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.
Robert Butera is a Professor jointly appointed in the School of Electrical/Computer Engineering at Georgia Tech and the Wallace H. Coulter Dept. of Biomedical Engineering at Georgia Tech and Emory University, both in Atlanta, GA USA. He is also the one of the founders of the Neural Engineering Center, focused on bringing together clinicians and neuroscientists with engineers to develop novel methods for neuromodulation, where he continues to serve on the executive committee. His lab develops methodologies for selectively stimulating and blocking peripheral nerve activity for sensorimotor and organ modulation applications. His group also develops open software (http://www.rtxi.org) for enabling real-time closed-loop control of electrophysiology experiments and more recently is developing ultra-low cost open hardware to do the same (http://www.puggleboard.com). For over 15 years Dr. Butera’s lab has been established in the fields of cellular neurophysiology and computational neuroscience and the development of novel experiments that combine the two through real-time computing. This experience and recent clinical collaborations has motivated his lab to shift research direction over the past few years towards translational neuroscience applications. Professionally, Dr. Butera serves as the Vice-President for Publications for the IEEE Engineering in Medicine and Biology Society. Dr. Butera is a Fellow of AIMBE and AAAS and a Distinguished Lecturer of the IEEE Engineering in Medicine and Biology Society.
Neuromodulation of peripheral nerve activity
Real-time control methods applied to electrophysiology measurements
Autonomic modulation of visceral organs.
Our laboratory combines engineering and neuroscience to tackle real-world problems. We utilize techniques including intracellular and extracellular electrophysiology, computational modeling, and real-time computing.
Stem cell policy, bioethics, science policy, and STEM education
The impact of ethical controversy on scientific research, with a particular emphasis on emerging biomedical technologies. Recent work has focused on a range of issues related to stem cell policy (including state-level science policy and the rise of unproven stem cell therapies) as well as the oversight of assisted reproduction.
It is our vision that one day mathematics and computation will be capable of reliably predicting, manipulating and optimizing biomedical systems for the advancement of medicine, drug development, biotechnology and productive and sustainable stewardship of the environment.
Pursuing this vision, the goal of our lab is to understand small biological systems in great detail. We work toward this goal by performing studies that target the fine-tuned synergism between genes, proteins and metabolites, and investigate the resultant, usually very effective functioning of healthy cells and organisms in comparison to those that are mutated or diseased. Milestones along the way are insights into the rationale for the intricate design and operation principles that govern biological systems.
The work in our lab is strictly mathematical and computational, but we collaborate with several superb experimental groups that provide us with data and appreciate our modeling efforts as tools for explanation and hypothesis generation.
Cichlid fishes from Lake Malawi offer the unprecedented opportunity to study the relationship between genotype and phenotype in wild vertebrates. Over the past ten years, with funding from the Alfred P. Sloan Foundation, NSF and NIH, we’ve pioneered genomic and molecular biology approaches in this natural system to solve problems difficult to address in traditional model organisms. Major projects include (i) tooth and taste bud patterning and regeneration; (ii) genomics of complex social behavior; and (iii) developmental diversification of the cranial neural crest, placodal plate and neural plate. We analyze and manipulate genomes and development in multiple species of Malawi cichlids, spanning divergence in embryonic/adult phenotypes and behavior – and translate our findings to zebrafish and mouse models.