CCAM Director

Professor, Department of Cell Biology, Center for Quantitative Medicine

Lab Website: Mendes Research Group

Research Interests:  My research is in the area of computational systems biology, which aims to better understand biological systems through the use of computer models. My active areas of research include the development of modeling and simulation software as the author of the popular simulator Gepasi and leader of the COPASI simulator (with U. Kummer) and have been actively involved in the development of SBML, the systems biology markup language, and the MIRIAM proposal for model annotation.  My group also constructs biochemical models, currently, this involves models of iron metabolism, eukaryotic translation, and microbial central metabolism. Through this work, I have pioneered the application of numerical global optimization in biochemical kinetic modeling and I am interested in using formal systems identification techniques in systems biology, particularly for reverse engineering models from data.  My research requires a broad interdisciplinary approach and I work with people from most areas of science, either in my own research group or as collaborators.

CCAM Deputy Director
Professor of Cell Biology

Research Interests:  My general research relates to the theoretical understanding of cellular processes, and developing tools for mathematical modeling in cell biology. Current work focuses on interfacing pathway/logic models and –omics data with kinetic quantitative models and dynamic simulations, both on new technology developments and the application to complex modeling of signaling pathways in normal and malignant cells. I am also the current lead developer of the Virtual Cell software platform for mathematical modeling and direct development of both the user interface and computational infrastructure.  In addition, my interest in model reproducibility has led to a powerful new web platform that provides a central portal for simulating a broad range of models of biological systems. I have been involved in community standards for a long time, contributing to the development of both Systems Biology Markup Language (SBML) and Simulation Experiment Description Markup Language (SED-ML).

Director of CCAM Microscopy User Facility
Associate Professor of Genetics and Genome Sciences

Research Interests: Research in our laboratory focuses on developing quantitative imaging tools that reveal dynamics of cellular signaling at high spatial and temporal resolution (biosensors), or that enable optical control of signaling proteins at with temporal and spatial precision (optogenetics). These tools are used with live cell microscopy to understand signaling networks underlying cellular function including cell polarity cell motility, axon guidance, and development of dendritic spines in neurons. In building biosensors, we use structural design strategies with fluorescent proteins to optimize FRET-based activity reporters for signaling proteins.  Multiple live cell imaging modalities are used in the lab including TIRF, confocal, intensity-based ratiometric imaging, and fluorescence lifetime microscopy (FLIM). Optogenetics has generated much interest as it allows precise control of signaling in living systems using genetic engineering of natural photosensory proteins. We are exploring the use of the flavin-binding LOV (light-oxygen-voltage) domain from the plant photoreceptor phototropin.  We used this technology to produce a genetically-encoded photoactivatable analog of Rac (PA-Rac) that enables precise modulation of Rac activity at regions that are submicrons in size and capable of controlling activation with microsecond precision in living cells. Current projects in the lab focus on extending such technology to other signaling proteins.

Lab members:

— Milda Stanislauskas is a PhD student whose work explores how cells sense physical cues from the external environment and convert them into chemical signals.

Assistant Professor of Cell Biology

Research Interests: Dr. Acker’s lab focuses on developing and applying advanced quantitative techniques from computational modeling to imaging to look at neurophysiology and cardiac electrophysiology in new, more direct, and powerful ways. The lab’s goal is to help accelerate our understanding of fundamental human physiology in order to find improved strategies for the prevention or treatment of cardiac and neurological disorders.

Voltage sensor development: together with Dr. Yan and Dr. Loew, Dr. Acker’s lab is actively testing and improving existing voltage sensors, which can be used in studies of the heart or brain, including studies of single cells up to whole organs. At the same time, new sensors are being developed for improved performance, allowing higher resolution, more accurate, and reliable measurements.

Neurodevelopmental disorders: in disorders such as autism, many genetic variations involving components of synapses, the chemical connections between neurons (brain cells), have been implicated. The functional implications of these variations can be studied at the level of single synapses as well as the network level, where altered synaptic signals ultimately lead to changes in patterns of brain activity. Better understanding the connection between the molecular (proteins and receptors) level changes in autism and the network (neuronal firing patterns and synaptic plasticity) level changes will improve our understanding of this disorder and provide new platforms for searching for new treatments or interventions.

Assistant Professor of Molecular Biology and Biophysics
Agmon Lab

Research Interests:  The Agmon Lab is focused on developing comprehensive, multi-scale models of cells – from their molecular underpinnings to their integrated functions, to the organismic level with many heterogeneous cells interacting in a shared environment. Recent decades of biological research have generated abundant data on the composition, spatial organization, and dynamics of thousands of cell types; however, we need new tools that can transform this data into predictive models that can be used for scientific discovery. Rather than building isolated models that capture a narrow range of cellular behavior with a single class of representation, the next generation of computational models will combine multi-source and multi-level data with diverse, meaningful representations of biological mechanisms into integrative simulations. These simulations will be used to interpret the input datasets, make experimental predictions, identify medical solutions, and help us understand the fundamental principles of biological organization.

Lab Members:

— Amin Boroomand, Postdoc

— Edwin Appiah, Graduate Student

Associate Professor of Genetics and Genome Sciences
Blinov Lab

Research Interests:  My major research focus is on the computational modeling of signal transduction networks.  Such networks often exhibit combinatorial complexity: the number of possible protein complexes and modification states is large. To accommodate this complexity we develop software to enable rule-based methods to specify a biological system using a set of rules. Using this rule-based approach, we create mathematical models of signal transduction networks in a single cell. We are specifically interested in describing activities and interactions among domains of biomolecules (e.g. phosphorylation of specific tyrosine residues, interactions between SH2 domain and phosphotyrosine) for receptor signaling and proteins-DNA interactions.  My research is also focused in the bioinformatics arena, developing tools and methods for integrating public databases with mathematical modeling approaches.  Data retrieval, visualization, flexible querying, and model annotation for future reuse, are some of the important requirements for modeling-based research in the modern age. In particular, we are developing ModelBricks as small, well-annotated, reusable model components that can be combined to develop complex models of biology.

Lab members:

— Nathan Schaumburger (UConn graduate) is working on modeling plant color patterns (in collaboration with Yaowu Yuan)  and aging phenotypes (in collaboration with Dr. Kuchel).

— Noah Liguori-Bills (UConn undergraduate) is working on ModelBricks and visualization projects.

Professor Emeritus of Molecular Biology and Biophysics

Research Interests: My laboratory investigates intracellular trafficking of mRNA in cells of the nervous system using a combination of molecular biological, microinjection, confocal microscopy, fluorescence correlation spectroscopy, and mathematical modeling techniques. We have delineated an RNA trafficking pathway consisting of export from the nucleus, granule assembly in the perikaryon, transport of RNA granules in the processes, localization to the distal regions of the cell, and translational activation. We are analyzing the cis/trans regulation of each step in this pathway and have identified a standard 21 nucleotide RNA trafficking signal (RTS) in many different transported mRNAs that bind specifically to hnRNPA2 and are involved at various steps in the trafficking pathway.

Professor Emeritus of Molecular Biology and Biophysics

Research Interests: I combine high-resolution quantitative imaging and biochemical analyses with mathematical modeling to develop computational simulations of specific cellular events using the Virtual Cell (VCell) modeling environment, a tool for creating spatially realistic mathematical models of cellular processes. I am also involved in the continued development of VCell and in developing a library of small, well-annotated models of specific cellular processes (ModelBricks) that can be used to build larger complex models of cellular events. As the first Director of the CCAM Microscopy User Facility, I established numerous collaborations based extensively on projects that apply quantitative fluorescence imaging to a wide range of cellular systems.

Associate Professor of Genetics and Genome Sciences

Guertin Lab

Research Interests: Precise regulation of transcription is central to cellular homeostasis and an organism’s response to developmental, nutritional, and environmental signals. Transcription factors bind to DNA to directly regulate gene expression and control cell fate. My lab develops and adopts molecular genomics approaches to study regulatory cascades initiated by hormone signaling. Our current work focuses on the basic mechanisms of estrogen signaling in breast cancer and how signaling cascades are disrupted upon drug treatment. We also use integrative genomics approaches to study adipogenesis. A long-term goal of my group is to identify transcription factors that are responsible for hormone-resistant phenotypes in disease states.
Lab members:

—Sathyan Kizhakke Mattada, Assistant Professor

Graduate students:
Jinhong Dong
Rudradeep Mukherjee
Tommy Scott
Siyu Sun
Jacob Wolpe

Assistant Professor of Biomedical Engineering
Investigator, Yale Center of Cancer Systems Biology
Visiting Faculty, Yale University

Kshitiz Lab

Research Interests: Our lab’s objective is to understand a cell’s interaction with its neighbors and the microenvironment. With a particular focus on the tumor microenvironment, we aim to unravel the language cells employ to converse with each other, how the grammar and the content of the language adapt to the environment, and how cells behave in response. We use a gamut of of techniques, including live microscopy, bioinformatics, tissue engineering, nanofabrication, cell patterning, evolutionary biology, and genetics to answer fundamental questions in biology and medicine. Our current physiological focus involves understanding how new phenotypes emerge within cancer populations by their neighborly interactions; the evolutionary basis of metastatic tolerance; as well as cardiac maturation for disease modeling.
— Cancer-Stroma Interaction:  We attempt to systematically understand how cancer and stromal cells interact with each other using a variety of approaches, including microfluidics, nanotechnology, live cell imaging, and genetic screens. We aim to elucidate the mechanisms through which stroma facilitates cancer to grow, become invasive, and resistant to chemotherapeutic drugs.
— Hypoxia and Metabolism: We study how lactate, a byproduct of anaerobic glycolysis, and accompanied acidosis in the microenvironment influences cancer phenotypes.  Using in vitro and in silico models of cancer combined with live cell microscopy, we aim to explore the role of lactate in regulating cancer growth and metastasis.
— Systems Cell Biology: We are advancing a new paradigm of cancer metastasis called Evolved Levels of Invasability (ELI) suggesting that stromal resistance (or assistance) to cancer invasion is evolutionarily derived. This paradigm presents a roadmap to observe the stromal compartment in cancer as a crucial player in regulating cancer phenotypes, as well as providing new avenues to understand and target cancer dissemination and metastasis.
— Mechanobiology and Cardiac Maturation: We focus on understanding how matrix rigidity and topography regulate cell signaling, and metabolism, as well as utilize mechanobiology for cardiac maturation. In our lab, we use a variety of tools to both elucidate the signaling machinery involved in mechanotransduction, as well as utilize the gained knowledge for specific therapeutic purposes by bioengineering. A dedicated effort in our lab focuses on creating mature, adult-like cardiac tissues from human pluripotent cell sources as a surrogate for drug screening.

Lab members:

–Yasir Suhail is a postdoctoral fellow working on the dependence of cancer metastasis on the surrounding stromal environment.

–Visar Ajeti is a postdoctoral fellow.

–Ashkan Novin is a Ph.D. student.

Professor, Department of Cell Biology

Professor of Computer Science and Engineering

Board of Trustees Distinguished Professor

Research Interests: My lab is focused on the development of new experimental and computational technologies to help us understand the mechanisms underlying cell function. We have a longstanding effort aimed at developing and characterizing fluorescent probes of membrane potential. This effort is continuing, using organic chemical design and synthesis to develop better more sensitive voltage indicators. This work has led to a continual interest in the organization of signaling pathways along the cell membrane and within the cytoplasm. We are interested in the very general question of how the intricate spatial organization of molecules in cells is used to control cell function. This is especially true of neuronal cells and we are actively investigating the cell biology of dendritic spines in brain tissue. This motivated us to develop a very general computational modeling software platform called the “Virtual Cell”, in which we have created a framework for using computer simulation to explore cell biological mechanisms. The models are built naturally from experimental images of cellular and subcellular structures combined with biochemical and electrophysiological data. We have used the “Virtual Cell” system to explain the pattern of electrical and signaling activity in neuronal and non-neuronal cells. Most recently, we have developed new software called SpringSaLaD that can model molecular interactions at the sub-cellular scale. This allows us to explore how the shape of individual molecules control their interactions, leading ultimately to cell-level responses.

Lab members:

–Kelvin Peterson is a medical student going for his MD. He is studying the kinetics and mechanisms membrane-associated reactions during cell signalling.

Professor and Vice-Chair of Genetics and Genome Sciences

Research Interests: Our group is interested in mechanisms of signal transduction. The ability of a cell to receive signals from the surrounding environment and respond to those signals appropriately is literally a matter of life and death. Whether a cell will proliferate, differentiate, or die, where it will adhere or migrate, virtually all aspects of its behavior depend on the ability to accurately interpret signals. Not only is signaling critical for normal development and the day-to-day function of an organism, but disregulated signaling underlies many human diseases such as cancer and autoimmune disorders. It is now appreciated that one of the central elements of the signaling machinery is the highly regulated and specific formation of protein-protein complexes. The fact that signaling relies on the binding of proteins to each other presents extraordinary opportunities: binding can be used as a means of identifying critical components of signaling pathways, and also provides the basis for strategies to inhibit those pathways in the laboratory or the clinic. We use a combination of biochemical and cell biological techniques to understand signaling pathways such as those that control cell proliferation and the organization of the cytoskeleton. We are also actively pursuing novel proteomic approaches to identify functionally important protein interactions and to characterize interactions on a global scale.

Lab members:

–Kazuya Machida is an associate professor in residence in the lab developing tools to map SH2 domain binding site utilization in cells as a cancer biomarker.

–Grace Curley-Jones is a UConn undergrad working with Dr. Machida on SH2 domain mapping

–Gavin Till is a UConn undergrad developing mathematical models to explore the role of membrane receptor clustering in the regulation of signaling pathways.

Professor of Cell Biology

Research Interests: Research in my laboratory is focused on molecular mechanisms of intracellular transport and the organization of microtubule cytoskeleton. Melanophores, pigment cells of lower vertebrates, are large cells that synchronously transport thousands of membrane-bounded pigment granules either rapidly to the cell center to form a tight aggregate or to disperse uniformly throughout the cytoplasm. During aggregation, granules move along microtubules using cytoplasmic dynein, but dispersion involves both initial microtubule-dependent transport to the periphery by Kinesin II and then slow diffusion-like movement along randomly arranged actin filaments. Transport is regulated by a Protein Kinase A (PKA) signaling cascade and thus provides a unique system for studying the role of the cytoskeleton in intracellular transport, mechanisms of switching between the two major transport systems, and regulation of activity of motor molecules by signal transduction mechanisms.  We use molecular biology and biochemistry along with live cell fluorescence microscopy, photobleaching, photoactivation, and microinjection of motor-specific probes to understand the molecular mechanisms underlying the regulation of intracellular transport.

Assistant Professor of Cell Biology

Research Interests. Our group is interested in understanding the mechanisms of signal transduction in cells and tissue. To do so, we combine techniques in multiple quantitative biological disciplines including biophysics, molecular biology, biochemistry and computational systems biology from single molecule measurements to multi-scale models of physiology and pathophysiology. We build multi-scale models of cells from their molecular interactions to their function in tissue to identify signal transduction mechanisms that contribute to cellular proliferation and migration in vascular and neuronal cells. The knowledge we gain is key in finding ways to modulate these critical signaling pathways for therapeutic potential for disease.

Associate Professor of Cell Biology

Research Interests: My research has been focused on developing and testing numerical algorithms for applications in cell biology, particularly related to the Virtual Cell software project. I also work with collaborators to develop novel mathematical models for applications in cell biology, including calcium dynamics, nucleocytoplasmic protein transport, cell cycle, cell signaling, diffusion in crowded intracellular environment, actin polymerization kinetics, actin mechanics and cell motility, and stem cell population dynamics.

Associate Professor of Genetics and Genome Sciences

Lab Website: Yu Lab

Research Interests:  The Yu lab is interested in developing new microscopy imaging techniques. Currently, our works are focused on two related areas: (1) Live cell single-molecule dynamics. We are working on techniques that allow better visualization of individual biomolecules in a living specimen using modern fluorescence microscopy techniques. We are particularly interested in understanding how protein molecules’ behavior changes during signal transduction, and how individual proteins are made during gene expression. See the following publications for more details: Das et al. PNAS 112(3), E267; Oh et al., PNAS 109(35):14024. (2) Super-resolution microscopy. For a long time, fluorescence microscopy had suffered from the curse of the so-called “diffraction-limited resolution”, which sets a fundamental limit on what is the smallest object the microscope can see. In the last decade, however, many new forms of microscopy design have emerged with the goal of breaking this resolution limit. Collectively, they are often called “super-resolution optical microscopy”. The lab is actively working on this new field trying to further improve the imaging quality of these new technologies. For more detail, check out these recent papers: Yu J et al. PNAS 201912634; Elmokadem A et al. Biophysical J 109(9):1772

Lab Members:

–Nizam ud Din is a postdoc fellow working on developing SH2 imaging techniques to understand the spatial distribution of phosphoproteome in cells during signal transduction.

–Meagan Cauble is a postdoc fellow studying the mechanisms of the growth factor pathways in the vertebral disk in response to tissue damage.

–Prem Shresha recently joined the lab and is preforming super-resolution imaging of chromatins in order to understand the rules of 4D folding of eukaryotic genome.