometry results, and to predict where interesting changes in sphingolipid metabolism might occur, we use tools for visualization of gene expression data in a pathway context (e.g., a "SphingoMAP"). These methods are used to characterize how sphingolipids are made, act, and turned over under both normal conditions and diseases where sphingolipids are involved, such as cancer, and where disruption of these pathways can cause disease, as occurs upon consumption of fumonisins. Since sphingolipids are also components of food, we determine how dietary sphingolipids are digested and taken up, and become part of the body's "sphingolipidome."
Immunoengineering, cancer, metastasis, immunotherapy, drug delivery
Dr. Thomas’s research focuses on the role of biological transport phenomena in physiological and pathophysiological processes. Her laboratory specializes in incorporating mechanics with cell engineering, biochemistry, biomaterials, and immunology in order to 1) elucidate the role mechanical forces play in regulating seemingly unrelated aspects of tumor progression such as metastasis and immune suppression as well as 2) develop novel immunotherapeutics to treat cancer.
Cancer progression is tightly linked to the ability of malignant cells to exploit the immune system to promote survival. Insight into immune function can therefore be gained from understanding how tumors exploit immunity. Conversely, this interplay makes the concept of harnessing the immune system to combat cancer an intriguing approach. Using an interdisciplinary approach, we aim to develop a novel systems-oriented framework to quantitatively analyze immune function in cancer. This multifaceted methodology to study tumor immunity will not only contribute to fundamental questions regarding how to harness immune response, but will also pave the way for novel engineering approaches to treat cancer such as with vaccines and cell- or molecular-based therapies.
Neuroengineering tools and robotics, ultra-high throughput genomics and molecular measurement instrumentation; 3-D microfabrication and bioMEMS technologies for neuroscience and genomics applications; and micro-lenslet arrays
The Precision Biosystems Laboratory is focused on the creation and application of miniaturized, high-throughput, biological instrumentation to advance genetic science. The development of instruments that can nimbly load, manipulate, and measure many biological samples—not only simultaneously, but also more sensitively, more accurately, and more repeatably than under current approaches—opens the door to essential, comprehensive biological system studies.
Our group strives to develop these tools, validate their performance with meaningful biological assays, and with our collaborators, pursue discoveries using the instruments. These instruments, and the discoveries they enable, could open new frontiers for the design and control of biological systems.
Development of novel polymeric biomaterials, regeneration of tendon/ligament, protein delivery for orthopaedic tissue engineering.
The goal of our laboratory is to design polymeric biomaterials for specific orthopaedic applications, including regeneration of tendon/ligament, cartilage and bone. These synthetic and naturally-derived biomaterials are used in conjunction with other biochemical and mechanical stimuli to promote priming of stem cells to express a particular phenotype, as well as deliver biomolecules to promote healing of tissues that have degenerated due to chronic conditions, such as osteoarthritis or overuse injuries.
Current research is directed at understanding the origin and evolution of RNA assemblies and activities that gave rise to RNA-based genetic and metabolic systems, and the interaction of a bacterial RNA-binding protein Hfq that is crucial for the regulation of gene expression by short regulatory RNAs.
The first research area is examining the assembly and activities of RNA under plausible early earth conditions ( e.g. anoxic environment, freeze-thaw cycles of aqueous solutions). We have shown that Fe2+can replace Mg2+ and enhance ribozyme function under anoxic conditions. Fe2+ was abundant on early earth and may have enhanced RNA activities in an anoxic environments. Freeze-thaw cycles can also promote RNA assembly under conditions where degradation is minimized.
The second area of research is investigating the mechanism of the Hfq protein. Hfq is a bacterial RNA-binding protein that facilitates the hybridization of short non-coding regulatory RNAs (sRNA)to their target regions on specific mRNAs. sRNAs are important elements in the regulation of gene expression for bacteria.Hfq is highly conserved among bacterial phyla and has been shown to be a virulence factor in several bacterial species. The interactions of wild type and mutant Hfq proteins with various RNAs are examined using biochemical/ biophysical methods such as the electrophoresis mobility shift assay, fluorescence spectroscopy, and mass spectrometry.
Nature has provided us with an arsenal of agents that have proven clinically useful in the treatment of many human diseases, and this is particularly apparent for infectious diseases and cancer. Resistance to current anticancer and antimicrobial chemotherapies will always necessitate the discovery and development of additional therapeutic compounds, both by screening of natural products and by synthetic design. Biosynthetic engineering is a promising tool that could be coupled with these proven techniques to generate novel bioactive metabolites. Dr. Kelly's group examines natural products biosynthesis and its applications from chemical and microbiological perspectives.
Dr. Kelly's group is interested in the biosynthesis of polyketide and nonribosomal peptide antibiotics in addition to the biosynthesis of post-translationally modified peptide antibiotics. We aim to understand the assembly of central scaffolds that appear in families of metabolites that vary in their biological activity according to unique peripheral modifications. This requires a detailed understanding of the enzymes responsible for construction of these molecules, including their catalytic mechanism and substrate specificity. Strategies and techniques from organic chemistry, biochemistry, molecular biology, and microbiology will be infused together to accomplish this task. Ultimately, we will apply the information gleaned from these studies to direct the biosynthesis of designer metabolites possessing antimicrobial or anticancer activities.
Microbiology, quorum sensing, regulatory small RNAs, signal transduction, host-pathogen interactions, microbial biofilms.
Our lab studies molecular mechanisms important for microbial interactions. Bacteria are genetically encoded with regulatory networks to integrate external information that tailors gene expression to particular niches. Bacteria use chemical signals to orchestrate behaviors that facilitate both cooperation and conflict with members of the communities they inhabit. We use genetics and genomics, biochemistry, bioinformatics, and ecological approaches with a focus on the waterborne pathogen Vibrio cholerae.
Computational genomics for public health. We are broadly interested in the relationship between genome sequence variation and health outcomes. We study this relationship through two main lines of investigation – human and microbial. Human: we study how genetic ancestry and population structure impact disease prevalence and drug response. Our human genomics research is focused primarily on complex common disease and aims to characterize the genetic architecture of health disparities, in pursuit of their elimination. Microbial: we develop and apply genome-enabled approaches to molecular typing and functional profiling of microbial pathogens that cause infectious disease. The goal of our microbial genomics research is to empower public health agencies to more effectively monitor and counter infectious disease agents.