We study the interface between signal transduction and cell function. Approaches employed include - molecular genetics, protein and lipid biochemistry, confocal and electron microscopy, protein crystallography, and model organisms approaches (e.g. yeast, Arabidopsis, C. elegans, mouse gene knockout technology).
We study interactions of proteins and peptides with membranes. Specifically we study the interaction of the A-beta peptide with lipids in the membrane. It is well known that Alzheimer’s is an aggregation disorder with A-beta being the aggregating species. However, it is unknown what initiates this aggregation. Experimental evidence has shown that A-beta peptides will undergo a conformational change to an aggregate structure when interacting with surfaces of certain lipid membranes. It is of interest to our group to understand what causes this conformational change and what properties of lipids most promote this effect.
We also study structural and dynamical properties of biomembranes containing cholesterol. The goal of our research on structural and dynamical properties of membranes containing cholesterol is to gain knowledge about the nature of phospholipid-cholesterol interactions that play an important role in functioning of membranes, in cell communications and in formation of domains called lipid rafts. Detailed knowledge of the membrane properties helps us to understand the normal functioning of cells and it is instrumental in the search for a cure from a large variety of diseases. We use computer simulation techniques to perform our studies. Member of the Molecular & Cellular Biophysics Training Program
Our objective is to understand the dynamic and structural properties of chromosomes during mitosis. We use live cell imaging techniques to address how kinetochores are assembled, capture microtubules and promote faithful segregation of chromosomes.
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 understand the features that control the rates of self-catalyzed phosphorylation and dephosphorylation of response regulator proteins. The kinetics of these reactions vary dramatically (>40,000x) 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
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.
We study how Cytotoxic T Lymphocytes (CTL) are activated during infection and cancer. Our long-term goal is to increase immunity in the case of infection or cancer and to decrease immunity in the case of autoimmunity. The approaches that we use include x-ray crystallography and other biophysical techniques such as SPR and ITC, and immunological assays. We are currently working on three systems. 1) basic immunology to understand how cytotoxic T cells are signaled to kill infected or cancer cells. 2) immunotherapy of melanoma using modified T cell receptors. 3) Determining why specific T cells populate pancreatic islets of Langerhans in Type I diabetes. Students working on these projects could work on immunological or biophysical aspects (or both) depending on their interests. Member of the Molecular & Cellular Biophysics Training Program.
The main research project is to determine the role of intercellular junctions in normal development, cell aging and cataract formation in human and animal lenses.
The Dokholyan group focuses primarily on understanding protein dynamics, more specifically on how induced changes in protein folding and aggregation lead to diseases, such as cystic fibrosis, many types of cancers, and a number of neurodegenerative diseases. The Dokholyan group focuses on several such diseases, including Amyotrophic Lateral Sclerosis (ALS), also known as Lou Gehrig’s disease, and Huntington disease. The Dokholyan group is developing a hierarchy of molecular models, from simplified coarse-grained models to more detailed ones, to create a novel multi-scale simulation methodology. This methodology will enable simulations of large molecular complexes at the biologically-relevant time scales, thereby allowing to directly glance into processes associated with human diseases. Member of the Molecular & Cellular Biophysics Training Program.
The Elston lab is interested in understanding the dynamics of complex biological systems, and developing reliable mathematical models that capture the essential components of these systems. The projects in the lab encompass a wide variety of biological phenomena including signaling through MAPK pathways, noise in gene regulatory networks, airway surface volume regulation, and understanding energy transduction in motor proteins. A major focus of our research is understanding the role of molecular level noise in cellular and molecular processes. We have developed the software tool BioNetS to accurately and efficiently simulate stochastic models of biochemical networks
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.
Our work is focused on understanding how major histocompatibility complex (MHC) molecules function in the immune response to pathogens. This simple question involves the most fundamental aspect of immunology - self/non-self discrimination.
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.
Dynamic control of signaling networks in living cells; Rho family and MAPK networks in motility and network plasticity; new tools to study protein activity in living cells (i.e., biosensors, protein photomanipulation, microscopy). Member of the Molecular & Cellular Biophysics Training Program and the Medicinal Chemistry Program.
Structure, dynamics and function of viral domains in biomembranes. Photomanipulation and traction mapping applied to the migration of single cells. Investigation of the mechanochemical basis of cell oscillations using systems biology approaches coupled with experiments.
Spatio-temporal regulation of signal relay systems in cells using live cell fluorescence imaging and targeted gene disruption of signaling proteins to define their role in development, physiology and pathophysiology.
Our research focuses on the structure and function of medically important proteins from the crystallographic approach. The current topics include cycolphilin, calcineurin, heat shock protein 90 (hsp90), and cyclic nucleotide phosphodiesterase.
I am interested in the comparative biomechanics of marine invertebrates. In particular, I study the functional morphology of musculoskeletal systems, the structure, function, development and evolution of muscle, and invertebrate zoology, with particular emphasis on the biology of cephalopod molluscs (octopus and squid). My research is conducted at a variety of levels and integrates the range from the behavior of the entire animal to the ultrastructure and biochemistry of its tissues.
We use a combination of experimental and computational methods to redesign protein-protein interactions. The potential applications for this technology include enhancing protein therapeutic and creating new tools to study signaling pathways.
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 regulatory role of platelet membrane phosphatidylserine in blood coagulation; mechanism of protein-mediated membrane fusion in secretory processes and virus infection. Director of the Molecular & Cellular Biophysics Training Program.
Dr. Macdonald is the Founder and Scientific Director of the new Metabolomic Facility and Co-Scientific Director of the joint UNC/NCSU/NOAA Marine MRI facility at Pivers Island near Beaufort NC. Dr. Macdonald's research goal is to combine metabolomics and tissue engineering and apply these tools to quantitative biosystem analysis.
Our laboratory studies the mechanisms of sensory information processing in the nervous system, with an emphasis on processing in the auditory pathways. We study the role of ion channels in integration at the single cell level, short and long-term synaptic plasticity, synaptic function, and ion channel dynamics in the auditory brainstem and auditory cortex. We are also studying how different kinds of hearing loss affect central auditory function. Experimentally, we use patch clamp (current, voltage and dynamic clamp) methods in brain slices, live optical imaging of activity, a variety of biochemical and molecular methods, mice with genetic hearing loss, noise-induced hearing loss, auditory brainstem evoked response, and acoustic startle response to evaluate hearing function in animal models. The laboratory extensively utilizes quantitative experimental techniques, complemented with detailed computational modeling at the single cell and network levels to further understand the normal information processing capacity of auditory neurons, and the consequences of changes in ion channel and synaptic function after hearing loss.
Protein-derived radicals, in vivo detection of free radical generation, biomarkers of oxidative stress and free radical formation in aids-related infection (Pseudomonas aeruginosa)
The goal of the laboratory’s research is to define the structure and function of an intracellular Ca2+ release channel in skeletal and cardiac muscle, using molecular biological and electrophysiological methods and by creating mutant mice.
We are a theoretical physical chemistry group in the Department of Chemistry at the University of North Carolina at Chapel Hill. We use advanced computational methods to study biological processes at multiple scales, from single protein functional dynamics and chromatin folding and stability to cell-level processes, such as stochastic signal transduction and regulation of cell motility.
Our sensory experiences leave indelible marks on the brain, and the Philpot Lab seeks to understand how this occurs at the level of the synapse. Our research examines the experience-dependent mechanisms that allow functional cortical circuits to emerge and for memories to be stored. We use electrophysiology, biochemistry, and genetic manipulations to study fundamental mechanisms of synaptic plasticity relevant to disease models and other neuropathologies (e.g. amblyopia, mental retardation, and schizophrenia). Through our studies in the visual cortex and hippocampus, we aim to provide insights into preventing common neuropathologies and to discover mechanisms for promoting neural regeneration in the mature brain.
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.
We examine dynamic cellular processes using structural biology. Current projects focus on Infectious disease, particularly the spread of antibiotic resistance and host-pathogen interactions; Protein-DNA complexes involved in DNA manipulation; the Design of protein therapeutics; Nuclear receptors in transcriptional control; and Enzymes central to drug recognition and metabolism.
The primary research focus is the structure, function and biosynthetic processing of membrane proteins which provide permeability pathways through the membranes of cells. Much of the current work is concentrated on the ion channel protein, CFTR (cystic fibrosis transmembrane conductance regulator) which is absent or dysfunctional in patients with cystic fibrosis. To elucidate the molecular mechanisms of CFTR function, we study single channel properties by electrophysiological techniques, enzymatic activity and physical interaction with other cellular molecules. A major objective of studies with the purified molecule is to obtain 3-dimensional structure information so that small molecules capable of recognizing features of its surface shape can be synthesized and used to modulate its folding and activity.
Spindle microtubule, microtubule motor and kinetochore mechanics for accurate chromosome segregation. We are also developing new fluorescence microscopy and electronic imaging methods for assays of protein function in living cells.
We have three main areas of research focus: (1) Nucleotide excision repair: The only known mechanism for the removal of bulky DNA adducts in humans. (2) DNA damage checkpoints: Biochemical pathways that transiently block cell cycle progression while DNA contains damage. (3) Circadian rhythm: The oscillations in biochemical, physiological and behavioral processes that occur with the periodicity of about 24 hours.
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.
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.
The mechanical properties, force response and force generating mechanisms of biological systems is of great interest for physiological function, for tissue engineering and embryogenesis and for drug delivery. In collaboration with the Computer Science Department, we develop and apply new technologies for applying and measuring forces on single molecules, cells and tissue cultures. In collaboration with the departments of Mathematics, Computer Science, Chemistry and the UCN Cystic Fibrosis Center we are pursuing an integrated computational model of mucus clearance in the lung. Affiliated with the Molecular & Cellular Biophysics Training Program.
The immune system is a network of interacting biological cells. The molecular events that lead to the activation and regulation of these cells often occur at the cell surface. However, little is known about the arrangement, motions and interactions of the participating cell-surface molecules. To examine these phenomena, we construct model cell membranes on planar supports from purified or synthesized molecules. Recently developed techniques in laser-based fluorescence microscopy can then be employed to examine the behavior of select fluorescently labeled molecules at or near the supported planar membranes. This research is significant not only in the basic understanding of the immune system, but also in other areas of cell-cell communication and cell membrane biophysics, in the physics of two-dimensional fluids, and in biotechnology.
Biophysics of cortical information processing, selective attention in the mammalian visual pathway and evidence for spike patterns in cortical spike trains
Our vision is to address one of the great remaining and intractable problems in cellular and molecular biology -- that of determining comprehensive and quantitative structures for all cellular and viral RNAs. To this end, we are developing high-throughput RNA structure analysis technologies (called SHAPE) with the goal of making RNA secondary and tertiary structure analysis as straightforward, in principle, as DNA sequencing is today. We then use these tools to understand otherwise daunting problems that play pivotal roles in cellular function. Current projects include (i) RNA folding and protein assembly reactions central to the infectivity and pathogenesis of human viruses and (ii) assembly of large biomedically important ribonucleoprotein complexes inside living cells.
Enzyme action; drug design; effects of solvent water on the structure and reactivity of biological molecules; rates of benchmark reactions for testing the catalytic prowess of enzymes.
The site of microtubule attachment to the chromosome is the kinetochore, a complex of over 60 proteins assembled at a specific site on the chromosome, the centromere. Almost every kinetochore protein identified in yeast is conserved through humans and the organization of the kinetochore in yeast may serve as the fundamental unit of attachment.
More recently we have become interested in the role of two different classes of ATP binding proteins, cohesions (Smc3, Scc1) and chromatin remodeling factors (Cac1, Hir1, Rdh54) in the structural organization of the kinetochore and their contribution to the fidelity of chromosome segregation.
