Current Research Projects

Study of the cystic form of Borrelia burgdorferi (the Lyme Disease bacteria)

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.
If filarial nematodes are indeed a tick-borne co-infection in Lyme disease patients, their eradication would require additional treatments using very specific filaricidal drugs.

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.
Parkinson’s disease, after Alzheimer’s disease, is a neurological disorder that afflicts people beyond a certain age. There is no known cure and treatment often is restricted to the symptoms. Celebrities like Michael J. Fox and Mohammed Ali who suffer from Parkinson’s disease have cast light on the need to address this condition. We will use mathematical methods such as Bayes and Clustering analyses to process the literature and data associated with Parkinson’s disease.

* 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.

Epidermal growth factor receptor (EGFR) is one of the key drivers of cancer cell growth. This receptor tyrosine kinase is frequently overexpressed in different cancer types, including breast and ovarian carcinomas, and high EGFR protein levels are associated with poor patient prognosis. However, overexpression of EGFR does not, by itself, confer a growth advantage to tumor cells. It first must be activated by binding one of the EGF-like growth factors. One of the reasons that EGFR is so important in cancer biology is that it is able to amplify its own signal by inducing the expression of its ligands. Dr. Reiter is credited with the identification and cloning of human soluble EGFR (sEGFR) splice variants, which have the potential to act as a brake in this positive feedback loop, which drives EGFR-mediated cell proliferation. Basic research studies in her laboratory use biochemical, molecular, and cell biology techniques to elucidate the functional role of these sEGFR variants in normal and oncogenic signaling pathways.

Advisor: Mark Collinge, Ph.D.

The interaction of circulating leukocytes with the vascular endothelium plays a key role in numerous disease processes, including inflammation, atherosclerosis and graft rejection, in addition to potentially beneficial processes such as angiogenesis (growth of new blood vessels) following ischemic injury. In order to understand these processes it is important to fully determine the nature of the interaction between these two cell types, and to determine how both leukocytes and endothelial cells become “activated”. This research primarily falls into two major areas. Firstly, to determine how leukocyte populations activate and/or damage endothelial cells, and secondly, how endothelial cells are able to activate leukocytes. Endothelial cells are capable of expressing an array of cell surface proteins whose expression is up regulated upon activation, and some of these surface antigens are then able to recruit other leukocyte subsets to the site of injury. Conversely, leukocytes produce a variety of immune cytokines and chemokines, the spectrum of which is altered upon cellular activation.

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.

ErbB4 is a member of the EGFR family of receptor tyrosine kinases. It is important in brain, heart and mammary development. It ‘s role in cancer is controversial with some clinical histopathology studies showing ErbB4 expression correlated with positive outcome while in other studies expression correlated with negative outcome.

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.

The major focus of my laboratory is on the effects of altered intracellular calcium signaling on early heart development. Using novel whole-embryo and organ cultures, we have shown that decreased intracellular calcium levels in the developing heart leads to abnormal development of the cardiac outflow tract. More recent evidence suggests that a defined population of cardiac precursor cells may be particularly sensitive to altered calcium. We are currently investigating the function of these cells which make up the "anterior heart field" and which contribute to the developing outflow tract. In relation to these studies, we are also studying the expression calcium-regulatory proteins in the developing heart and are studying the role of L- and T-type calcium channels in the developing heart using transgenic mice and the culture systems. In another project, our lab has an interest in small animal fetal ultrasound imaging. In particular, we have become interested in the use of high-frequency ultrasound to examine cardiac structure and function in the mouse embryo and fetus.

Advisor: Yilun Liu, Ph.D.

Understanding Genome Instability and Tumorigenesis: The Roles of RecQ Family Helicases.

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

Investigation of Viral Immune Evasion Strategies

Advisor: Sabine M. Lang

Investigation of Herpes Virus Entry and Assembly

Advisor: Lyndsay Harris, MD (contact Kimberly Lezon-Geyda, PhD)

Investigation of Biomarkers in Human Breast Cancer