Current Research Projects for Academic Year 2013-2014
LYME DISEASE RESEARCH AT UNH
The University of New Haven established the Lyme disease research group 8 years ago. To date, over 70 graduate students have received training in Lyme disease related research. The Lyme disease research group has identified an alarming increase in the co-infection rate in deer ticks, including discovery of novel co-infections such as mycoplasma and microfilarial nematode species. In the last several years the Lyme disease research group has received several extramural grants from the Lymedisease.org, Tick Borne Disease Alliance, Lyme Research Alliance, Lyme Disease Association, Charles E. Holman, Schwartz Foundation, Warman Family and Portman Foundation, which will allow the group to investigate novel ideas for Lyme disease research.
In the Fall of 2007, the our research group began one of the largest tick counting and Borrelia testing surveys in the North East (testing over 50 sites in Fairfield County). The uniqueness of this survey is that the tick collection is being conducted at school yards, public parks and playgrounds, to evaluate exposure of our children to tick borne diseases. We have collected ~2500 deer tick samples and tested ~1500 samples for Borrelia burgdorferi (Bb) infection. The overall Bb infection rate was 72%, ranging from 51%-94%.
The group also studies different forms of Borrelia bacteria to better understand how Borrelia can hide from the immune system and from different therapies. For example, our research group demonstrated that Borrelia is capable forming a protective layer around itself, called biofilm, which could render it very resistant to antibiotics and provide a logical explanation as to why extensive antibiotic treatment for patients with a tick-bite history could fail.
Our final goal is to better understand Borrelia survival mechanisms, and ultimately to provide new research information for the chronic Lyme debate.
Furthermore, our research group has held six National Lyme Disease Symposiums during the last several years (2006-2013) with over 200 attendees/symposium.
The Lyme disease research group has a website (www.newhaven.edu/lyme)
and a Facebook page: UNH.Lymegroup, where updates of our latest research activities can be found.
Changes in cellular attachment associated with metastasis
This work is to develop models of epithelial to mesenchymal transition (EMT) progression from clones of established carcinoma cell lines and correlate the various behaviors to the expression and activation of cell attachment pathway proteins. For carcinomas the initial EMT is critical in the formation of a mobile population of cells potentially capable of establishing metastases. This transition step requires the change in expression and regulation of a host of proteins. These cells normally have very specific attachment to the neighboring cells that determine the tissue architecture. By selecting subclones of established epithelial cell lines that have gained mesenchymal characteristics, we will have model systems that permit comparisons between the original epithelial state and the potentially more invasive state. Proteins such as the integrin-linked kinase, cadherins, and integrins have been shown to play a role in EMT in systems where the expression is manipulated. This study will expand on this by looking at the proteins' expression and activity in cells that have spontaneously, or in response to various extracellular matrices, made the EMT.
My research focuses on cellular and molecular biology of reproductive immunology. The overarching theme of my research is the communication between different cell types, as well as the interaction of the immune and endocrine systems. During my doctoral work, I examined estradiol regulation of uterine stromal fibroblast-secreted keratinocyte growth factor (KGF) on the innate immune function of uterine epithelial cells. As a post-doctoral associate, I examined embryo implantation into the endometrium and the effect of trophoblast cells on the maternal immune system. In addition, I studied how ovarian cancer cells “educate” the host immune system (i.e., macrophages) to be tolerant and even support tumor growth.
Protein phosphatases that regulate sensitivity to targeted cancer therapies
My overall interest is in the role of protein kinases and protein phosphatases in oncogenesis. In particular I am interested in studying the role the phosphatase SHP2 may play in cardiac toxicity that is often seen when women with HER2 positive breast cancer are treated with the chemotherapeutic, Herceptin. SHP2 is known to function downstream of the intracellular target of Herceptin, the HER2/ErbB2 receptor. SHP2 is also known to have a role in cardiac myopathy; I am interested in working out the cross talk between SHP2s role in these two divergent pathways. Studies will be carried out in 2D and 3D cultures of both cardiac and breast cancer cell lines.
Computational Models of Prebiotic Chemical Systems
Dr. Pauline M. Schwartz is a Professor in the Department of Chemistry and Chemical Engineering. Her research interests include designing and exploring novel computational models of chemical systems. Current studies in collaboration with Dr. Carl Barratt are investigating prebiotic chemistry – the chemistry to generate the chiral building blocks necessary for life and the evolution of metabolic systems from simple chemical cycles.
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: Robert Means, PH.D.
Investigation of Viral Immune Evasion Strategies
Through co-evolution with their hosts, viruses have acquired exquisite mechanisms for coping with the anti-viral immune responses. Our lab is interested in detailing these viral coping mechanisms and examining their importance to pathogenicity, with the eventual goal of developing better prophylactic and treatment strategies. The major pathogens that we study are the gamma-herpesviruses, which include the most recently described human viral pathogen, Kaposi's sarcoma-associated herpesvirus (KSHV). This virus is the causal agent of one of the most common AIDS-associated cancers in the Western world, as well as being a leading cause of cancer deaths in many regions of Africa. We are in the process of characterizing several gene products of KSHV that are able to modulate and block the host immune response. Amoung these proteins are K3 and K5, able to down regulate multiple key immunomodulatory proteins from the surface of expressing cells, including MHC class I, B7.2, ICAM-1 and CD31. Studies of the molecular mechanisms of action of these proteins have not only provided potential targets for anti-viral therapies, but have also provided insights into the mechanisms of cellular endocytosis, trafficking and host control of the immune response.
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.