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.
Dr. Sulchek's research focuses primarily on the measurement and prediction of how multiple individual biological bonds produce a coordinated function within molecular and cellular systems. There are two complementary goals. The first is to understand the kinetics of multivalent pharmaceuticals during their targeting of disease markers; the second is to quantify the host cell signal transduction resulting from pathogen invasion. Several tools are developed and employed to accomplish these goals. The primary platform for study is the atomic force microscope (AFM), which controls the 3-D positioning of biologically functionalized micro- and nanoscale mechanical probes. Interactions between biological molecules are quantified in a technique called force spectroscopy. Membrane protein solubilized nanolipoprotein particles (NLPs) are also used to functionalize micro/nano-scale probes with relevant biological mediators. This scientific program requires the development of enabling instrumentation and techniques, which include the following:
Advanced microscopy and MEMs;
Nanomechanical linkers, which provide a convenient platform to control biomolecular interactions and study multivalent molecular kinetics;
Biological mimetics, which provide a simple system to study cell membranes and pathogens.
Ultimately, this work is used to optimize molecular drug targeting, improve chem/bio sensors, and develop more efficient pathogen countermeasures.
Dr. García's research centers on cellular and tissue engineering, areas which integrate engineering and biological principles to control cell function in order to restore and/or enhance function in injured or diseased organs. Specifically, his research focuses on fundamental structure-function relationships governing cell-biomaterials interactions for bone and muscle applications. Current projects involve the analysis and manipulation of cell adhesion receptors and their extracellular matrix ligands. For example, a mechanochemical system has been developed to analyze the contributions of receptor binding, clustering, and interactions with other cellular structural proteins to cell adhesion strength.
In another research thrust, bio-inspired surfaces, including micropatterned substrates, are engineered to control cell adhesion in order to direct signaling and cell function. For instance, biomolecular surfaces have been engineered to target specific adhesion receptors to modulate cell signaling and differentiation. These biomolecular strategies are applicable to the development of 3D hybrid scaffolds for enhanced tissue reconstruction,"smart" biomaterials, and cell growth supports. Finally, genetic engineering approaches have been applied to engineer cells that form bone tissue for use in the development of mineralized templates for enhanced bone repair.
Bioorganic Chemistry, Biochemistry and Drug Design. The overarching research objective of our laboratory is to delineate the chemical basis of the molecular recognition events employed by biomolecules to drive important biological processes and how perturbation of these events, by natural and synthetic ligands, can be used to understand the molecular basis of various human disease conditions, especially cancer, viral- and bacterial-infections; and to use the information gleaned from such perturbation studies to arrive at potentially new therapeutic solutions for these conditions. Individual research project involves a unique blend of the tools of synthetic organic chemistry with biochemistry and molecular biology. Enumerated below are specific interrelated research projects that are currently underway:
RNA-Small Molecule Interaction. RNAs adopt intricate and structurally diversed motifs susceptible to direct interactions by small molecules in similar manner to proteins. An atomic level understanding of RNA-small molecule interactions will aid identification of a myriad of biologically useful molecules including novel RNA structural probes; and new anti-viral, anti-tumor and antibacterial agents. One class of nucleic acid targeting drugs are the anthracyclines. Literature evidence suggests that anthracyclines partly derived their anti-tumor activities through DNA-intercalation mediated "poisoning' of the eukaryotes topoisomerase II. Despite their chemical similarity to DNA and direct role in gene expression, little is known about the extent to which RNA interactions with anthracyclines contribute to anthracyclines' biological activities. The primary objective of this research is to elucidate the molecular features essential for the interaction of anthracyclines with the iron responsive elements (IREs), the hairpin loops located in the untranslated regions of mRNAs encoding key proteins involved in iron metabolism; and the effects of such interactions on the formation of the crucial RNA-protein complexes that regulate intracellular iron homeostatis.
Targeted Histone Deacetylase (HDAC) Inhibition. One nucleic acid associated protein that is of current interest to us is the Histone Deacetylase (HDAC). HDACs and histone acetyltransferases (HATs) are two functionally opposing enzymes, which tightly regulate the chromatin structure and function via sustenance of equilibrium between the acetylated- and deacetylated-states of nucleosomal histones. Aberrations in intracellular histone acetylation-deacetylation equilibrium have been linked to the repression of a subset of genes resulting in excessive proliferation and are implicated in a number of malignant diseases. HDACs function as part of multiprotein complexes that catalyze the removal of acetyl groups from the -amino groups of specific lysine residues located near the N-termini of nucleosomal core histones. Inhibition of HDACs activity results in the weakening of the bond between histones and DNA, thus increasing DNA accessibility and gene transcription. This has recently been clinically validated as a new therapeutic strategy for cancer treatment with the FDA approval of SAHA for the treatment of cutaneous T cell lymphoma. To date, several other structurally distinct small molecule HDAC inhibitors have been reported, however, most of these agents non-selectively inhibit the deacetylase activity of class I/II HDAC enzymes. Toward improving the therapeutic index of current HDAC inhibitors, we are developing new HDAC inhibitors for targeted cancer therapy applications. Our goals here are two-fold: (1) to develop HDAC inhibitors that sensitize cancer cells to nucleic acid interacting anticancer drugs and (2) to develop methodology for cell type-selective delivery of HDAC inhibitors.
Design and Synthesis of Novel Bioconjugates for Molecular Delivery Applications. We are also investigating new molecular delivery systems for nanoparticles and small molecule drugs. In collaboration with Professor El-Sayed's group, we are developing new approaches for targeting gold nanorods into the nucleus of live cells. Additionally, we are exploring the periplasmic protein secretion pathway to deliver cell wall damaging agents to the bacterial periplasm. This effort could result in novel diagnostic and therapeutic strategies.
The Weitz group is interested in the structure and dynamics of complex biological systems. The primary mission is to understand how viruses transform human health and the fate of our planet.
The research group includes physicists, computational biologists, mathematicians, and bioinformaticians working on three major research themes: (i) viral dynamics at the molecular, population and evolutionary scales; (ii) theoretical ecology and evolutionary biology; (iii) disease dynamics and epidemiology. The work in the Weitz group is primarily theoretical/computational in nature, and utilizes the tools of nonlinear dynamics, stochastic processes, and large-scale data analysis to interact with experimentalists.
Examples of recent and ongoing projects include studies of viral-host infection networks, dynamics of complex viral-host communities, the spread and control of infectious diseases, and the link between game theory and strategic behavior of viruses and microbes.
Cell biophysics. Cell mechanics of adhesion, migration and dynamics. Immunophysics and immunoengineering. Hyaluronan glycobiology. Hyaluronan synthase. Physics of tissues.
The Curtis lab is primarily focused on the physics of cell-cell and cell-extracellular matrix interactions, in particular within the context of glycobiology and immunobiology. Our newest projects focus on questions of collective and single cell migration in vitro and in vivo; immunophage therapy "an immunoengineering approach - that uses combined defense of immune cells plus viruses (phage) to overcome bacterial infections"; and the study of the molecular biophysics and biomaterials applications of the incredible enzyme, hyaluronan synthase.
A few common scientific themes emerge frequently in our projects: biophysics at interfaces, the use of quantitative modeling, collective interactions of cells and/or molecules, cell mechanics, cell motility and adhesion, and in many cases, the role of bulky sugars in facilitating cell integration and rearrangements in tissues.
Optical microscopy and in vivo imaging, RNA virus pathogenesis, HIV/SIV and hRSV, and detection, RNA regulation, therapeutics and vaccines.
Research in the Santangelo lab is primarily focused on three areas, native RNA regulation, RNA virus pathogenesis, and RNA therapeutics and vaccines, where the application and development of imaging technology is applied to all three areas. To address RNA regulation, localization and dynamics in the cellular milieu, we have developed single molecule sensitive approaches for imaging native RNAs and RNA dynamics in live cells, as well as the first assay to detect native RNA-protein interactions in situ. To date, the results of these methods have been applied to the cell biology of human respiratory syncytial virus infections and RNA regulation during tumorigenesis. These methods are also being used to interrogate and develop RNA-based therapeutics and vaccines. In addition we have been developing whole-body, PET/CT imaging tools for interrogating SIV infections within the macaque model. The purpose of this tool is to answer fundamental questions regarding the location of residual virus during treatment, in the hope of learning vital information that could be applied to approaches seeking to “cure” SIV or HIV.