Yeast genetics and molecular biology, chaperones and protein misfolding, amyloid and prion diseases, epigenetics and protein-based inheritance.
My laboratory employs yeast models to study prions and amyloids. Prions were initially identified as proteins in an unusual conformation that cause infectious neurodegenerative diseases, such as "mad cow" disease, kuru or Creutzfeldt-Jakob disease. Infection depends on the prion's ability to convert anon-prion protein, encoded by the same host maintenance gene, into the prion conformation. Prions form ordered cross-beta fibrous aggregates, termed amyloids. A variety of human diseases, includingAlzheimer's disease, are associated with amyloids and possess at least some prion properties. Someamyloids have positive biological functions. Many proteins can form amyloids in specific conditions. It is thought that amyloid represents one of the ancient types of the protein fold. Some yeast non-Mendelianheritable elements are based on a prion mechanism. This shows that heritable information can be coded in protein structures, in addition to information coded in DNA sequence. Therefore, prions provide a basis for the protein-based inheritance in yeast (and possibly in other organisms).
Major topics of research in my lab include cellular control of prion formation and propagation (with a specific emphasis on the role of chaperone proteins), and development of the yeast models for studying mammalian and human amyloids, involved in diseases. Our research has demonstrated that prions can be induced by transient protein overproduction and discovered the crucial role of chaperones in prionpropagation, shown evolutionary conservation of prion-forming properties, established a yeast system for studying species-specificity of prion transmission, and uncovered links between prions, cytoskeletalnetworks and protein quality control pathways.
Develop microneedle patches for vaccination that is simpler and more effective than conventional injection.
Design microneedle patches for rapid and slow-release delivery of drugs.
Translate microneedle technology from the laboratory into human clinical studies and advanced manufacturing.
Study targeted drug delivery to the eye using microneedle injection into the suprachoroidal space.
Examine the effects of laser-activated nanoparticles on delivery of molecules into cells to manipulate cellular behavior
Dr. Prausnitz and his colleagues carry out research on biophysical methods of drug delivery, which employ microneedles, ultrasound, lasers, electric fields, heat, convective forces and other physical means to control the transport of drugs, proteins, genes and vaccines into and within the body. A major area of focus involves the use of microneedle patches to administer vaccines to the skin in a painless, minimally invasive manner that improves vaccine effectiveness by targeting delivery to the skin’s immune cells. In collaboration with Emory University, the Centers for Disease Control and Prevention and other organizations, Dr. Prausnitz’s group is advancing microneedles from device design and fabrication through pharmaceutical formulation and preclinical animal studies through studies in human subjects. In addition to developing a self-administered influenza vaccine using microneedles, Dr. Prausnitz is translating microneedles technology especially to make vaccination in developing countries more effective.
Dr. Lu’s research lies at the interface of engineering and biology. The lab engineers microfluidic devices and BioMEMS (Bio Micro-Electro-Mechanical Systems) to study neuroscience, genetics, cancer biology, systems biology, and biotechnology. These miniaturized Lab-on-a-chip tools enable us to study biology in a unique way unavailable to conventional techniques. Applied to the study of fundamental biological questions, these new techniques allow us to gather large-scale quantitative data about complex systems. Microfluidic devices are especially suitable for solving these problems because of the many advantages associated with shrinking the devices down to a scale comparable to typical biological systems. Furthermore, unique phenomena at the micro and nano length scale, such as enhanced surface effects and transport phenomena, can be exploited in designing novel techniques and devices.
In neuroscience, we are interested in how the nervous system develops and functions, and how genes and environment influence behavior. In cancer biology, we are interested in the roll of extra cellular matrix and soluble factors in cell migrations. In cancer therapy, we are interested in signal transductions for adoptive transfer. For systems biology, we are interested in large-scale experimentation and automation, and applications in neuroscience and cell biology. In general, we bring together molecular and genetic techniques and the micro devices to further our understanding of the complex biological systems. We make micro devices to investigate molecular events and signaling networks, cellular behavior, connectivity and activities of populations of cells, and the resulting complex behaviors of the animals. The ultimate goal is to bring new technologies to understand natural and dysfunctional states of biological systems and ultimately bring cures to diseases.
Structural biology, protein misfolding, amyloid, glaucoma, crystallography, and molecular biophysics
The Lieberman research group focuses on biophysical and structural characterization of proteins involved in misfolding disorders. One major research project in the lab has been investigations of the glaucoma-associated myocilin protein. The lab has made major strides toward detailed molecular understanding of myocilin structure, function, and disease pathogenesis. Our research has clearly demonstrated similarities between myocilin glaucoma and other protein misfolding disorders, particularly amyloid diseases. The work has led to new efforts aimed at ameliorating the misfolding phenotype using chemical biology approaches. Our second project involves the study of membrane-spanning proteolytic enzymes, which have been implicated disorders such as Alzheimer disease. Our group is tackling questions surrounding discrimination among and presentation of transmembrane substrates as well as the enzymatic details of peptide hydrolysis. In addition to the biochemical characterization of intramembrane aspartyl proteases, our group is developing new crystallographic tools to improve the likelihood of determining structures of similarly challenging membrane proteins more generally.
Biomechanics and mechanobiology of cell adhesion and signaling molecules of the immune system and the vascular systems:
Our interests lie in the adhesion and signaling molecules of the immune system as well as those involved in platelet adhesion and aggregation. We are primarily focused on early cell surface interaction kinetics and their primary signaling responses, as these are critical in determining how a cell will ultimately respond upon contact with another cell. The majority of our work ranges from single molecule interaction studies using atomic force microscopy, molecular dynamics simulations, or biomembrane force probe assays to single cell studies using micropipette adhesions assays, fluorescence imaging techniques, or real-time confocal microscopy. These assays focus on the mechanics and kinetics of receptor-ligand binding and their downstream signaling effects within cells. T cell receptors, selectins, integrins, and their respective ligands are some of the cell surface molecules currently under investigation in our lab. Understanding the initial interaction between molecules such as these and their subsequent early signaling processes is crucial to elucidating the response mechanisms of these physiological systems. Ultimately, our research strives to help better understand the mechanisms within these systems for possible medical applications in autoimmunity, allergy, transplant rejection, and thrombotic disorders.
Dr. Vito's research interest is in the mechanical determinants of rupture of atherosclerotic plaque. Plaque rupture is important in stroke and heart attack because it precipitates the formation of a thrombus (blood clot) which then breaks away and causes an obstruction of flow. Experiments and modeling are used to determine what compositional factors predispose a plaque to rupture. Dr. Vito collaborates with people interested in detecting vulnerable plaque using magnetic resonance imaging and with others who want to intervene with drugs or genetic manipulation to reduce the likelihood of plaque rupture. His current research is sponsored by the National Science Foundation.
Bio-inspired colloidal assembly for multifunctional drug delivery vehicles and colloidal-based sensing.
Dr. Milam’s current research interests focus on designing and characterizing colloids functionalized with biologically-relevant macromolecules such as oligonucleotides and cellular adhesion molecules. The specific recognition between matching macromolecules such as complementary DNA strand pairs allows for programmable adhesion between either complementary particle surfaces or between complementary particle and matrix interfaces. Using a variety of biocompatible and biodegradable materials as the colloidal substrate, these biocolloids will serve as building blocks to fabricate novel material constructs ranging from stimuli-responsive hybrid materials to therapeutic delivery vehicles.
Microdevices for Drug & Gene Delivery, MEMS Ion Sources for Bioanalytical Mass Spectrometry, Scanning Probes for BioElectroChemical Imaging on Nanoscale, Thermomechanical Aspects of Tissue Repair & Regeneration, Lab-on-a-Chip Instrumentation
Dr. Fedorov’s research is at the interface of basic sciences and engineering. His research portfolio is diverse, covering the areas of portable/ distributed power generation with synergetic carbon dioxide management, including hydrogen/CO2 separation/capture and energy storage, novel approaches to nanomanufacturing (see Figure), microdevices (MEMS) and instrumentation for biomedical research, and thermal management of high performance electronics. Dr. Fedorov's research includes experimental and theoretical components, as he seeks to develop innovative design solutions for the engineering systems whose optimal operation and enhanced functionality require fundamental understanding of thermal/fluid sciences.
Applications of Dr. Fedorov’s research range from fuel reformation and hydrogen generation for fuel cells to cooling of computer chips, from lab-on-a-chip microarrays for high throughput biomedical analysis to mechanosensing and biochemical imaging of biological membranes on nanoscale.
The graduate and undergraduate students working with Dr. Fedorov's lab have a unique opportunity to develop skills in a number of disciplines in addition to traditional thermal/fluid sciences because of the highly interdisciplinary nature of their thesis research. Most students take courses and perform experimental and theoretical research in chemical engineering and applied physics. Acquired knowledge and skills are essential to starting and developing a successful career in academia as well as in many industries ranging from automotive, petrochemical and manufacturing to electronics to bioanalytical instrumentation and MEMS.
Neuroscience, neural engineering, human augmentation, human-robot interaction, rehabilitation, sport science
Physiological and biomechanical mechanisms underlying fine motor skills and their adjustments and adaptations to heightened sympathetic nerve activity, aging or inactivity, space flight or microgravity, neuromuscular fatigue, divided attention, and practice in humans. He uses state-of-the-art techniques in neuroscience, physiology, and biomechanics (e.g., TMS, EEG, fMRI, single motor unit recordings, microneurography, mechanomyography, ultrasound elastography, and exoskeleton robot) in identifying these mechanisms.
Using yeast Saccharomyces cerevisiae as a model, my laboratory investigates molecular mechanisms underlying eukaryotic genome stability. Chromosomal rearrangements create genetic variation that can have deleterious or advantageous consequences. Karyotypic abnormalities are a hallmark of many tumors and hereditary diseases in humans. Chromosome rearrangements can also be a part of the programmed genetic modifications during cellular differentiation and development. In addition, gross DNA rearrangements play a major role in chromosome evolution of eukaryotic organisms. Therefore, elucidation of molecular mechanisms leading to chromosome instability is important for studying the human pathology and also for our understanding of the fundamental processes that determine the architecture and dynamics of eukaryotic genomes.
My overall contribution to the field of genome instability has been the demonstration of the phenomenon that repeats often found in higher eukaryotic genomes including the human genome are potent sources of double-strand breaks (DSB) and gross chromosomal rearrangements (GCR). Specifically, my lab, is investigating how repetitive sequences that can adopt non-B DNA secondary structures pose a threat to chromosomal integrity dictated by their size and arrangement. Currently three sequence motifs are studied in my laboratory: inverted repeats; Friedreich’s ataxia GAA/TTC trinucleotide repeats and G-quadruplex-forming tracts. We also are collaborating with Dr. Malkova lab, University of Iowa, to study one of the outcomes of the DSB formation at unstable repeats – break-induced replication.