Current Research Projects
Current Research Projects for Academic Year 2007-2008
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Advisor: Eva Sapi, Ph.D.
Study of the cystic form of Borrelia burgdorferi (the Lyme Disease bacteria) Lyme disease, one of the fastest growing infectious diseases in the United States, is transmitted by tick vector infected with spirochete bacteria called Borrelia burgdorferi. In most cases of Lyme disease, early detection and a course of oral antibiotics is enough for a successful treatment. Unfortunately, there are substantial numbers of patients who go undiagnosed and advance to a debilitating long-term illness. It was suggested that one reason why the infection could persist because the commonly used antibiotics can stimulate the conversion of B. burgdorferi from mobile spirochete forms to cystic forms. The cyst forms show a very high resistance to commonly used therapeutic treatments.This study will examine the susceptibility of mobile and cystic forms of Borrelia burgdorferi to different natural therapeutic agents.We will also investigate whether the cyst can penetrate into mammalian cells and exist as "intracellular" cystic forms using cellular and molecular biology techniques. The project also investigates the structures of the cyst and unknown granule-like particles which rise from the cyst under certain condition using several state of the art microscopic technologies such as Atomic Force Microscopy, Dark Field and Scanning Electro-microscopy. Detection of Microfiliarial Parasites in the Deer Tick – and its Potential Implication in Morgellon Disease The purpose of this study is to identify microfilarial nematodes (worms) as potential tick-borne human pathogens in the US. The deer tick, Ixodes scapularis, is a vector for different tick-borne diseases including Lyme bacteria. In the last decade, there were a numbers of efforts to identify potential co-infection in Lyme disease patients, with the goal of providing a rational for more specific treatments. Most investigators focused on identifying novel tick-borne bacteria, viruses and even fungi in ticks or patients with a tick bite history, but filarial worms were not suspected to be potential tick-borne human pathogens. Morgellon disease is a very mysterious disease, with non-healing skin lesion and fatigue. Recent data suggested that Morgellon patients frequently have tick-bite history. In this project we will analyze specific skin samples from Morgellon patients to see if filarial nematose can cause and/or contribute to their illness. | |
Advisor: Michael J. Rossi, Ph.D. Toxin Induced Muscular Dystrophies Toxins and parasites have been implicated in several dystrophic diseases, but the mechanism of action on the muscles is not clear. Muscular dystrophies and atrophies can result from disruption of the proteins necessary for muscular maintenance, either genetically or due to a physical interaction. The muscle's loss of function may be due to the direct interaction of the parasite or its toxin directly with the mature skeletal muscle fibers, or the satellite cells required for muscle growth and maintenance. Alternatively, the effect could be indirect, acting on the neurons that control the muscles. These interactions could act through transcription factors such as NF-?B or degradation pathways. I am exploring the potential role of Borrelia burgdorferi in muscular dysfunction. Initially, I will be studying the interactions of Borrelia surface proteins and toxins with cultured myoblasts, myotubes and motor neurons. This will begin by looking for specific binding of Borrelia factors to the cells. Detection of specific binding will lead to a characterization of the receptors and an examination of the signaling pathways involved. Advisor: Anthony Melillo, M.S. Tick-borne Pathogen Genomic Database Due to recent research advances at UNH, we now know that many different organisms can infect ticks and cause the symptoms of Lyme Disease. The goal of this project is to create a curated, web-based database to store genomic data for these organisms. The scope of the data will be two-fold. In addition to data generated at UNH, it will also store and organize data gleaned from the scientific literature and from collaborating institutions. Advisor: Chiquito Crasto, Ph.D. Microtia is a genetic birth condition. This condition manifests in the form of deformities in the ear (like a cleft lip a similar birth defect). There are other region-specific characteristics of microtia: children born in the USA with microtia also have deformities in other parts of the face and body; children born with microtia in other regions of the world do not have afflictions other than in the ear lobes. We will carry out a genome-wide study of microtia-related genes to try and arrive at an understanding of the genetic underpinnings of this condition. Development of therapeutic methodologies to combat disease caused by viruses often involve the treatment of the symptoms and not the cause. Even when treatment methods are used, they focus on regions of the virus that are most active, these sites mutate rampantly and randomly, which render the treatment methods ineffectual. We will carry out a comprehensive bio-informatics based sequence analysis of viruses to identify sequence-regions that are not susceptible to mutation. Treatment methods that concentrate on the non-active, non-mutating sites would be a different way of approaching virology. * Please note the Professor Crasto is lives and works in Birmingham, Alabama. All communication related to the projects described above will be through email and telephone correspondence. Advisor: Jill L. Reiter, Ph.D. Advisor: Mark Collinge, Ph.D. The interaction of ICAM-1, a cell-adhesion protein expressed on endothelial cells, with LFA-1, an integrin-family member expressed on leukocytes, is the primary focus of my research. Specifically, we have demonstrated that engagement of LFA-1 on the surface of leukocytes, by ICAM-1, leads to the increased production of pro-inflammatory cytokines and angiogenic factors. We have shown this to be mediated via an RNA-stabilization mechanism, rather than a transcriptional response, and have identified an RNA-binding protein (HuR) as a key regulator in this process. Ongoing work involves using cell-specific HuR knockout mice, which we have generated, in animal models of inflammation and angiogenesis. This should provide insight into the role of HuR in various leukocyte populations, in the development of these processes. In addition, we are using proteomic approaches to determine key protein:protein interactions that are modulated in leukocytes in response to LFA-1 activation. Discoveries in this area will allow us to identify critical pathways involved in leukocyte activation following interactions with the vascular endothelium. Advisor: David Stern Ph.D. and Maureen Gilmore-Hebert Ph.D. There are four isoforms of ErbB4 which come from splice variants of the same gene: JMA-Cyt-1, JMA-Cyt2, JMB-Cyt1 and JMBCyt-2. Two of the isoforms JMA-Cyt1 and JMA-Cyt2 undergo cleavage upon ligand stimulation to generate an intracellular domain(ICD) which can travel to the nucleus. There the ICDs interact with both positive and negative acting transcription factors. It is the goal of this project to identify all the promoters to which the ICDs bind. So far we have used a ChIP-Chip strategy. Anti-ErbB4 antibody was used to immuno-precipitate ErbB4 ICD containing chromatin. The DNA was amplified, labeled with fluorescent dyes and then used to probe tiling DNA arrays (Chips) that contain all of the known human promoters. We have preliminary results that need to be repeated both by ChIP- Chip and by ChIp-high thru-put sequencing. We believe that these experiments would make an interesting and important masters project. Advisor: George A. Porter, Jr., MD, PhD. Advisor: Yilun Liu, Ph.D. A set of proteins belonging to the RecQ family are among the cancer suppressors linked to DNA repair. During the course of evolution, RecQ genes appear to have been amplified and diverged from a single copy of the RecQ gene in bacteria and yeast to fiveRecQ homologs in humans. Among the five RecQ homologs in humans, mutations in three RecQ proteins, BLM, WRN and RecQ4, have been associated with three separate diseases. They are Bloom Syndrome, Werner Syndrome and Rothmund-Thomson Syndrome. These patients all have increased incidence in developing various types of cancer. These different clinical features indicate that the human RecQ homologs have evolved to function in distinct pathways to protect the integrity of our genome and ensure proper development. A defect in one RecQ protein is sufficient to cause cell transformation and tumorigenesis, and this defect cannot be compensated by other RecQproteins. To date, we have limited understanding on what makes the human RecQproteins different from each other in order to cause different phenotypes or clinical syndromes. Our long-term agenda is to dissect the functions of individual RecQ proteins in human cells, and these studies will allow us to compare the similarities and differences among the RecQ proteins. Through these comparisons we can then understand what aspects of genome maintenance and DNA metabolism are required for normal development and cancer prevention. Advisor: Robert Means Another facet of our research is the characterization of the host immune responses being made against the virus. To aid us in these studies, we are taking advantage of several animal models utilizing closely related herpes viruses including murid g-herpesvirus (MHV-68) of rodents, Herpesvirus saimiri (HVS) of New World non-human primates and rhesus rhadinovirus (RRV) of Old World non-human primates. In vitro gene expression and characterization experiments combined with in vivo infection experiments are allowing us to better describe the relationship between the virus and the host. These experiments have the promise of not only leading to a better understanding of the mechanisms of viral entry and tropism, but also to an understanding of what host responses are important to controlling viral infection, crucial in the design of anti-viral immunization strategies. Advisor: Sabine M. Lang This project will utilize the mouse gamma herpesvirus 68 (MHV68) as a model system for human KSHV, since no in vitro culture system is available for KSHV. Initially, glycoprotein B will be cloned from MHV68, expressed and characterized in mammalian cells. Using directed mutagenesis, interesting amino acid motifs in glycoprotein B will be deleted or modified. The effect of these alterations on protein stability, protein modification and localization within the cell will be characterized in vitro. Ambitious students have the opportunity to reintroduce selected mutations back into the virus genome using the newly developed bacmid system. Mutant viruses will then be analyzed for i) virus replication in different target cell lines, and ii) viral pathogenicity, as well as iii) cell tropism will be evaluated following infection of mice. Advisor: Lyndsay Harris, MD (contact Kimberly Lezon-Geyda, PhD)
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