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Click here for our group's current research poster. Our research centers on the application of chemical engineering principles to the study of fundamental problems in biology and medicine. In particular, we focus on the biochemical and biophysical mechanisms a cell uses to sense, respond to, and interact with its environment. This communication between cells and their surroundings is critical not only to normal mammalian cell function but also to the detection of foreign invaders (immunology) and the response to drugs (pharmacology). An ability to quantitatively understand and manipulate these mechanisms is thus crucial to many areas of modern biotechnology. Receptors, specialized glycoproteins embedded in the membranes of nearly all cells, are responsible for much of the communication between a cell and its environment. Receptors have high affinity binding sites for molecules termed ligands (e.g. hormones, antibodies, drugs) in the cell's local environment. The binding of a ligand to its receptor can result in signal transduction, the translation of the binding event into an intracellular sequence of reactions and an eventual response (e.g. growth, differentiation, contraction, secretion). These receptor-mediated events are critical to both single cell and whole organism function. For example, receptors are vital to the functioning of your brain, the detection of light in your eye, and the functioning of your immune system.  While it is clear that cell receptors need to be bound by ligands in order to initiate a cellular response, the details following that binding are murky. The entire field of signal transduction is exploding in terms of data but lacking in any real understanding of the role that reaction kinetics and diffusion play, for example. We use both experimental and theoretical approaches to understand receptor-mediated phenomena. The impact of this work is in the fields of biology, engineering, mathematical/theoretical biology, pharmacology, biophysics, and bioinformatics.
Research Areas 1. A multi-scale and multi-system approach to understand granuloma formation in TB  Tuberculosis is responsible for 2 million deaths per year. The interplay between host and bacterial factors leads to different disease outcomes (latency, primary tuberculosis, reactivation tuberculosis). A key outcome is the formation of a collection of immune cells termed the granuloma. This structure acts not only as an immune microenvironment and a barrier to dissemination but also as a niche for long-term bacterial survival. The long-term goal of this project is to identify factors that contribute to different outcomes of M. tuberculosis infection. We hypothesize that these different infection outcomes are reflected locally at the level of the granuloma and that granuloma structure is the result of the interplay of events at organ, tissue, cellular, and molecular scales over the time course of minutes to years. Our studies will include multiple spatial and temporal scales to determine how specific immune cells and effector molecules in the lung influence the formation of different granuloma structures, and to identify the mechanisms that determine TNF availability for the purpose of understanding how granulomas form as well as how treatment with anti-TNF-therapies leads to TB reactivation. We are collaborating with a team of investigators on this project. The project team includes JoAnne L. Flynn (Molecular Genetics and Biochemistry, University of Pittsburgh)
2. Models of receptor dynamics, signal transduction, and cell responses   These models may aim to answer many different types of questions. For example, why do different ligands that bind to the same receptor elicit different responses? What types of control strategies might a cell use? What is the purpose of receptor dimerization? Do models of receptor binding and signaling tell us how best to screen for new drugs? How do diffusion and reaction events determine the overall rates of signal transduction and cellular responses? A variety of relevant experimental data for many different systems are available to begin testing these models.
3. Computer modeling for tissue engineering  Tissue engineering is an exciting new field that uses an engineering approach to solve biological problems with clinical significance. Tissue engineers build replacement tissues by seeding cells onto specially engineered polymer scaffolds then delivering the appropriate chemical signals to the cells. Until now, much of the focus of tissue engineering has been on repairing tissues inside the body. This project, however, aims to build fully functioning bones entirely in the laboratory, complete with mineralized tissue, microcirculatory compartments and marrow. These bones could provide extremely novel and life saving biosensors and tissue replacements. The project includes determining the appropriate adult stem cells to seed the polymers with. The polymer scaffolds will be engineered to control osteogenic differentiation. Finally, the scaffolds will be cultured in a bioreactor with well-engineered fluid delivery to promote development of the final bone. We are working with a team of leading investigators in the relevant research areas to accomplish the challenging goal to cultivate the functional bone in vitro. The project team includes S. Takayama (Biomedical Engineering) The mathematical modeling aspect of this project aims to build a quantitative platform to analyze and integrate the information of events at a cellular level to the macroscopic environment. The work attempts to develop a predictive tool, which should link the cell population response to the external environment using the fundamental principles of transport phenomena and cell biology. Models are constructed to quantify the effect of growth factor/nutrient concentration distributions in the bioreactor, and will be used for design optimization of the bioreactor. We are working on engineering tissue culture scaffolds at the nanoscale to alter cell/scaffold adhesive forces. It is hypothesized that such nano–patterned scaffolds can determine the process of cell differentiation to various fates required to form the different tissue types in the bone. We use the help of computer models to investigate and understand the relation between nanoscale organization of adhesion ligands and its influence on cell differentiation.
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